Expert Perspective
Maria Q. Baggstrom, MD
Assistant Professor of Medicine
Ramaswamy Govindan, MD
Associate Professor of Medicine
Division of Oncology
Washington University
St. Louis, Missouri
In this edition of Clinical Quandaries, Ramalingam et al present a 67-year-old man who seeks care for a new, asymptomatic left upper lobe lung mass, which was found incidentally on a routine chest x-ray as part of a preoperative work-up for an elective surgery. Further staging studies included a computed tomography (CT) scan of the chest and a positron-emission tomography (PET) scan followed by a magnetic resonance imaging (MRI) scan of the liver. Pathology from a fine-needle aspiration biopsy of the left lingular lesion was consistent with poorly differentiated adenocarcinoma and immunohistochemical stains consistent with a lung primary. The left lingular lesion and the prevascular lymph node were felt to be the only sites of involvement, making this stage IIIA (T1, N2, M0) lung cancer.
The patient had an excellent functional status with minimal medical comorbidities and was treated with three cycles of neoadjuvant chemotherapy followed by restaging with a PET/CT scan. Since the prevascular lymph node showed near-complete resolution while the lingular lesion continued to be 18F-fluorodeoxyglucose (FDG)-avid, the patient underwent a left upper lobectomy with mediastinal lymph node sampling. Pathology confirmed the primary lesion, and 3 out of 28 lymph nodes were positive, resulting in a pathologic stage of T2, N2. The patient subsequently underwent thoracic radiation and has had no evidence of recurrence during the 1 year of routine follow-up care.
This case presentation brings up many of the complex issues in the management of patients with stage III non–small-cell lung cancer (NSCLC). They include the optimal evaluation of the mediastinum, the heterogeneous nature of this subgroup of NSCLC, the role of surgery with or without induction therapy (and the optimal induction therapy, ie, chemotherapy vs chemoradiation), as well as the role of adjuvant radiation therapy in patients who had undergone surgery for stage III NSCLC.
Multiple Subgroups
Patients with stage III NSCLC tend to be a very heterogeneous population with multiple subgroups, ranging from microscopic N2 involvement to bulky multistation node involvement to tumors that directly invade the chest wall. Andre et al reported striking differences in 5-year survival, from 34% for those with microscopic N2 disease to 3% for those with multiple level N2 involvement discernible clinically when treated with primary surgery.[1] Ademuyiwa et al examined prognostic factors in patients with stage III NSCLC considered for definitive chemoradiation.[2] These investigators found that higher pretreatment hemoglobin levels and a forced expiratory volume in 1 second (FEV1) greater than 2 liters were associated with improved overall survival.
Although data are sparse, the use of FDG-PET scanning and the intensity of uptake at baseline would identify subgroups with varying outcomes. In the coming years, it is very likely that global genomic expression analysis would help predict survival as well.
Roles of Surgery and Induction Chemotherapy
Surgery alone in patients with stage III NSCLC has been previously examined. Historically, patients have had poor outcomes with single-modality therapy such as surgery, leading the way to the investigation of the multimodality approach.[3] Radiation alone in stage III NSCLC has also shown poor results. Adjuvant radiation in patients with resectable NSCLC was associated with worse outcomes compared with surgery alone.[4]
Since the majority of relapses occur at distant sites, induction chemotherapy followed by surgery has received a great deal of attention. Roth et al[5] and Rosell et al[6] showed that patients with stage IIIA NSCLC who received induction chemotherapy prior to surgery had significantly improved survival compared to patients who received surgery alone. These studies were terminated early due to these differences, but long-term follow-up of these patients showed that this survival difference was maintained.
These findings of a significant survival advantage to induction chemotherapy were supported by a retrospective review published by Andre et al.[1] In addition, clinical N2 status, involvement of multiple lymph node levels, pathologic T3/4 stage, and no preoperative chemotherapy were found to be negative prognosticators for overall and event-free survival on multivariate analysis. This further supported the likelihood that there are different patient subgroups among those with stage III NSCLC, warranting different management strategies.
Chemoradiation Trials
Another approach combined chemotherapy and concurrent thoracic radiation as induction therapy prior to surgical resection, as reported by Cancer and Leukemia Group B (CALGB) and the Southwest Oncology Group (SWOG). The CALGB studied 41 patients with stage IIIA NSCLC undergoing trimodality treatment and found that this treatment was feasible but associated with significant toxicities. Approximately 66% of the patients achieved a complete response, and there were nine long-term survivors. However, this study also reported 6 (15%) treatment-related deaths.[7] The SWOG study of 126 patients with stage IIIA/IIIB NSCLC undergoing trimodality treatment reported a 26% 3-year survival rate and 13 (10%) treatment-related deaths.[8]
The role of surgery following induction therapy with systemic chemotherapy and thoracic radiation was recently examined in the Radiation Therapy Oncology Group (RTOG) 9309 trial . This study enrolled medically fit patients with T1–3, pathologic N2, M0 NSCLC.[9] These patients received two cycles of cisplatin and etoposide with concurrent thoracic radiation (45 Gy), were reevaluated, and, if there was no evidence of progression, were randomized to surgical resection or continuation of radiation to complete 61 Gy without interruption. All patients then received two more cycles of chemotherapy as consolidation therapy.
The overall survival (primary endpoint of the trial) was not improved by the addition of surgery. However, those assigned to the surgery arm had a significantly decreased risk of local relapse and improved progression-free survival. The investigators noted a trend by year 5 for an absolute survival benefit of 7% in the surgery arm. Improved overall survival was seen with favorable prognostic factors such as minimal weight loss, female gender, and only one positive N2 station lymph node. Patients who achieved pathologic N0 also had a significantly improved overall survival with surgery compared to those who had persistently positive mediastinal lymph glands.
A subset analysis was performed looking at patients undergoing lobectomy vs pneumonectomy, who were then matched to patients who underwent chemoradiation only. Those who underwent pneumonectomy showed a trend toward worse overall survival, but this subset analysis was limited due to small numbers. Patients who underwent lobectomy did show a significantly improved 5-year overall survival compared to patients who received chemoradiation alone (36% vs 18%, P = .002). It is worth remembering that this analysis was retrospective and unplanned. Moreover, decisions regarding pneumonectomy are often (if not always) made at the time of surgery.
Summary and Conclusions
This case illustrates several quandaries clinicians face in the care of patients with stage III NSCLC. As mentioned earlier, they include the role of surgery, the appropriate induction regimen when surgery becomes part of treatment, and the optimal approach to evaluating the mediastinum, to mention a few.
The role of surgery in stage III continues to be a debatable issue. Our own approach is to consider surgery for patients with single-station N2 following induction therapy, provided they have adequate pulmonary reserves and are not "obvious candidates" for pneumonectomy. Following induction therapy (chemotherapy or chemoradiation), patients are evaluated by CT and FDG-PET scan before surgery in order to identify those with distant progression.
The optimal induction therapy is another matter of continued debate. The Radiation Therapy Oncology Group (RTOG) attempted to study the question of the optimal induction therapy (chemotherapy or chemoradiation) in patients with stage III NSCLC prior to surgery. However, this study had to be closed prematurely because of poor accrual.
One of the ongoing quandaries is how to reassess the mediastinum following concurrent chemoradiation and how to use that information to make decisions regarding the addition of surgery. Repeat mediastinoscopy is fraught with dangers, particularly after induction therapy. Simmering inflammation following induction chemoradiation limits the utility of FDG-PET scan as a useful tool. A prospective phase II trial conducted by the CALGB demonstrated that it is feasible to use video-assisted thoracoscopic evaluation (VATS) to restage the mediastinum, with a sensitivity of 75%, specificity of 100%, and negative predictive value of 76%.[10] It is likely that diligent use of endoscopic ultrasound or endobronchial ultrasound may be useful in this setting as well. Hopefully, the next generation of trials in this area will clarify the role of surgery and optimal induction therapy.
—Maria Q. Baggstrom, MD
—Ramaswamy Govindan, MD
References
1. Andre F, Grunenwald D, Pignon JP, et al: Survival of patients with resected N2 non-small cell lung cancer. Evidence of a subclassification and implications. J Clin Oncol 18:2981-2989, 2000.
2. Ademuyiwa FO, Johnson CS, White AS, et al: Prognostic factors in stage III non-small-cell lung cancer. Clin Lung Cancer 8:478-482, 2007.
3. Bains MS: Surgical treatment of lung cancer. Chest 100:826-837, 1991.
4. Postoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialist Group. Lancet 352:257-263, 1998.
5. Roth JA, Atkinson EN, Fossella F, et al: Long-term follow up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. Lung Cancer 21:1-6, 1998.
6. Rosell R, Gomez-Codina J, Camps C, et al: Preresectional chemotherapy in stage IIIA non-small cell lung cancer: A 7-year assessment of a randomized controlled trial. Lung Cancer 28:247-251, 2000.
7. Strauss GM, Herndon JE, Sherman DD, et al: Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small-cell carcinoma of the lung. Report of a Cancer and Leukemia Group B phase II study. J Clin Oncol 10:1237-1244, 1992.
8. Albain KS, Rusch VW, Crowley JJ, et al: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA(N2) and IIIB non-small-cell lung cancer: Mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13:1880-1892, 1995.
9. Albain KS, Swann RS, Rusch VR, et al: Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309) (abstract 7014). J Clin Oncol 23(16S):624s, 2005.
10. Jaklitsch MT, Gu L, Harpole DH, et al: Prospective phase II trial of pre-resection thoracoscopic (VATS) restaging following neoadjuvant therapy for IIIA(N2) non-small cell lung cancer (NSCLC): Results of CALGB 39803 (abstract 7065). J Clin Oncol 23(16S):636s, 2005.
Friday, March 13, 2009
Ohio State Experts Using New Method for Lung Cancer Diagnosis
Interventional pulmonologists at The Ohio State University Medical Center are using an improved and more efficient technique to diagnose lung cancer. Attached at the tip of the bronchoscope, an ultrasound probe identifies the location of the cancerous masses in a patient's chest, allowing for an accurate biopsy, or tissue sample, under ultrasound guidance.
Traditionally, chest biopsies were obtained through a small incision in the neck. This technique also required an operating room and general anesthesia. In addition, pulmonologists could also obtain a diagnosis using a biopsy needle through a bronchoscope. However, there was no real-time guidance and the site of the tumor would be determined after reviewing a patient's x-ray or other diagnostic scan.
"Studies have shown that accurate staging, along with diagnosis of lung cancer, can be done without any surgical procedures," says Dr. Shaheen Islam, an interventional pulmonologist and critical care specialist at Ohio State's Medical Center.
Outpatient Procedure
"Some lung cancer patients also have emphysema from smoking, which does not make them very good surgical candidates," adds Islam. "Using this new technique allows patients for an accurate staging through an outpatient procedure with minimal, conscious sedation, so that appropriate treatment can be offered."
Lung cancer is the leading cause of cancer deaths in the United States, killing over 160,000 people yearly. Approximately 213,000 people are diagnosed with lung cancer each year, and 85% of those diagnosed with the disease will die within the first 5 years of diagnosis.
Traditionally, chest biopsies were obtained through a small incision in the neck. This technique also required an operating room and general anesthesia. In addition, pulmonologists could also obtain a diagnosis using a biopsy needle through a bronchoscope. However, there was no real-time guidance and the site of the tumor would be determined after reviewing a patient's x-ray or other diagnostic scan.
"Studies have shown that accurate staging, along with diagnosis of lung cancer, can be done without any surgical procedures," says Dr. Shaheen Islam, an interventional pulmonologist and critical care specialist at Ohio State's Medical Center.
Outpatient Procedure
"Some lung cancer patients also have emphysema from smoking, which does not make them very good surgical candidates," adds Islam. "Using this new technique allows patients for an accurate staging through an outpatient procedure with minimal, conscious sedation, so that appropriate treatment can be offered."
Lung cancer is the leading cause of cancer deaths in the United States, killing over 160,000 people yearly. Approximately 213,000 people are diagnosed with lung cancer each year, and 85% of those diagnosed with the disease will die within the first 5 years of diagnosis.
ASA404 pivotal trial in lung cancer begins
BASEL—Novartis’ ASA404 has entered a phase III lung cancer trial following positive outcomes of a phase II study. ASA404 is a small-molecule tumor-vascular disrupting agent that selectively causes the collapse of existing tumor blood supply leading to extensive tumor cell death. Its action is distinct from that of angiogenesis inhibitors, which inhibit the formation of new tumor blood vessels.
The ATTRACT-1 trial will include 1,200 patients with previously untreated locally advanced or metastatic NSCLC, randomized to carboplatin/paclitaxel plus either ASA404 or placebo.
The ATTRACT-1 trial will include 1,200 patients with previously untreated locally advanced or metastatic NSCLC, randomized to carboplatin/paclitaxel plus either ASA404 or placebo.
Evaluating lung cancer response to therapy: Thinking beyond RECIST
LAS VEGAS—CT multitasks in the lungs, serving as a tool for cancer screening, disease diagnosis, lesion characterization, and lung cancer treatment response. CT can be used more effectively to assess treatment response in lung cancer patients, but clinicians must look beyond current response parameters, Michael McNitt-Gray, PhD, said at the 2008 Stanford International Symposium on Multidetector-Row CT.
The Response Evaluation Criteria in Solid Tumors (RECIST) is the standard for treatment evaluation, said Dr. McNitt-Gray, director of the Biomedical Physics Graduate Program at the Thoracic Imaging Research Group, based at UCLA.
RECIST, which relies on changes to the unidimensional diameter of a lesion, does offer some benefits. It’s easy to implement and can be used to measure up to five lesions at a time. Measurements can be done directly on the film. Dr. McNitt-Gray pointed out several issues, however, that compromise RECIST’s reliability to offer the most accurate information.
“It’s difficult to estimate the diameter of irregular lesions. How do we know that the [diameter] change we’re seeing is real change and not just measurement variability?” he said. “When a patient comes back for follow-up, he or she isn’t always imaged in the same scan plane. There is also intra- and interobserver variability. How long do we have to wait for a response—a few weeks, a month?”
Other parameters important
While tumor size is important, Dr. McNitt-Gray suggested other parameters for measuring response: mass, density, shape, and function. Changes in tumor volume can be assessed with segmentation on thin-slice CT, he said. PET/CT has value for measuring tumor function.
At his institution, Dr. McNitt-Gray performs 4D mapping of contrast enhancement through the nodule. These contrast uptake patterns can be measured at multiple time points with low-dose CT, offering rapid information on nodule perfusion and permeability, he said.
“Ultimately, what is the minimum amount of change that we can detect?” Dr. McNitt-Gray asked. “And how long would it take to see this minimally detectable change?”
In a separate interview, Claus Peter Heussel, MD, agreed with Dr. McNitt-Gray that RECIST does not tell the whole story. Dr. Heussel, of the Department of Diagnostic and Interventional Radiology, Thoraxklinik am Universitätsklinikum, Heidelberg, Germany, told Oncology News International that tumor size alone may have limited value and suggested also looking at volume and perfusion.
Dr. Heussel led a study that compared RECIST and World Health Organization response criteria to CT-generated volumetry data in liver malignoma. The researchers found that the estimation of the relative tumor development was different based on the measurement criteria used.
“Relatively reliable tumor response evaluation can only take place by means of thin-section [CT] investigation and volumetric analysis,” Dr. Heussel’s group wrote (RöFo 179:958-964, 2007).
The Response Evaluation Criteria in Solid Tumors (RECIST) is the standard for treatment evaluation, said Dr. McNitt-Gray, director of the Biomedical Physics Graduate Program at the Thoracic Imaging Research Group, based at UCLA.
RECIST, which relies on changes to the unidimensional diameter of a lesion, does offer some benefits. It’s easy to implement and can be used to measure up to five lesions at a time. Measurements can be done directly on the film. Dr. McNitt-Gray pointed out several issues, however, that compromise RECIST’s reliability to offer the most accurate information.
“It’s difficult to estimate the diameter of irregular lesions. How do we know that the [diameter] change we’re seeing is real change and not just measurement variability?” he said. “When a patient comes back for follow-up, he or she isn’t always imaged in the same scan plane. There is also intra- and interobserver variability. How long do we have to wait for a response—a few weeks, a month?”
Other parameters important
While tumor size is important, Dr. McNitt-Gray suggested other parameters for measuring response: mass, density, shape, and function. Changes in tumor volume can be assessed with segmentation on thin-slice CT, he said. PET/CT has value for measuring tumor function.
At his institution, Dr. McNitt-Gray performs 4D mapping of contrast enhancement through the nodule. These contrast uptake patterns can be measured at multiple time points with low-dose CT, offering rapid information on nodule perfusion and permeability, he said.
“Ultimately, what is the minimum amount of change that we can detect?” Dr. McNitt-Gray asked. “And how long would it take to see this minimally detectable change?”
In a separate interview, Claus Peter Heussel, MD, agreed with Dr. McNitt-Gray that RECIST does not tell the whole story. Dr. Heussel, of the Department of Diagnostic and Interventional Radiology, Thoraxklinik am Universitätsklinikum, Heidelberg, Germany, told Oncology News International that tumor size alone may have limited value and suggested also looking at volume and perfusion.
Dr. Heussel led a study that compared RECIST and World Health Organization response criteria to CT-generated volumetry data in liver malignoma. The researchers found that the estimation of the relative tumor development was different based on the measurement criteria used.
“Relatively reliable tumor response evaluation can only take place by means of thin-section [CT] investigation and volumetric analysis,” Dr. Heussel’s group wrote (RöFo 179:958-964, 2007).
Cetuximab Plus Platinum-Based Chemotherapy Improves Survival for Patients With Newly Diagnosed Advanced Lung Cancer
A large phase III study has found that the targeted therapy cetuximab (Erbitux), combined with platinum-based chemotherapy, is effective as a first-line treatment for patients with advanced non–small-cell lung cancer (NSCLC). This is the first time a targeted drug has shown a survival benefit as a first-line treatment for patients with NSCLC, including all subtypes of the disease, reported lead author Robert Pirker, md, associate professor of medicine at Medical University of Vienna in Austria at the ASCO meeting (abstract 3).
“Patients with advanced NSCLC have limited treatment options and life expectancy is short, so the survival increase shown in this study is an important step for these patients” said Dr. Pirker. For patients with the most advanced form of NSCLC, 1-year survival is about 30% and 5-year survival is just 1% to 2%. “These results clearly establish cetuximab in combination with chemotherapy as a new standard in first-line treatment of NSCLC.”
Study Design
This study evaluated the addition of the epidermal growth factor receptor (EGFR) antibody cetuximab to platinum-based chemotherapy (cisplatin and vinorelbine). The current standard of care for newly diagnosed patients with advanced NSCLC is platinum (either cisplatin or carboplatin) combined with a “third-generation drug” (vinorelbine, gemcitabine [Gemzar], paclitaxel, or docetaxel [Taxotere]). Earlier studies of different EGFR-targeted drugs, such as the tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva), did not show an additional benefit over first-line standard chemotherapy and are currently approved for patients whose initial chemotherapy has failed.
In this study, 1,125 patients in 30 countries were randomized to receive either chemotherapy alone (568) or chemotherapy plus cetuximab (557); 94% had stage IV disease (meaning the cancer had spread to other parts of the body). Overall survival was higher for those who received cetuximab plus chemotherapy (11.3 months) compared to those receiving chemotherapy alone (10.1 months). Also, the response rate was better in the chemotherapy plus cetuximab arm (36.3%) vs chemotherapy alone (29.2%).
The benefit of cetuximab was seen in patients with all histologic subtypes of NSCLC, including adenocarcinoma and squamous cell carcinoma, the two most common subtypes. Other targeted therapies for lung cancer have only proven effective against certain subtypes.
Toxicity Findings
As expected, the most frequent side effect was an acne-like rash, which was manageable with medication. Moderate rashes were seen more frequently in patients receiving cetuximab (10.4%) than in patients receiving chemotherapy alone (0.2%).
The authors state that based on these findings, there will be more studies evaluating cetuximab in earlier stages of the disease, such as in combination with chemotherapy or chemoradiotherapy in patients with locally advanced disease or as an additional treatment after surgery in patients with early-stage disease.
“Patients with advanced NSCLC have limited treatment options and life expectancy is short, so the survival increase shown in this study is an important step for these patients” said Dr. Pirker. For patients with the most advanced form of NSCLC, 1-year survival is about 30% and 5-year survival is just 1% to 2%. “These results clearly establish cetuximab in combination with chemotherapy as a new standard in first-line treatment of NSCLC.”
Study Design
This study evaluated the addition of the epidermal growth factor receptor (EGFR) antibody cetuximab to platinum-based chemotherapy (cisplatin and vinorelbine). The current standard of care for newly diagnosed patients with advanced NSCLC is platinum (either cisplatin or carboplatin) combined with a “third-generation drug” (vinorelbine, gemcitabine [Gemzar], paclitaxel, or docetaxel [Taxotere]). Earlier studies of different EGFR-targeted drugs, such as the tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva), did not show an additional benefit over first-line standard chemotherapy and are currently approved for patients whose initial chemotherapy has failed.
In this study, 1,125 patients in 30 countries were randomized to receive either chemotherapy alone (568) or chemotherapy plus cetuximab (557); 94% had stage IV disease (meaning the cancer had spread to other parts of the body). Overall survival was higher for those who received cetuximab plus chemotherapy (11.3 months) compared to those receiving chemotherapy alone (10.1 months). Also, the response rate was better in the chemotherapy plus cetuximab arm (36.3%) vs chemotherapy alone (29.2%).
The benefit of cetuximab was seen in patients with all histologic subtypes of NSCLC, including adenocarcinoma and squamous cell carcinoma, the two most common subtypes. Other targeted therapies for lung cancer have only proven effective against certain subtypes.
Toxicity Findings
As expected, the most frequent side effect was an acne-like rash, which was manageable with medication. Moderate rashes were seen more frequently in patients receiving cetuximab (10.4%) than in patients receiving chemotherapy alone (0.2%).
The authors state that based on these findings, there will be more studies evaluating cetuximab in earlier stages of the disease, such as in combination with chemotherapy or chemoradiotherapy in patients with locally advanced disease or as an additional treatment after surgery in patients with early-stage disease.
RNA Analysis Can Predict Lung Cancer Among Smokers
CHICAGO—A genetic “fingerprint” detectable in the blood is able to predict with 80% accuracy which asymptomatic smokers will develop lung cancer 2 years later, according to investigators who described the test at ASCO 2008 (abstract 1509).
A group of German scientists, led by Thomas Zander, MD, of the University of Cologne, studied the genetic profiles in the peripheral blood of smokers with lung cancer (prevalent cohort) and controls without lung cancer, and generated an RNA fingerprint based on transcriptional changes associated with the cancer. The fingerprint had a 90% sensitivity and 85% specificity for identifying patients with lung cancer, and 88% accuracy.
"What is remarkable is that most of the relevant transcripts are derived from immune response–related genes."
— Dr. Thomas Zander
“We think there are lung-cancer-specific expression profiles in the peripheral blood,” Dr. Zander said at an ASCO press conference.
After validating this in a second cohort, they examined records of 25,000 participants in the European Prospective Investigation on Cancer and Nutrition (EPIC) trial, identifying 12 smokers who had developed lung cancer within 2 years of enrolling in EPIC (incident cohort).
Using archived specimens, the researchers applied the RNA fingerprint to the incident cancer cohort and to a matched control group without cancer, looking for the evidence of the marker before the cancers became clinically apparent.
In this cohort, the test predicted the development of cancer with 80% accuracy (P = .05). Sensitivity was 75% and specificity was 85% (P = .0001), Dr. Zander reported.
“What is remarkable is that most of the relevant transcripts are derived from immune response–related genes,” Dr. Zander said. Other enriched genes were related to homeostasis.
The hope is that the RNA fingerprint may eventually be suitable for identifying patients with early lung cancer and predicting risk among smokers.
Julie Gralow, MD, of the University of Washington, Seattle, noted that the findings were preliminary but that “this is a promising lead for a means of early detection of lung cancer.”
A group of German scientists, led by Thomas Zander, MD, of the University of Cologne, studied the genetic profiles in the peripheral blood of smokers with lung cancer (prevalent cohort) and controls without lung cancer, and generated an RNA fingerprint based on transcriptional changes associated with the cancer. The fingerprint had a 90% sensitivity and 85% specificity for identifying patients with lung cancer, and 88% accuracy.
"What is remarkable is that most of the relevant transcripts are derived from immune response–related genes."
— Dr. Thomas Zander
“We think there are lung-cancer-specific expression profiles in the peripheral blood,” Dr. Zander said at an ASCO press conference.
After validating this in a second cohort, they examined records of 25,000 participants in the European Prospective Investigation on Cancer and Nutrition (EPIC) trial, identifying 12 smokers who had developed lung cancer within 2 years of enrolling in EPIC (incident cohort).
Using archived specimens, the researchers applied the RNA fingerprint to the incident cancer cohort and to a matched control group without cancer, looking for the evidence of the marker before the cancers became clinically apparent.
In this cohort, the test predicted the development of cancer with 80% accuracy (P = .05). Sensitivity was 75% and specificity was 85% (P = .0001), Dr. Zander reported.
“What is remarkable is that most of the relevant transcripts are derived from immune response–related genes,” Dr. Zander said. Other enriched genes were related to homeostasis.
The hope is that the RNA fingerprint may eventually be suitable for identifying patients with early lung cancer and predicting risk among smokers.
Julie Gralow, MD, of the University of Washington, Seattle, noted that the findings were preliminary but that “this is a promising lead for a means of early detection of lung cancer.”
Celecoxib Shows Benefit in First-of-Its-Kind Lung Cancer Chemoprevention Trial
The anti-inflammatory medication celecoxib (Celebrex) has proven to be safe and reduces a specific proliferation measurement of precancerous lesions in the lung, according to a study from The University of Texas M. D. Anderson Cancer Center. This finding demonstrates the significance of COX-2 inhibition toward preventing lung cancer in individuals at higher risk of developing the disease. The study is the first large randomized trial of celecoxib in lung cancer prevention.
"With this study, in principal, we've been able to demonstrate the importance of COX-2 and the implications on inflammation pathway in lung cancer development," said Edward Kim, md, assistant professor in M. D. Anderson's Department of Thoracic Head and Neck Medical Oncology. "We've also been able to demonstrate that this drug class is safe and tolerable for this patient population. As we move forward in lung cancer chemoprevention, the importance of this class of drugs cannot be ignored."
Ki-67 Levels Measured
From November 2001 to September 2006, the M. D. Anderson study enrolled 212 individuals, all of whom were current or former smokers with at least a 20-pack-year smoking habit. Most participants did not have any history of cancer; however, patients with a history of cancer who had been disease-free for 6 months could participate. The median age of participants was 53. The study examined levels of Ki-67, a biomarker associated with precancerous lung lesions.
Participants underwent a baseline broncoscopy in which six predetermined biopsies were performed. They then were randomized to receive celecoxib at either 200 mg (low dose) or 400 mg (high dose) twice a day or placebo. After 3 months, participants received a second broncoscopy, the primary endpoint of the trial. Patients had the option to continue on the trial for 3 more months per their prior randomized arm; for those participants, a third and final broncoscopy was conducted at 6 months.
"In patients who had high-risk features such as smoking, especially in the current smokers, we were able to see that a higher dose of Celebrex could decrease the proliferation marker Ki-67 in these patients, as seen through their bronchial epithelium," said Kim. "We are encouraged that we have a drug like Celebrex that decreases the expression of this proliferation marker."
These findings are also significant in that the study shows that serial broncoscopies are feasible, explained Kim. "Although CT scanning and other imaging techniques are important, for lung cancer, it may be vital to examine actual tissue to see what the markers are doing in the actual epithelium of the lung so as to best understand if an individual has a higher or lower risk of developing lung cancer."
Trial Suspended, Then Resumed
In December 2004, M. D. Anderson voluntarily suspended the trial at the request of Pfizer and the National Cancer Institute (NCI), the funding source for the study, until further data on the drug's risk for cardiac toxicities, specifically heart attacks and strokes, could be investigated. Months later, advisors to the US Food and Drug Administration recommended that celecoxib continue to be studied in the treatment and prevention of cancer, and the NCI supported the continuation of the trials, encouraging investigators to weigh the risks and benefits of the drug for their specific clinical setting.
After adding stringent guidelines to further reduce the cardiac risk to patients, the M. D. Anderson investigators then reapplied to the institution's Institutional Review Board to reactivate the trial. The study reopened in May 2005.
Kim noted that there were no adverse cardiac events in the M. D. Anderson trial. Three patients experienced grade 3 toxicities on the higher dose of the drug, which were not cardiac-related.
"With this study, in principal, we've been able to demonstrate the importance of COX-2 and the implications on inflammation pathway in lung cancer development," said Edward Kim, md, assistant professor in M. D. Anderson's Department of Thoracic Head and Neck Medical Oncology. "We've also been able to demonstrate that this drug class is safe and tolerable for this patient population. As we move forward in lung cancer chemoprevention, the importance of this class of drugs cannot be ignored."
Ki-67 Levels Measured
From November 2001 to September 2006, the M. D. Anderson study enrolled 212 individuals, all of whom were current or former smokers with at least a 20-pack-year smoking habit. Most participants did not have any history of cancer; however, patients with a history of cancer who had been disease-free for 6 months could participate. The median age of participants was 53. The study examined levels of Ki-67, a biomarker associated with precancerous lung lesions.
Participants underwent a baseline broncoscopy in which six predetermined biopsies were performed. They then were randomized to receive celecoxib at either 200 mg (low dose) or 400 mg (high dose) twice a day or placebo. After 3 months, participants received a second broncoscopy, the primary endpoint of the trial. Patients had the option to continue on the trial for 3 more months per their prior randomized arm; for those participants, a third and final broncoscopy was conducted at 6 months.
"In patients who had high-risk features such as smoking, especially in the current smokers, we were able to see that a higher dose of Celebrex could decrease the proliferation marker Ki-67 in these patients, as seen through their bronchial epithelium," said Kim. "We are encouraged that we have a drug like Celebrex that decreases the expression of this proliferation marker."
These findings are also significant in that the study shows that serial broncoscopies are feasible, explained Kim. "Although CT scanning and other imaging techniques are important, for lung cancer, it may be vital to examine actual tissue to see what the markers are doing in the actual epithelium of the lung so as to best understand if an individual has a higher or lower risk of developing lung cancer."
Trial Suspended, Then Resumed
In December 2004, M. D. Anderson voluntarily suspended the trial at the request of Pfizer and the National Cancer Institute (NCI), the funding source for the study, until further data on the drug's risk for cardiac toxicities, specifically heart attacks and strokes, could be investigated. Months later, advisors to the US Food and Drug Administration recommended that celecoxib continue to be studied in the treatment and prevention of cancer, and the NCI supported the continuation of the trials, encouraging investigators to weigh the risks and benefits of the drug for their specific clinical setting.
After adding stringent guidelines to further reduce the cardiac risk to patients, the M. D. Anderson investigators then reapplied to the institution's Institutional Review Board to reactivate the trial. The study reopened in May 2005.
Kim noted that there were no adverse cardiac events in the M. D. Anderson trial. Three patients experienced grade 3 toxicities on the higher dose of the drug, which were not cardiac-related.
Anti-IGF-1R antibody plus chemo active in advanced non-small-cell lung cancer
CHICAGO—An antibody to the insulin-like growth factor type 1 receptor (IGF-1R), when given with chemotherapy, is active as first-line therapy in advanced non-small-cell lung cancer, especially squamous type, finds the first trial to test an IGF inhibitor in lung cancer. Daniel D. Karp, MD, of M.D. Anderson Cancer Center, reported the trial results at ASCO 2008 (abstract 8015).
In the randomized phase II trial among patients with locally advanced or metastatic NSCLC, 97 patients were assigned to a TCI arm—paclitaxel, carboplatin, and the investigational CP-751,871 antibody (Pfizer) in a higher or lower dose—and 53 patients were assigned to a TC arm (paclitaxel and carboplatin).
Some 46% of the patients had adenocarcinoma, 18% had squamous-cell tumors, 10% had large-cell tumors, and 26% had tumors types not otherwise specified (NOS).
Response rate
The overall response rate according to RECIST criteria was significantly higher with TCI than withVantage Point TC (54% vs 41%), Dr. Karp reported.
Further analyses suggested a dose response to the antibody component of TCI as well as a higher overall response rate with TCI among patients with squamous histology than among those with other tumor types (see Figure). The latter finding was supported by results in a single-arm post-trial extension study among 14 evaluable patients with squamous histology given TCI with higher-dose antibody.
“These responses were rapid and dramatic, and got our attention,” he commented of the shrinkage of bulky squamous tumors.
Among the randomized patients overall, median progression-free survival was 4.3 months for TC, 3.6 months for TCI with the lower-dose antibody, and 5.0 months for TCI with the higher-dose antibody. The hazard ratio for progression was 0.80 for higher-dose TCI, compared with TC (P = 0.07).
Among the subset of randomized patients with squamous histology, median progression-free survival was 4.3 months for TC and lower-dose TCI combined vs 5.6 months for higher-dose TCI.
Compared with their counterparts in the TC arm, patients in the TCI arm had higher rates of grade 3-4 neutropenia (30% vs 16%) and hyperglycemia (20% vs 8%).
“I think it’s intuitively clear that this agent should be associated with some extra hyperglycemia,” Dr. Karp said. Moreover, “we know these patients are getting steroids to get Taxol [paclitaxel], and we regularly see some elevations of blood sugar in our patients.” The hyperglycemia was quite manageable, he said.
Graph“Our strategy for the future is to build on this with histology-specific studies,” Dr. Karp said. A trio of phase III trials are currently planned or initiated in patients with NSCLC.
One trial will compare TCI vs TC for untreated nonadenocarcinoma, a second will test the combination of erlotinib (Tarceva) and CP-751,871 against erlotinib alone in refractory nonadenocarcinoma, and the third will expand on the phase II trial among patients with all histologies excluding NOS, he said.
In the randomized phase II trial among patients with locally advanced or metastatic NSCLC, 97 patients were assigned to a TCI arm—paclitaxel, carboplatin, and the investigational CP-751,871 antibody (Pfizer) in a higher or lower dose—and 53 patients were assigned to a TC arm (paclitaxel and carboplatin).
Some 46% of the patients had adenocarcinoma, 18% had squamous-cell tumors, 10% had large-cell tumors, and 26% had tumors types not otherwise specified (NOS).
Response rate
The overall response rate according to RECIST criteria was significantly higher with TCI than withVantage Point TC (54% vs 41%), Dr. Karp reported.
Further analyses suggested a dose response to the antibody component of TCI as well as a higher overall response rate with TCI among patients with squamous histology than among those with other tumor types (see Figure). The latter finding was supported by results in a single-arm post-trial extension study among 14 evaluable patients with squamous histology given TCI with higher-dose antibody.
“These responses were rapid and dramatic, and got our attention,” he commented of the shrinkage of bulky squamous tumors.
Among the randomized patients overall, median progression-free survival was 4.3 months for TC, 3.6 months for TCI with the lower-dose antibody, and 5.0 months for TCI with the higher-dose antibody. The hazard ratio for progression was 0.80 for higher-dose TCI, compared with TC (P = 0.07).
Among the subset of randomized patients with squamous histology, median progression-free survival was 4.3 months for TC and lower-dose TCI combined vs 5.6 months for higher-dose TCI.
Compared with their counterparts in the TC arm, patients in the TCI arm had higher rates of grade 3-4 neutropenia (30% vs 16%) and hyperglycemia (20% vs 8%).
“I think it’s intuitively clear that this agent should be associated with some extra hyperglycemia,” Dr. Karp said. Moreover, “we know these patients are getting steroids to get Taxol [paclitaxel], and we regularly see some elevations of blood sugar in our patients.” The hyperglycemia was quite manageable, he said.
Graph“Our strategy for the future is to build on this with histology-specific studies,” Dr. Karp said. A trio of phase III trials are currently planned or initiated in patients with NSCLC.
One trial will compare TCI vs TC for untreated nonadenocarcinoma, a second will test the combination of erlotinib (Tarceva) and CP-751,871 against erlotinib alone in refractory nonadenocarcinoma, and the third will expand on the phase II trial among patients with all histologies excluding NOS, he said.
PET/CT, 3T MRI perform equally well in lung cancer staging
No clear winner has emerged in a head-to-head comparison of whole-body FDG-PET/CT and whole-body 3T MRI for non-small-cell lung (NSCLC) cancer staging. Unenhanced PET/CT proved better for detecting metastatic lymph nodes and soft-tissue involvement, while MR was more sensitive to the presence of brain and liver metastases.
Although thoracic CT is considered the modality of choice for assessing the intrathoracic spread of lung disease, no consensus exists for which modality is best for evaluations of metastases.
Chin A. Yi, MD and colleagues at the Sungkyunkwan University School of Medicine in Seoul, Korea, examined findings from 165 NSCLC patients screened with whole-body PET/CT and whole-body 3T MRI.
None of the patients were thought to have metastatic disease on the basis of a physical exam, lab findings, and enhanced thoracic CT covering the thorax and upper abdomen.
No statistically significant advantage was identified for either PET/CT or whole-body MRI for tumor staging.
Whole-body PET/CT and 3T MRI correctly staged 82% and 86% of the primary tumors, respectively. For N-staging, the performance of the two modalities was again nearly equal. PET/CT correctly staged 70% of patients, and 3T MR correctly staged 68% (Radiology 248: 632-642, 2008).
Both PET/CT and whole-body MR showed 86% accuracy on a per-patient basis for detecting metastases. PET/CT was 48% sensitive and 96% specific for their presence. Three-T MRI was 52% sensitive and 94% specific.
Dr. Yi and colleagues found that PET/CT may have been more useful for metastasis detection in lymph nodes and soft tissue because of prominent FDG uptake in lesions in these areas.
Dr. Yi credited the higher field strength of 3T MRI and the use of a phased-array cardiac coil for thoracic imaging for improvements compared with earlier studies performed with 1.5T MRI. The better contrast of the MR images compared with PET/CT may have provided improved metastasis detection in the brain, liver, and kidneys, he said.
This article is adapted from ONI’s sister publication Diagnostic Imaging Online (July 31, 2008).
Although thoracic CT is considered the modality of choice for assessing the intrathoracic spread of lung disease, no consensus exists for which modality is best for evaluations of metastases.
Chin A. Yi, MD and colleagues at the Sungkyunkwan University School of Medicine in Seoul, Korea, examined findings from 165 NSCLC patients screened with whole-body PET/CT and whole-body 3T MRI.
None of the patients were thought to have metastatic disease on the basis of a physical exam, lab findings, and enhanced thoracic CT covering the thorax and upper abdomen.
No statistically significant advantage was identified for either PET/CT or whole-body MRI for tumor staging.
Whole-body PET/CT and 3T MRI correctly staged 82% and 86% of the primary tumors, respectively. For N-staging, the performance of the two modalities was again nearly equal. PET/CT correctly staged 70% of patients, and 3T MR correctly staged 68% (Radiology 248: 632-642, 2008).
Both PET/CT and whole-body MR showed 86% accuracy on a per-patient basis for detecting metastases. PET/CT was 48% sensitive and 96% specific for their presence. Three-T MRI was 52% sensitive and 94% specific.
Dr. Yi and colleagues found that PET/CT may have been more useful for metastasis detection in lymph nodes and soft tissue because of prominent FDG uptake in lesions in these areas.
Dr. Yi credited the higher field strength of 3T MRI and the use of a phased-array cardiac coil for thoracic imaging for improvements compared with earlier studies performed with 1.5T MRI. The better contrast of the MR images compared with PET/CT may have provided improved metastasis detection in the brain, liver, and kidneys, he said.
This article is adapted from ONI’s sister publication Diagnostic Imaging Online (July 31, 2008).
Progress and Pitfalls in Small-Cell Lung Cancer
GREGORY P. KALEMKERIAN, MD
Co-Director, Thoracic Oncology
Professor of Medicine
University of Michigan
Ann Arbor, Michigan
Financial Disclosure:
Dr. Kalemkerian is a member of the speakers bureau for Genentech and Lily and is a consultant for Merck and ImClone. He has also received research support from Pfizer, Abbott, Lilly, and Genentech.
Small-cell lung cancer (SCLC) is a distinct clinicopathologic entity that is characterized by neuroendocrine differentiation, early metastatic spread, and initial responsiveness to cytotoxic therapy. Despite appropriate therapy, most patients eventually relapse and die of chemoresistant disease, resulting in an overall 5-year survival rate of only 5%. Although the incidence of SCLC appears to be declining in the United States, it still accounts for 15% to 20% of all cases of lung cancer and 25,000 to 30,000 deaths per year.[1]
Historical Background
Twenty-five years ago, oncologists were optimistic that SCLC would soon be routinely cured with chemotherapy.[2] Cisplatin-based regimens had just tamed testicular cancer, and the dramatic responses reported in patients with SCLC suggested that a cure for this disease was just around the corner. However, we learned that responses—even complete responses—do not necessarily translate into cures, and the overall survival of patients with SCLC has changed little in the past 2½ decades.[3,4]
Historically, patients with SCLC who did not receive therapy had a very poor prognosis, with a median survival of 7 weeks for those with extensive-stage disease (ES) and 14 weeks for limited-stage disease (LS).[5] Over the years, many therapeutic strategies have been evaluated in an attempt to improve the outcome of patients with SCLC. Some of these approaches have succeeded in prolonging survival (Table 1), while many others have proven to be ineffective despite promising preclinical or early clinical findings (Table 2). With modern therapy, we can now expect a median survival of 9 to 10 months in patients with ES SCLC and 18 to 24 months in those with LS SCLC. Most importantly, long-term survival is now possible in 20% to 25% of patients with LS SCLC.
In this issue of ONCOLOGY, Hann and Rudin present a concise and practical overview of the management of SCLC that is consistent with the current National Comprehensive Cancer Network (NCCN) guidelines.[6] They accurately summarize the historical development of therapy for SCLC and present data from clinical studies that support current therapeutic recommendations. Since there is little to disagree with in their review, the remainder of this commentary will focus on some controversial advances that have not been widely incorporated into standard care.
Radiotherapy
Since SCLC is primarily considered a systemic disease, with over two-thirds of patients presenting with hematogenous metastases, it is somewhat surprising that recent progress has mainly involved the use of radiotherapy. From the standpoint of absolute survival, the greatest potential gain was noted in the study by Turrisi et al, in which patients with LS SCLC receiving early, concurrent hyperfractionated thoracic radiotherapy plus EP (etoposide plus cisplatin [Platinol]) were found to have a 10% improvement in long-term survival over those receiving once-daily radiation plus EP.[7] Although this study has been criticized for the relatively low biologic equivalent dose given in the once-daily radiation arm, the results achieved with hyperfractionated radiation are the best reported to date in patients with LS SCLC. Clearly, the acute toxicity of hyperfractionated radiation may be prohibitive in patients with poor performance status or large treatment fields. However, this approach remains underutilized even in those without contraindications, and more effort needs to be made to incorporate hyperfractionated radiotherapy into the care of our patients.
Prophylactic cranial irradiation (PCI) is another radiotherapy approach that has been shown to improve survival in patients with both LS and ES SCLC. In LS SCLC, PCI can improve long-term survival by 5.4%, suggesting that some patients were destined to relapse only in the brain.[8] As expected, the benefit of PCI in patients with ES SCLC is more limited (since they will ultimately relapse at other sites), and PCI may not be appropriate for all patients, particularly the elderly and those with preexisting neurologic or cognitive deficits. Nevertheless, the 14% improvement in 1-year survival after PCI noted in the recent European Organisation for Research and Treatment of Cancer (EORTC) trial represents a significant advance in ES SCLC.[9] Interestingly, many oncologists have not embraced the use of PCI in this setting, whereas they have overwhelmingly incorporated bevacizumab (Avastin) into the treatment of patients with advanced non–small-cell lung cancer (NSCLC) despite a 1‑year survival benefit of only 7%, half of that seen with PCI.
Chemotherapy
Platinum-based chemotherapy is the standard in both SCLC and NSCLC, but the issue of cisplatin vs carboplatin remains a point of controversy. In advanced NSCLC, meta-analyses have demonstrated a small, statistically significant, but clinically meaningless benefit for cisplatin.[10,11] Data directly comparing cisplatin- to carboplatin-based regimens in SCLC are sparse. A small, randomized trial of cisplatin plus etoposide vs carboplatin plus etoposide in patients with LS or ES SCLC revealed no differences in response or survival, but less toxicity with carboplatin.[12] Informal comparison of response rates and survival data from phase II and III trials using either cisplatin- or carboplatin-based regimens suggests similar outcomes with either drug in both LS and ES SCLC.
Therefore, in light of the palliative nature of therapy in ES SCLC and the increased nonhematologic toxicity of cisplatin, it seems prudent to favor carboplatin-based therapy for patients with ES SCLC. In LS SCLC—a curable disease for which there is less data on the equivalence of carboplatin—it is reasonable to favor cisplatin-based therapy, with use of carboplatin reserved for those in whom cisplatin is contraindicated or poorly tolerated.
Despite the availability of numerous chemotherapeutic agents with activity against SCLC (Table 3), it is unlikely that empiric regimens of traditional cytotoxic drugs will lead to dramatic improvements in survival. Over the past 2 decades, our understanding of the molecular events that mediate the development and progression of SCLC has expanded dramatically. The identification of numerous molecular targets in SCLC cells has spawned a wide variety of novel therapeutic strategies.[13] Thus far, none of these approaches has demonstrated substantial clinical activity (Table 2). However, SCLC is a molecularly heterogeneous disease, so we must continue to refine emerging strategies in the laboratory and efficiently evaluate them in the clinic in an effort to identify patients who will benefit most from any specifically targeted approach.
1. Navada S, Lai P, Schwartz AG, Kalemkerian GP: Temporal trends in small cell lung cancer: Analysis of the national Surveillance, Epidemiology, and End Results database (abstract 7082). J Clin Oncol 24(18S):384s, 2006.
2. Aisner J, Alberto P, Bitran J, et al: Role of chemotherapy in small cell lung cancer: A consensus report of the International Association for the Study of Lung Cancer workshop. Cancer Treat Rep 67:37-43, 1983.
3. Lassen UN, Hirsh FR, Osterlind K, et al: Outcome of combination chemotherapy in extensive stage small-cell lung cancer: Any treatment related progress? Lung Cancer 20:151-160, 1998.
4. Chute JP, Chen T, Feigal E, et al: Twenty years of phase II trials for patients with extensive-stage small-cell lung cancer: Perceptible progress. J Clin Oncol 17:1794-1801, 1999.
5. Greco FA, Oldham RK: Clinical management of patients with small cell lung cancer, in Greco FA, Oldham RK, Bunn PA (eds): Small Cell Lung Cancer, pp 353-379. New York, Grun & Stratton, 1981.
6. Kalemkerian GP, Akerley W, Downey RJ, et al: Small cell lung cancer. J Natl Compr Canc Netw 6:294-314, 2008. 7. Turrisi AT, Kim K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999.
8. Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 341:476-484, 1999.
9. Slotman B, Faivre-Finn C, Kramer G, et al: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664-672, 2007.
10. Ardizzoni A, Boni L, Tiseo M, et al: Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer: An individual patient data meta-analysis. J Natl Cancer Inst 99:847-857, 2007.
11. Hotta K, Matsuo K, Ueoka H, et al: Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22:3852-3859, 2004.
12. Sklaros DV, Samantas E, Kosmidis P, et al: Randomized comparison of etoposide-cisplatin vs etoposide-carboplatin and irradiation in small-cell lung cancer. Ann Oncol 5:601-607, 1994.
13. Worden FP, Kalemkerian GP: Therapeutic advances in small cell lung cancer. Expert Opin Invest Drugs 9:565-579, 2000.
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Co-Director, Thoracic Oncology
Professor of Medicine
University of Michigan
Ann Arbor, Michigan
Financial Disclosure:
Dr. Kalemkerian is a member of the speakers bureau for Genentech and Lily and is a consultant for Merck and ImClone. He has also received research support from Pfizer, Abbott, Lilly, and Genentech.
Small-cell lung cancer (SCLC) is a distinct clinicopathologic entity that is characterized by neuroendocrine differentiation, early metastatic spread, and initial responsiveness to cytotoxic therapy. Despite appropriate therapy, most patients eventually relapse and die of chemoresistant disease, resulting in an overall 5-year survival rate of only 5%. Although the incidence of SCLC appears to be declining in the United States, it still accounts for 15% to 20% of all cases of lung cancer and 25,000 to 30,000 deaths per year.[1]
Historical Background
Twenty-five years ago, oncologists were optimistic that SCLC would soon be routinely cured with chemotherapy.[2] Cisplatin-based regimens had just tamed testicular cancer, and the dramatic responses reported in patients with SCLC suggested that a cure for this disease was just around the corner. However, we learned that responses—even complete responses—do not necessarily translate into cures, and the overall survival of patients with SCLC has changed little in the past 2½ decades.[3,4]
Historically, patients with SCLC who did not receive therapy had a very poor prognosis, with a median survival of 7 weeks for those with extensive-stage disease (ES) and 14 weeks for limited-stage disease (LS).[5] Over the years, many therapeutic strategies have been evaluated in an attempt to improve the outcome of patients with SCLC. Some of these approaches have succeeded in prolonging survival (Table 1), while many others have proven to be ineffective despite promising preclinical or early clinical findings (Table 2). With modern therapy, we can now expect a median survival of 9 to 10 months in patients with ES SCLC and 18 to 24 months in those with LS SCLC. Most importantly, long-term survival is now possible in 20% to 25% of patients with LS SCLC.
In this issue of ONCOLOGY, Hann and Rudin present a concise and practical overview of the management of SCLC that is consistent with the current National Comprehensive Cancer Network (NCCN) guidelines.[6] They accurately summarize the historical development of therapy for SCLC and present data from clinical studies that support current therapeutic recommendations. Since there is little to disagree with in their review, the remainder of this commentary will focus on some controversial advances that have not been widely incorporated into standard care.
Radiotherapy
Since SCLC is primarily considered a systemic disease, with over two-thirds of patients presenting with hematogenous metastases, it is somewhat surprising that recent progress has mainly involved the use of radiotherapy. From the standpoint of absolute survival, the greatest potential gain was noted in the study by Turrisi et al, in which patients with LS SCLC receiving early, concurrent hyperfractionated thoracic radiotherapy plus EP (etoposide plus cisplatin [Platinol]) were found to have a 10% improvement in long-term survival over those receiving once-daily radiation plus EP.[7] Although this study has been criticized for the relatively low biologic equivalent dose given in the once-daily radiation arm, the results achieved with hyperfractionated radiation are the best reported to date in patients with LS SCLC. Clearly, the acute toxicity of hyperfractionated radiation may be prohibitive in patients with poor performance status or large treatment fields. However, this approach remains underutilized even in those without contraindications, and more effort needs to be made to incorporate hyperfractionated radiotherapy into the care of our patients.
Prophylactic cranial irradiation (PCI) is another radiotherapy approach that has been shown to improve survival in patients with both LS and ES SCLC. In LS SCLC, PCI can improve long-term survival by 5.4%, suggesting that some patients were destined to relapse only in the brain.[8] As expected, the benefit of PCI in patients with ES SCLC is more limited (since they will ultimately relapse at other sites), and PCI may not be appropriate for all patients, particularly the elderly and those with preexisting neurologic or cognitive deficits. Nevertheless, the 14% improvement in 1-year survival after PCI noted in the recent European Organisation for Research and Treatment of Cancer (EORTC) trial represents a significant advance in ES SCLC.[9] Interestingly, many oncologists have not embraced the use of PCI in this setting, whereas they have overwhelmingly incorporated bevacizumab (Avastin) into the treatment of patients with advanced non–small-cell lung cancer (NSCLC) despite a 1‑year survival benefit of only 7%, half of that seen with PCI.
Chemotherapy
Platinum-based chemotherapy is the standard in both SCLC and NSCLC, but the issue of cisplatin vs carboplatin remains a point of controversy. In advanced NSCLC, meta-analyses have demonstrated a small, statistically significant, but clinically meaningless benefit for cisplatin.[10,11] Data directly comparing cisplatin- to carboplatin-based regimens in SCLC are sparse. A small, randomized trial of cisplatin plus etoposide vs carboplatin plus etoposide in patients with LS or ES SCLC revealed no differences in response or survival, but less toxicity with carboplatin.[12] Informal comparison of response rates and survival data from phase II and III trials using either cisplatin- or carboplatin-based regimens suggests similar outcomes with either drug in both LS and ES SCLC.
Therefore, in light of the palliative nature of therapy in ES SCLC and the increased nonhematologic toxicity of cisplatin, it seems prudent to favor carboplatin-based therapy for patients with ES SCLC. In LS SCLC—a curable disease for which there is less data on the equivalence of carboplatin—it is reasonable to favor cisplatin-based therapy, with use of carboplatin reserved for those in whom cisplatin is contraindicated or poorly tolerated.
Despite the availability of numerous chemotherapeutic agents with activity against SCLC (Table 3), it is unlikely that empiric regimens of traditional cytotoxic drugs will lead to dramatic improvements in survival. Over the past 2 decades, our understanding of the molecular events that mediate the development and progression of SCLC has expanded dramatically. The identification of numerous molecular targets in SCLC cells has spawned a wide variety of novel therapeutic strategies.[13] Thus far, none of these approaches has demonstrated substantial clinical activity (Table 2). However, SCLC is a molecularly heterogeneous disease, so we must continue to refine emerging strategies in the laboratory and efficiently evaluate them in the clinic in an effort to identify patients who will benefit most from any specifically targeted approach.
1. Navada S, Lai P, Schwartz AG, Kalemkerian GP: Temporal trends in small cell lung cancer: Analysis of the national Surveillance, Epidemiology, and End Results database (abstract 7082). J Clin Oncol 24(18S):384s, 2006.
2. Aisner J, Alberto P, Bitran J, et al: Role of chemotherapy in small cell lung cancer: A consensus report of the International Association for the Study of Lung Cancer workshop. Cancer Treat Rep 67:37-43, 1983.
3. Lassen UN, Hirsh FR, Osterlind K, et al: Outcome of combination chemotherapy in extensive stage small-cell lung cancer: Any treatment related progress? Lung Cancer 20:151-160, 1998.
4. Chute JP, Chen T, Feigal E, et al: Twenty years of phase II trials for patients with extensive-stage small-cell lung cancer: Perceptible progress. J Clin Oncol 17:1794-1801, 1999.
5. Greco FA, Oldham RK: Clinical management of patients with small cell lung cancer, in Greco FA, Oldham RK, Bunn PA (eds): Small Cell Lung Cancer, pp 353-379. New York, Grun & Stratton, 1981.
6. Kalemkerian GP, Akerley W, Downey RJ, et al: Small cell lung cancer. J Natl Compr Canc Netw 6:294-314, 2008. 7. Turrisi AT, Kim K, Blum R, et al: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271, 1999.
8. Auperin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 341:476-484, 1999.
9. Slotman B, Faivre-Finn C, Kramer G, et al: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664-672, 2007.
10. Ardizzoni A, Boni L, Tiseo M, et al: Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer: An individual patient data meta-analysis. J Natl Cancer Inst 99:847-857, 2007.
11. Hotta K, Matsuo K, Ueoka H, et al: Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22:3852-3859, 2004.
12. Sklaros DV, Samantas E, Kosmidis P, et al: Randomized comparison of etoposide-cisplatin vs etoposide-carboplatin and irradiation in small-cell lung cancer. Ann Oncol 5:601-607, 1994.
13. Worden FP, Kalemkerian GP: Therapeutic advances in small cell lung cancer. Expert Opin Invest Drugs 9:565-579, 2000.
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Find peer-reviewed literature and websites for practicing medical professionals
CME on Lung Cancer
Evidence on Lung Cancer
Guidelines on Lung Cancer
Patient Education on Lung Cancer
Clinical Trials on Lung Cancer
Practical Articles on Lung Cancer
Research and Reviews on Lung Cancer
All "Lung Cancer" results
Click here to find out more!
Click here!
PET/CT shows high value in lung cancer staging trial
BY ALISON FROMME
Bicenter German study shows cost and clinical effectiveness of fusion imaging over CT alone.
NEW ORLEANS—An in-depth assessment of PET/CT at two German teaching hospitals has shown the fusion imaging technology improves on CT alone and pays dividends clinically and financially for staging non-small-cell lung cancer.
The research leading to these conclusions was based on evaluations of 205 patients with proven non-small-cell lung cancer who were staged with FDGPET/ CT and conventional contrast-enhanced imaging with only the CT component of the hybrid scanner. Follow-up was performed five years after staging to assess survival and clinical status.
Patients were imaged at the Technical University Munich and University of Ulm, both in Germany. Results were presented at the 2008 SNM meeting by principal investigator Andreas K. Buck, MD, a researcher in the nuclear medicine department at Technical University Munich.
“Cost-effectiveness of PET/CT in lung cancer or other malignancies has not been examined to this extent before,” said Markus Schwaiger, MD, dean of the Technical University Munich and a contributor to the study.
“This is the first study indicating that PET/CT leads to an increase of survival in NSCLC patients due to more precise description of the tumor stage at initial presentation,” Dr. Schwaiger pointed out.
The combined PET/CT approach improved diagnostic accuracy and altered therapy decisions. Study subjects evaluated with PET/CT also survived longer than those who were not examined with fusion imaging technology.
Figures 1-3PET/CT was more accurate than CT alone for tumor, nodal, and metastatic staging (see Figures 1-3).
CT alone led to seven false T-stage readings, compared to none for PET/CT. CT alone contributed to 28 false Nstage findings, compared to three for PET/CT, and it found distant metastases in 28% of patients compared to the 35% of patients in whom PET/CT found such metastases.
The PET/CT studies led investigators to downstage 21 patients (10.2%), which, in turn, led to recommendations for 13 additional surgical procedures. Fourteen patients were upstaged, leading to the cancellation of nine surgeries.
The mean survival of patients staged with PET/CT was 957 days, compared with 453 days for patients staged with CT alone.
The improvements in diagnostic accuracy and the changes in therapeutic management with PET/CT were due, in part, to the nature of the two modalities, Dr. Buck said.
PET characterizes tumor cells that are biologically alive and active, whereas CT shows a physical picture of the tumor size and shape. Both are informative, but the combined image gives physicians more information than either technology by itself can.
Cost-effective
In addition to finding measurable clinical benefits for PET/CT, the study also established the cost-eff ectiveness of a fusion-imaging approach for staging nonsmall- cell lung cancer, Dr. Buck said.
“We believe that in the era of evidence- based medicine we cannot stick to diagnostic efficiency but have to address survival advantages for the individual patient and cost efficiency as well,” he said.
The cost of an additional quality-adjusted year of life, including diagnosis and treatment, was assessed at $81,762 (about €52,000), according to the study. This was substantially less than the $147,980 (about €100,000) considered the ceiling for a cost-effective diagnosis, Dr. Buck said.
It cost an average of $4,330 to correctly stage a tumor using PET/CT.
“Demonstration of cost-effectiveness helps to further establish PET/CT as standard for tumor staging, not only for lung cancer, but also for other malignancies,” Dr. Schwaiger said.
Bicenter German study shows cost and clinical effectiveness of fusion imaging over CT alone.
NEW ORLEANS—An in-depth assessment of PET/CT at two German teaching hospitals has shown the fusion imaging technology improves on CT alone and pays dividends clinically and financially for staging non-small-cell lung cancer.
The research leading to these conclusions was based on evaluations of 205 patients with proven non-small-cell lung cancer who were staged with FDGPET/ CT and conventional contrast-enhanced imaging with only the CT component of the hybrid scanner. Follow-up was performed five years after staging to assess survival and clinical status.
Patients were imaged at the Technical University Munich and University of Ulm, both in Germany. Results were presented at the 2008 SNM meeting by principal investigator Andreas K. Buck, MD, a researcher in the nuclear medicine department at Technical University Munich.
“Cost-effectiveness of PET/CT in lung cancer or other malignancies has not been examined to this extent before,” said Markus Schwaiger, MD, dean of the Technical University Munich and a contributor to the study.
“This is the first study indicating that PET/CT leads to an increase of survival in NSCLC patients due to more precise description of the tumor stage at initial presentation,” Dr. Schwaiger pointed out.
The combined PET/CT approach improved diagnostic accuracy and altered therapy decisions. Study subjects evaluated with PET/CT also survived longer than those who were not examined with fusion imaging technology.
Figures 1-3PET/CT was more accurate than CT alone for tumor, nodal, and metastatic staging (see Figures 1-3).
CT alone led to seven false T-stage readings, compared to none for PET/CT. CT alone contributed to 28 false Nstage findings, compared to three for PET/CT, and it found distant metastases in 28% of patients compared to the 35% of patients in whom PET/CT found such metastases.
The PET/CT studies led investigators to downstage 21 patients (10.2%), which, in turn, led to recommendations for 13 additional surgical procedures. Fourteen patients were upstaged, leading to the cancellation of nine surgeries.
The mean survival of patients staged with PET/CT was 957 days, compared with 453 days for patients staged with CT alone.
The improvements in diagnostic accuracy and the changes in therapeutic management with PET/CT were due, in part, to the nature of the two modalities, Dr. Buck said.
PET characterizes tumor cells that are biologically alive and active, whereas CT shows a physical picture of the tumor size and shape. Both are informative, but the combined image gives physicians more information than either technology by itself can.
Cost-effective
In addition to finding measurable clinical benefits for PET/CT, the study also established the cost-eff ectiveness of a fusion-imaging approach for staging nonsmall- cell lung cancer, Dr. Buck said.
“We believe that in the era of evidence- based medicine we cannot stick to diagnostic efficiency but have to address survival advantages for the individual patient and cost efficiency as well,” he said.
The cost of an additional quality-adjusted year of life, including diagnosis and treatment, was assessed at $81,762 (about €52,000), according to the study. This was substantially less than the $147,980 (about €100,000) considered the ceiling for a cost-effective diagnosis, Dr. Buck said.
It cost an average of $4,330 to correctly stage a tumor using PET/CT.
“Demonstration of cost-effectiveness helps to further establish PET/CT as standard for tumor staging, not only for lung cancer, but also for other malignancies,” Dr. Schwaiger said.
Minimal Progress, Potential Promise in Small-Cell Lung Cancer
TAOFEEK OWONIKOKO, MD, PhD
Assistant Professor of Hematology-Oncology
SURESH RAMALINGAM, MD
Associate Professor of Hematology-Oncology
Director of Lung Cancer Program
Department of Hematology
and Medical Oncology
Emory University
School of Medicine
Winship Cancer Institute
Atlanta, Georgia
Financial Disclosure:
Dr. Ramalingam has received honoraria from Genentech.
Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers diagnosed in the United States. It is characterized by initial sensitivity to chemotherapy, but a rapid progression to refractory disease and death in a majority of patients. Minimal progress has been achieved in the past several years in the treatment of patients with SCLC. The paper by Drs. Hann and Rudin, published in this issue of the journal, is a comprehensive review of the diagnosis and management of small-cell lung cancer, and also provides insight into ongoing research efforts.
New Staging System
As the authors illustrate, SCLC is broadly staged as either “limited” or “extensive.” This categorization has helped physicians choose the optimal treatment approach for patients with SCLC. Recent efforts by the International Association for Study of Lung Cancer (IASLC) to develop a new staging system for lung cancer have led to a few interesting observations.[1] Among patients with SCLC (approximately 12,000 in the database), significant differences in outcome were noted between patients with various T stages in the absence of metastatic disease. Similarly, differences in outcome were noted between patients with N0/N1 disease and those with N2/N3. Based on these findings, the staging committee has recommended the use of the tumor-node-metastasis (TNM) classification for SCLC as a standard approach. The use of the TNM system will provide more accurate prognostic information about patients with SCLC. In other words, even among patients with limited-stage disease, it will be possible to identify subsets with a more favorable outcome. It also underscores the need to stratify patients based on the T and N stage in clinical trials for limited-stage disease in order to eliminate differences in outcome based on stage alone.
As such, the new system is unlikely to change the management of patients for the immediate future. Chemotherapy with radiation will continue to be used for patients with disease confined to one hemithorax with or without contralateral nodal involvement. The management of patients with a pleural effusion continues to be a challenge, since some studies in limited-stage disease have included this subgroup. In the new staging project, the outcome for patients with pleural effusion (cytologically positive or negative) was intermediate to those with limited and extensive stages of the disease.
Radiotherapy for Limited-Stage Disease
For patients with limited-stage disease, administration of platinum-based chemotherapy with concurrent thoracic radiation is the standard approach. The role of thoracic radiation in limited-stage disease is now well established following the meta-analysis conducted by Pignon et al, who demonstrated a 5% survival advantage at 3 years and an improvement in local control.[2] Though the use of twice-daily fractions (45 Gy) of radiation is the evidence-based method, it has not gained popularity among physicians in the United States and many other parts of the world. This has largely been due to logistical challenges. As an alternative, in routine practice, many radiologists use a once-daily fraction of approximately 60 to 70 Gy, which is considered to be biologically equivalent to the 45 Gy twice-daily regimen.
Recently, a phase III study was initiated to compare the two radiation schedules (45 Gy twice daily vs 70 Gy once daily) in combination with chemotherapy for patients with limited-stage disease. This study will also evaluate a third regimen consisting of a combined strategy of daily dosing initially followed by twice-daily administration for the last 2 weeks (total of 61.2 Gy). The results of this ongoing study will help to determine the optimal radiation therapy strategy for patients with limited-stage SCLC. It is hoped that improvements in local control will lead to better disease control and a higher survival rate.
Systemic Treatment
The Hann/Rudin paper also illustrates the challenges involved in systemic treatment of patients with SCLC. Though a number of novel approaches such as alternating cycles of two regimens, high-dose therapy, dose-intense therapy, and three-drug combinations have all been studied, the results have been consistently disappointing. The combination of cisplatin and etoposide administered for four cycles remains the standard therapy in the United States. The regimen of cisplatin and irinotecan, although efficacious in the Japanese patient population,[3] failed to demonstrate a survival advantage over cisplatin/etoposide in two phase III studies conducted outside of Japan.[4,5]
Topotecan, a topoisomerase inhibitor, is efficacious in both front-line therapy (in combination with cisplatin) and for patients with sensitive relapse. It is now available in an oral formulation, which may increase convenience for patients, but this could hardly be viewed as progress. Recently, the anthracycline derivative amrubicin demonstrated robust response rates in patients with refractory and relapsed disease. Confirmation of these results in phase III studies is eagerly awaited.
Targeted Therapy
Several studies have evaluated the addition of a molecularly targeted agent to combination chemotherapy for patients with extensive-stage SCLC. The addition of bevacizumab (Avastin) to chemotherapy or administration of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors in the maintenance setting or in relapsed disease have not been successful. It is clear that the situation calls for evaluation of newer classes of anticancer agents for the treatment of SCLC.
The Hann/Rudin paper describes some of the promising agents—such as inhibitors of the insulin-like growth factor receptor (IGF-1R) pathway and the hedgehog pathway—that are currently under clinical evaluation for the treatment of SCLC. Another targeted strategy under evaluation involves the use of histone deacetylase inhibitors in combination with standard agents. This is based on observations that epigenetic modulation through DNA methylation and histone deacetylation may play a role in the clinical and biologic progression of the disease.
From the experience to date with targeted agents, it is difficult to understand whether the failures were due to the pursuit of the wrong targets or inadequate modulation of the target. The high rate of genetic instability in small-cell lung cancer might result in significant redundancy in signaling pathways such that the cancer cells are no longer dependent on any one specific target. Of course this is speculative, but future clinical trials of biologic or targeted agents should be undertaken after a robust demonstration in the preclinical setting that the cancer is dependent on the targeted pathway(s) or mechanism(s), and that abrogating that pathway produces demonstrable tumor regression.
Finally, the importance of enrolling patients in novel clinical trials to accelerate drug discovery efforts cannot be overemphasized.
1. Shepherd FA, Crowley J, Van Houtte P, et al: The International Association for the Study of Lung Cancer lung cancer staging project: Proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2:1067-1077, 2007.
2. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992.
3. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85-91, 2002.
4. Hanna N, Bunn PA Jr, Langer C, et al: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038-2043, 2006.
5. Natale RB, Lana PN, Chansky K, et al: S0124: A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC) (abstract 7512). J Clin Oncol 26(15S):400s, 2008.
Assistant Professor of Hematology-Oncology
SURESH RAMALINGAM, MD
Associate Professor of Hematology-Oncology
Director of Lung Cancer Program
Department of Hematology
and Medical Oncology
Emory University
School of Medicine
Winship Cancer Institute
Atlanta, Georgia
Financial Disclosure:
Dr. Ramalingam has received honoraria from Genentech.
Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers diagnosed in the United States. It is characterized by initial sensitivity to chemotherapy, but a rapid progression to refractory disease and death in a majority of patients. Minimal progress has been achieved in the past several years in the treatment of patients with SCLC. The paper by Drs. Hann and Rudin, published in this issue of the journal, is a comprehensive review of the diagnosis and management of small-cell lung cancer, and also provides insight into ongoing research efforts.
New Staging System
As the authors illustrate, SCLC is broadly staged as either “limited” or “extensive.” This categorization has helped physicians choose the optimal treatment approach for patients with SCLC. Recent efforts by the International Association for Study of Lung Cancer (IASLC) to develop a new staging system for lung cancer have led to a few interesting observations.[1] Among patients with SCLC (approximately 12,000 in the database), significant differences in outcome were noted between patients with various T stages in the absence of metastatic disease. Similarly, differences in outcome were noted between patients with N0/N1 disease and those with N2/N3. Based on these findings, the staging committee has recommended the use of the tumor-node-metastasis (TNM) classification for SCLC as a standard approach. The use of the TNM system will provide more accurate prognostic information about patients with SCLC. In other words, even among patients with limited-stage disease, it will be possible to identify subsets with a more favorable outcome. It also underscores the need to stratify patients based on the T and N stage in clinical trials for limited-stage disease in order to eliminate differences in outcome based on stage alone.
As such, the new system is unlikely to change the management of patients for the immediate future. Chemotherapy with radiation will continue to be used for patients with disease confined to one hemithorax with or without contralateral nodal involvement. The management of patients with a pleural effusion continues to be a challenge, since some studies in limited-stage disease have included this subgroup. In the new staging project, the outcome for patients with pleural effusion (cytologically positive or negative) was intermediate to those with limited and extensive stages of the disease.
Radiotherapy for Limited-Stage Disease
For patients with limited-stage disease, administration of platinum-based chemotherapy with concurrent thoracic radiation is the standard approach. The role of thoracic radiation in limited-stage disease is now well established following the meta-analysis conducted by Pignon et al, who demonstrated a 5% survival advantage at 3 years and an improvement in local control.[2] Though the use of twice-daily fractions (45 Gy) of radiation is the evidence-based method, it has not gained popularity among physicians in the United States and many other parts of the world. This has largely been due to logistical challenges. As an alternative, in routine practice, many radiologists use a once-daily fraction of approximately 60 to 70 Gy, which is considered to be biologically equivalent to the 45 Gy twice-daily regimen.
Recently, a phase III study was initiated to compare the two radiation schedules (45 Gy twice daily vs 70 Gy once daily) in combination with chemotherapy for patients with limited-stage disease. This study will also evaluate a third regimen consisting of a combined strategy of daily dosing initially followed by twice-daily administration for the last 2 weeks (total of 61.2 Gy). The results of this ongoing study will help to determine the optimal radiation therapy strategy for patients with limited-stage SCLC. It is hoped that improvements in local control will lead to better disease control and a higher survival rate.
Systemic Treatment
The Hann/Rudin paper also illustrates the challenges involved in systemic treatment of patients with SCLC. Though a number of novel approaches such as alternating cycles of two regimens, high-dose therapy, dose-intense therapy, and three-drug combinations have all been studied, the results have been consistently disappointing. The combination of cisplatin and etoposide administered for four cycles remains the standard therapy in the United States. The regimen of cisplatin and irinotecan, although efficacious in the Japanese patient population,[3] failed to demonstrate a survival advantage over cisplatin/etoposide in two phase III studies conducted outside of Japan.[4,5]
Topotecan, a topoisomerase inhibitor, is efficacious in both front-line therapy (in combination with cisplatin) and for patients with sensitive relapse. It is now available in an oral formulation, which may increase convenience for patients, but this could hardly be viewed as progress. Recently, the anthracycline derivative amrubicin demonstrated robust response rates in patients with refractory and relapsed disease. Confirmation of these results in phase III studies is eagerly awaited.
Targeted Therapy
Several studies have evaluated the addition of a molecularly targeted agent to combination chemotherapy for patients with extensive-stage SCLC. The addition of bevacizumab (Avastin) to chemotherapy or administration of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors in the maintenance setting or in relapsed disease have not been successful. It is clear that the situation calls for evaluation of newer classes of anticancer agents for the treatment of SCLC.
The Hann/Rudin paper describes some of the promising agents—such as inhibitors of the insulin-like growth factor receptor (IGF-1R) pathway and the hedgehog pathway—that are currently under clinical evaluation for the treatment of SCLC. Another targeted strategy under evaluation involves the use of histone deacetylase inhibitors in combination with standard agents. This is based on observations that epigenetic modulation through DNA methylation and histone deacetylation may play a role in the clinical and biologic progression of the disease.
From the experience to date with targeted agents, it is difficult to understand whether the failures were due to the pursuit of the wrong targets or inadequate modulation of the target. The high rate of genetic instability in small-cell lung cancer might result in significant redundancy in signaling pathways such that the cancer cells are no longer dependent on any one specific target. Of course this is speculative, but future clinical trials of biologic or targeted agents should be undertaken after a robust demonstration in the preclinical setting that the cancer is dependent on the targeted pathway(s) or mechanism(s), and that abrogating that pathway produces demonstrable tumor regression.
Finally, the importance of enrolling patients in novel clinical trials to accelerate drug discovery efforts cannot be overemphasized.
1. Shepherd FA, Crowley J, Van Houtte P, et al: The International Association for the Study of Lung Cancer lung cancer staging project: Proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2:1067-1077, 2007.
2. Pignon JP, Arriagada R, Ihde DC, et al: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618-1624, 1992.
3. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85-91, 2002.
4. Hanna N, Bunn PA Jr, Langer C, et al: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038-2043, 2006.
5. Natale RB, Lana PN, Chansky K, et al: S0124: A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC) (abstract 7512). J Clin Oncol 26(15S):400s, 2008.
Small-Cell Lung Cancer: Translational Research Enroute to Therapeutic Advances
JONATHAN DOWELL, MD
Associate Professor of Internal Medicine
(Medical Oncology)
Financial Disclosure:
Dr. Minna served on the scientific advisory board for Neotropix and reserved Neotropix stock options. Dr. Dowell has done research for Genentech as an independent contractor.
Hann and Rudin have provided a comprehensive and thoughtful review of the current management of small-cell lung cancer (SCLC). As they note, for approaching 2 decades, little has changed in the pretreatment evaluation, staging, or treatment of this disease. As a result, only modest improvements in survival have been seen. During this time, however, a considerable understanding of the biology of this malignancy has emerged, and this knowledge should soon translate into improved therapies for patients with SCLC.
One of the treatment advances discussed in the review is the definitive demonstration by Turrisi et al that radiation to 45 Gy (given concurrently with cisplatin and etoposide) administered in 1.5-Gy fractions twice daily significantly improved survival in patients with limited-stage disease, compared with the prior standard of 1.8-Gy fractions daily for 5 weeks. The authors did not mention that physicians and patients have failed to embrace this regimen due to the practical issues associated with the administration of twice-daily radiation. As a result, several current studies are evaluating whether a radiobiologically similar dose administered in once-daily fractions is safe and effective for patients with limited-stage disease.
Extensive-Stage Disease
In their overview of treatment for extensive-stage disease, the authors point out that a number of chemotherapy agents (pemetrexed [Alimta], irinotecan [Camptosar], topotecan [Hycamtin]) have been evaluated in combination with platinum in recent years as first-line therapy for extensive-stage disease. Despite initial indications that these regimens might be shown to be superior to the current standard of etoposide and a platinum analog (PE), all three failed to demonstrate superiority to PE in phase III randomized trials. As Hann and Rudin then discuss, the one chemotherapy agent currently under evaluation that still appears to hold promise is the synthetic anthracycline amrubicin. Amrubicin has shown significant activity in the second-line setting in both chemosensitive and chemorefractory populations. Currently, a randomized, phase III trial comparing cisplatin/amrubicin with PE as first-line therapy in extensive-stage disease is underway in China (NCT00660504), and in the second-line setting, amrubicin is being evaluated against parenteral topotecan in another phase III trial (NCT00547651).
Somewhat ironically, despite the long-established relative chemosensitivity of SCLC, the only significant advance in the treatment of extensive-stage disease in recent years can be attributed to radiation rather than chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) demonstrated in a phase III randomized trial that prophylactic cranial irradiation in extensive-stage SCLC patients whose tumors have responded to first-line therapy more than doubles survival at 1 year from randomization (13% vs 27%).
Underlying Mechanisms
Current research seeks to exploit the ever-increasing understanding of the molecular pathways involved in SCLC. As Rudin and Hann touch on in their review, approaches targeting angiogenesis showed initial promise in this disease. However, thus far, trials combining standard chemotherapy with agents such as bevacizumab (Avastin) and thalidomide (Thalomid) did not demonstrate clear progress over standard treatment. In addition, therapies targeting the c-Kit tyrosine kinase and the antiapoptotic protein Bcl-2 also failed to demonstrate significant activity.
One additional area that deserves mention is the possible identification of the tumor stem cell population in SCLC. Several studies have suggested the presence of a subpopulation of cells (tumor stem cells) in solid tumors that are able to regenerate and propagate the tumor. Recently, Gutova and colleagues identified a rare population of cells in SCLC cell lines that were urokinase-type plasminogen activator receptor (uPAR)-positive and possessed clonigenic activity and marked resistance to chemotherapy when compared with the uPAR-negative population that was chemosensitive and did not posses clonigenic activity.[1] Further study is required to demonstrate whether this uPAR-positive group of cells may be the putative stem cell population for SCLC. Hedgehog Signaling Pathway
In addition, the hedgehog pathway (an embryonic signaling pathway) has been shown to be activated in airway epithelium in response to injury, and this is thought to lead to malignant change by repeatedly expanding the airway stem cell pool. The cells within SCLC tumors in vivo that are involved in hedgehog signaling are compartmentalized and appear to recapitulate the process seen in airway development and injury repair. It has therefore been speculated that these cells are maintained as tumor stem cells through ongoing hedgehog signaling.[2,3] Treatment of SCLC cell lines and xenografts with cyclopamine (a specific hedgehog pathway inhibitor) produces tumor growth arrest in both models.[4] Currently, GDC-0449, an orally bioavailable synthetic inhibitor of the hedgehog pathway is in phase I and II studies in patients with solid tumors, including SCLC.
Finally, increasing evidence suggests that cancer stem cells are controlled by an epigenetic program and that treatment with epigenetic-targeted agents may convert the cancer stem cells to progenitors with less malignant behavior.[5,6] The outcome of these and future studies will determine whether targeting these cell populations will prove to be a successful therapeutic approach in SCLC.
1. Gutova M, Najbauer J, Gevorgyan A, et al: Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS ONE 2(2):e243, 2007.
2. Watkins DN, Berman DM, Burkholder SG, et al: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422:313-317, 2003.
3. Watkins DN, Berman DM, Baylin SB: Hedgehog signaling: Progenitor phenotype in small-cell lung cancer. Cell Cycle 2:196-198, 2003.
4. Daniel VC, Peacock CD, Watkins DN: Developmental signalling pathways in lung cancer. Respirology 11:234-240, 2006.
5. Peacock CD,Watkins DN: Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 26:2883-2889, 2008.
6. Ohm JE, McGarvey KM, Yu X, et al: A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237-242, 2007.
Associate Professor of Internal Medicine
(Medical Oncology)
Financial Disclosure:
Dr. Minna served on the scientific advisory board for Neotropix and reserved Neotropix stock options. Dr. Dowell has done research for Genentech as an independent contractor.
Hann and Rudin have provided a comprehensive and thoughtful review of the current management of small-cell lung cancer (SCLC). As they note, for approaching 2 decades, little has changed in the pretreatment evaluation, staging, or treatment of this disease. As a result, only modest improvements in survival have been seen. During this time, however, a considerable understanding of the biology of this malignancy has emerged, and this knowledge should soon translate into improved therapies for patients with SCLC.
One of the treatment advances discussed in the review is the definitive demonstration by Turrisi et al that radiation to 45 Gy (given concurrently with cisplatin and etoposide) administered in 1.5-Gy fractions twice daily significantly improved survival in patients with limited-stage disease, compared with the prior standard of 1.8-Gy fractions daily for 5 weeks. The authors did not mention that physicians and patients have failed to embrace this regimen due to the practical issues associated with the administration of twice-daily radiation. As a result, several current studies are evaluating whether a radiobiologically similar dose administered in once-daily fractions is safe and effective for patients with limited-stage disease.
Extensive-Stage Disease
In their overview of treatment for extensive-stage disease, the authors point out that a number of chemotherapy agents (pemetrexed [Alimta], irinotecan [Camptosar], topotecan [Hycamtin]) have been evaluated in combination with platinum in recent years as first-line therapy for extensive-stage disease. Despite initial indications that these regimens might be shown to be superior to the current standard of etoposide and a platinum analog (PE), all three failed to demonstrate superiority to PE in phase III randomized trials. As Hann and Rudin then discuss, the one chemotherapy agent currently under evaluation that still appears to hold promise is the synthetic anthracycline amrubicin. Amrubicin has shown significant activity in the second-line setting in both chemosensitive and chemorefractory populations. Currently, a randomized, phase III trial comparing cisplatin/amrubicin with PE as first-line therapy in extensive-stage disease is underway in China (NCT00660504), and in the second-line setting, amrubicin is being evaluated against parenteral topotecan in another phase III trial (NCT00547651).
Somewhat ironically, despite the long-established relative chemosensitivity of SCLC, the only significant advance in the treatment of extensive-stage disease in recent years can be attributed to radiation rather than chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) demonstrated in a phase III randomized trial that prophylactic cranial irradiation in extensive-stage SCLC patients whose tumors have responded to first-line therapy more than doubles survival at 1 year from randomization (13% vs 27%).
Underlying Mechanisms
Current research seeks to exploit the ever-increasing understanding of the molecular pathways involved in SCLC. As Rudin and Hann touch on in their review, approaches targeting angiogenesis showed initial promise in this disease. However, thus far, trials combining standard chemotherapy with agents such as bevacizumab (Avastin) and thalidomide (Thalomid) did not demonstrate clear progress over standard treatment. In addition, therapies targeting the c-Kit tyrosine kinase and the antiapoptotic protein Bcl-2 also failed to demonstrate significant activity.
One additional area that deserves mention is the possible identification of the tumor stem cell population in SCLC. Several studies have suggested the presence of a subpopulation of cells (tumor stem cells) in solid tumors that are able to regenerate and propagate the tumor. Recently, Gutova and colleagues identified a rare population of cells in SCLC cell lines that were urokinase-type plasminogen activator receptor (uPAR)-positive and possessed clonigenic activity and marked resistance to chemotherapy when compared with the uPAR-negative population that was chemosensitive and did not posses clonigenic activity.[1] Further study is required to demonstrate whether this uPAR-positive group of cells may be the putative stem cell population for SCLC. Hedgehog Signaling Pathway
In addition, the hedgehog pathway (an embryonic signaling pathway) has been shown to be activated in airway epithelium in response to injury, and this is thought to lead to malignant change by repeatedly expanding the airway stem cell pool. The cells within SCLC tumors in vivo that are involved in hedgehog signaling are compartmentalized and appear to recapitulate the process seen in airway development and injury repair. It has therefore been speculated that these cells are maintained as tumor stem cells through ongoing hedgehog signaling.[2,3] Treatment of SCLC cell lines and xenografts with cyclopamine (a specific hedgehog pathway inhibitor) produces tumor growth arrest in both models.[4] Currently, GDC-0449, an orally bioavailable synthetic inhibitor of the hedgehog pathway is in phase I and II studies in patients with solid tumors, including SCLC.
Finally, increasing evidence suggests that cancer stem cells are controlled by an epigenetic program and that treatment with epigenetic-targeted agents may convert the cancer stem cells to progenitors with less malignant behavior.[5,6] The outcome of these and future studies will determine whether targeting these cell populations will prove to be a successful therapeutic approach in SCLC.
1. Gutova M, Najbauer J, Gevorgyan A, et al: Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS ONE 2(2):e243, 2007.
2. Watkins DN, Berman DM, Burkholder SG, et al: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422:313-317, 2003.
3. Watkins DN, Berman DM, Baylin SB: Hedgehog signaling: Progenitor phenotype in small-cell lung cancer. Cell Cycle 2:196-198, 2003.
4. Daniel VC, Peacock CD, Watkins DN: Developmental signalling pathways in lung cancer. Respirology 11:234-240, 2006.
5. Peacock CD,Watkins DN: Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 26:2883-2889, 2008.
6. Ohm JE, McGarvey KM, Yu X, et al: A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237-242, 2007.
Management of Small-Cell Lung Cancer: Incremental Changes but Hope for the Future
CHRISTINE L. HANN, MD, PhD
Assistant Professor of Oncology
CHARLES M. RUDIN, MD, PhD
Associate Professor of Oncology
Co-director, Upper Aerodigestive Cancer Program
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland
Financial Disclosure:
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgement:
The authors work on SCLC is supported by the Burroughs Wellcome Fund (CMR) and Flight Attendant Research Institute (CLH and CMR).
ABSTRACT: Over 25,000 people are diagnosed with small-cell lung cancer (SCLC) in the United States annually. SCLC is a highly aggressive tumor with a propensity for early metastases and a high case-fatality rate. Systemic treatment with etoposide plus a platinum agent is recommended for all stages of this disease and has been a standard first-line therapy for SCLC since the 1980s. Three recently presented randomized clinical trials failed to show superiority of newer regimens over etoposide and cisplatin. Patients with limited-stage (LS) disease benefit from the addition of radiotherapy to systemic chemotherapy, a combination that affords high complete response rates and potential cures. Incremental improvements in radiotherapy delivery over the past decade include the use of accelerated hyperfractionated thoracic radiotherapy for LS disease. Prophylactic cranial irradiation, previously recommended for patients with LS disease, has recently been shown to benefit those with extensive-stage (ES) disease as well. Surgery, largely abandoned in the 1970s, is being reevaluated as primary local therapy in patients with very early-stage SCLC. Topotecan remains the only US Food and Drug Administration–approved therapy for recurrent disease. Amrubicin has demonstrated single-agent activity in multiple phase II trials in both chemotherapy-sensitive and -refractory relapse. The past 2 decades have been marked by an improved understanding of SCLC biology, and these discoveries are reflected in the number and diversity of novel therapies entering early-phase testing in this disease.
Small-cell lung cancer (SCLC) accounts for approximately 15% of the 215,000 new lung cancer diagnoses in the United States annually. With a case-fatality rate greater than 90%, SCLC will be the cause of over 25,000 deaths in 2008 alone. SCLC is seen almost exclusively in current or former smokers and is characterized by a rapid tumor doubling time, high growth fraction, and early development of metastases. At the time of diagnosis, SCLC is usually disseminated and, if left untreated, rapidly fatal with an average survival of less than 4 months. Essentially all patients are treated with chemotherapy, either alone or in combination with local therapy such as radiation therapy. EP (etoposide and cisplatin [Platinol]), a chemotherapy regimen established in the 1980s, remains a primary standard of care for first-line therapy today. Here we describe the clinical presentation, diagnosis, and staging of SCLC and discuss standard disease management in the context of recently presented trials.
Clinical Presentation
SCLC typically arises in the central airways and can quickly metastasize to the lymph nodes and beyond. As such, many patients present with symptoms related to central airway disease, including cough, dyspnea, and chest discomfort.[1] SCLC displays the propensity for early metastases to sites including the liver, bones, adrenal glands, and brain. Reflecting the systemic nature of this disease, up to 50% of patients will present with weight loss, fatigue, and anorexia.
SCLC patients may also present with an endocrinologic or neurologic paraneoplastic syndrome. Hyponatremia, due to ectopic production of antidiuretic hormone or atrial natriuretic peptide, is observed in up to 15% of patients with SCLC, while Cushing's syndrome is seen in 2% to 5% of SCLC patients.[2] Clinically disabling paraneoplastic neurologic syndromes, thought to be mediated by antibodies directed against "onconeural" antigens, are observed in 1% to 3% of SCLC patients. Anti-Hu antibodies are seen in multifocal encephalomyelitis/sensory neuronopathy and limbic encephalitis.[3] Lambert-Eaton myasthenic syndrome (LEMS) is associated with anti–voltage-gated calcium channel (VGCC) antibodies. Fifty percent of LEMS patients will eventually be diagnosed with SCLC; accordingly, a smoker diagnosed with LEMS should be closely followed and screened for SCLC.[4] In a minority of patients who present with neurologic paraneoplastic syndromes, symptoms may remit with treatment of the underlying cancer.
Diagnosis
The diagnosis of SCLC is primarily made by light microscopy. With standard hematoxylin-and-eosin stain, the tumors appear as small blue cells with scant cytoplasm and a high mitotic index. Nuclear molding is considered characteristic, and the nuclei themselves have fine granular chromatin and absent nucleoli.[5] Keratin and epithelial membrane antigen are seen almost uniformly. At least one marker of neuroendocrine differentiation is observed in 75% of SCLC cases, including dopa decarboxylase, calcitonin, synaptophysin, chromogranin A, CD56 (nuclear cell adhesion molecule, or NCAM), and gastrin-releasing peptide.[6,7]
Staging
Introduced by the Veterans' Administration Lung Study Group (VALSG) in the 1950s, the two-stage classification system is typically used clinically to stage SCLC.[8] The VALSG system defines patients as having either limited-stage (LS) or extensive-stage (ES) SCLC. Patients with LS SCLC have disease confined to the ipsilateral hemithorax that can be safely included in a tolerable radiation portal, and ES disease includes all remaining patients. Approximately 30% of all new SCLC diagnoses are classified as LS. Patients with LS disease have a median survival of 18 to 23 months, and up to 20% of patients can achieve long-term remission with concurrent chemoradiotherapy. The median survival of patients with ES disease is 8 to 10 months despite aggressive chemotherapy.
In 1987 the International Association for the Study of Lung Cancer (IASLC) published a consensus report revising the VALSG classification in accordance with TNM staging for malignant tumors. By TNM criteria, limited-stage disease includes stages I–III, whereas ES disease is comprised of stage IV tumors only.[9] By convention, LS and ES descriptors are still predominantly used. Staging evaluation for SCLC patients should include a routine history and physical exam, hematology and chemistry panels, and computed tomography (CT) scan of the chest to evaluate the extent of intrathoracic disease, including pleural effusion. Concurrent chemotherapy can offer cures in up to 20% of LS patients but at the cost of significant toxicity. Thus, accurate assessment of extrathoracic disease is imperative. Common sites of metastases include bone, liver, adrenal glands, and brain, and therefore, CT scan of the abdomen, magnetic resonance imaging (MRI) of the brain, and bone scan are recommended. A bone marrow biopsy may be performed as clinically indicated; however, it is rare that patients have bone marrow involvement as a sole site of metastasis.[10] Patients, who present with a pleural effusion in the absence of extrathoracic disease should have further studies of their pleural fluid—such as chemistry studies consistent with an exudate or, better yet, cytopathologic confirmation—to verify tumor involvement.
As SCLC is a highly metabolic tumor that avidly takes up fluorodeoxyglucose, positron-emission tomography (PET) scanning is an attractive modality for staging. In small prospective studies, PET scans have correctly upstaged patients to ES disease.[11,12] However, larger prospective studies are still needed, and reimbursement in the United States for this particular indication remains an issue.
Assistant Professor of Oncology
CHARLES M. RUDIN, MD, PhD
Associate Professor of Oncology
Co-director, Upper Aerodigestive Cancer Program
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland
Financial Disclosure:
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgement:
The authors work on SCLC is supported by the Burroughs Wellcome Fund (CMR) and Flight Attendant Research Institute (CLH and CMR).
ABSTRACT: Over 25,000 people are diagnosed with small-cell lung cancer (SCLC) in the United States annually. SCLC is a highly aggressive tumor with a propensity for early metastases and a high case-fatality rate. Systemic treatment with etoposide plus a platinum agent is recommended for all stages of this disease and has been a standard first-line therapy for SCLC since the 1980s. Three recently presented randomized clinical trials failed to show superiority of newer regimens over etoposide and cisplatin. Patients with limited-stage (LS) disease benefit from the addition of radiotherapy to systemic chemotherapy, a combination that affords high complete response rates and potential cures. Incremental improvements in radiotherapy delivery over the past decade include the use of accelerated hyperfractionated thoracic radiotherapy for LS disease. Prophylactic cranial irradiation, previously recommended for patients with LS disease, has recently been shown to benefit those with extensive-stage (ES) disease as well. Surgery, largely abandoned in the 1970s, is being reevaluated as primary local therapy in patients with very early-stage SCLC. Topotecan remains the only US Food and Drug Administration–approved therapy for recurrent disease. Amrubicin has demonstrated single-agent activity in multiple phase II trials in both chemotherapy-sensitive and -refractory relapse. The past 2 decades have been marked by an improved understanding of SCLC biology, and these discoveries are reflected in the number and diversity of novel therapies entering early-phase testing in this disease.
Small-cell lung cancer (SCLC) accounts for approximately 15% of the 215,000 new lung cancer diagnoses in the United States annually. With a case-fatality rate greater than 90%, SCLC will be the cause of over 25,000 deaths in 2008 alone. SCLC is seen almost exclusively in current or former smokers and is characterized by a rapid tumor doubling time, high growth fraction, and early development of metastases. At the time of diagnosis, SCLC is usually disseminated and, if left untreated, rapidly fatal with an average survival of less than 4 months. Essentially all patients are treated with chemotherapy, either alone or in combination with local therapy such as radiation therapy. EP (etoposide and cisplatin [Platinol]), a chemotherapy regimen established in the 1980s, remains a primary standard of care for first-line therapy today. Here we describe the clinical presentation, diagnosis, and staging of SCLC and discuss standard disease management in the context of recently presented trials.
Clinical Presentation
SCLC typically arises in the central airways and can quickly metastasize to the lymph nodes and beyond. As such, many patients present with symptoms related to central airway disease, including cough, dyspnea, and chest discomfort.[1] SCLC displays the propensity for early metastases to sites including the liver, bones, adrenal glands, and brain. Reflecting the systemic nature of this disease, up to 50% of patients will present with weight loss, fatigue, and anorexia.
SCLC patients may also present with an endocrinologic or neurologic paraneoplastic syndrome. Hyponatremia, due to ectopic production of antidiuretic hormone or atrial natriuretic peptide, is observed in up to 15% of patients with SCLC, while Cushing's syndrome is seen in 2% to 5% of SCLC patients.[2] Clinically disabling paraneoplastic neurologic syndromes, thought to be mediated by antibodies directed against "onconeural" antigens, are observed in 1% to 3% of SCLC patients. Anti-Hu antibodies are seen in multifocal encephalomyelitis/sensory neuronopathy and limbic encephalitis.[3] Lambert-Eaton myasthenic syndrome (LEMS) is associated with anti–voltage-gated calcium channel (VGCC) antibodies. Fifty percent of LEMS patients will eventually be diagnosed with SCLC; accordingly, a smoker diagnosed with LEMS should be closely followed and screened for SCLC.[4] In a minority of patients who present with neurologic paraneoplastic syndromes, symptoms may remit with treatment of the underlying cancer.
Diagnosis
The diagnosis of SCLC is primarily made by light microscopy. With standard hematoxylin-and-eosin stain, the tumors appear as small blue cells with scant cytoplasm and a high mitotic index. Nuclear molding is considered characteristic, and the nuclei themselves have fine granular chromatin and absent nucleoli.[5] Keratin and epithelial membrane antigen are seen almost uniformly. At least one marker of neuroendocrine differentiation is observed in 75% of SCLC cases, including dopa decarboxylase, calcitonin, synaptophysin, chromogranin A, CD56 (nuclear cell adhesion molecule, or NCAM), and gastrin-releasing peptide.[6,7]
Staging
Introduced by the Veterans' Administration Lung Study Group (VALSG) in the 1950s, the two-stage classification system is typically used clinically to stage SCLC.[8] The VALSG system defines patients as having either limited-stage (LS) or extensive-stage (ES) SCLC. Patients with LS SCLC have disease confined to the ipsilateral hemithorax that can be safely included in a tolerable radiation portal, and ES disease includes all remaining patients. Approximately 30% of all new SCLC diagnoses are classified as LS. Patients with LS disease have a median survival of 18 to 23 months, and up to 20% of patients can achieve long-term remission with concurrent chemoradiotherapy. The median survival of patients with ES disease is 8 to 10 months despite aggressive chemotherapy.
In 1987 the International Association for the Study of Lung Cancer (IASLC) published a consensus report revising the VALSG classification in accordance with TNM staging for malignant tumors. By TNM criteria, limited-stage disease includes stages I–III, whereas ES disease is comprised of stage IV tumors only.[9] By convention, LS and ES descriptors are still predominantly used. Staging evaluation for SCLC patients should include a routine history and physical exam, hematology and chemistry panels, and computed tomography (CT) scan of the chest to evaluate the extent of intrathoracic disease, including pleural effusion. Concurrent chemotherapy can offer cures in up to 20% of LS patients but at the cost of significant toxicity. Thus, accurate assessment of extrathoracic disease is imperative. Common sites of metastases include bone, liver, adrenal glands, and brain, and therefore, CT scan of the abdomen, magnetic resonance imaging (MRI) of the brain, and bone scan are recommended. A bone marrow biopsy may be performed as clinically indicated; however, it is rare that patients have bone marrow involvement as a sole site of metastasis.[10] Patients, who present with a pleural effusion in the absence of extrathoracic disease should have further studies of their pleural fluid—such as chemistry studies consistent with an exudate or, better yet, cytopathologic confirmation—to verify tumor involvement.
As SCLC is a highly metabolic tumor that avidly takes up fluorodeoxyglucose, positron-emission tomography (PET) scanning is an attractive modality for staging. In small prospective studies, PET scans have correctly upstaged patients to ES disease.[11,12] However, larger prospective studies are still needed, and reimbursement in the United States for this particular indication remains an issue.
First-Line Maintenance With Erlotinib/Bevacizumab Improves Progression-Free Survival in Advanced Lung Cancer
Genentech, Inc, announced that a phase III study (ATLAS) of erlotinib (Tarceva) in combination with bevacizumab (Avastin) as maintenance therapy following initial treatment with Avastin plus chemotherapy in advanced non–small-cell lung cancer (NSCLC) met its primary endpoint. The study was stopped early on the recommendation of an independent data safety monitoring board after a preplanned interim analysis showed that combining erlotinib and bevacizumab significantly extended the time patients lived without their disease advancing, as defined by progression-free survival (PFS), compared to bevacizumab plus placebo. A preliminary safety analysis showed adverse events were consistent with previous bevacizumab or erlotinib studies, as well as trials evaluating the two drugs together, and no new safety signals were observed. Data will be submitted for presentation at a future medical meeting.
“This is the second study to show that people with lung cancer who took the daily pill Tarceva following initial treatment lived longer without their cancer getting worse. We plan to discuss these data with the FDA to determine next steps,” said Hal Barron, MD, Genentech’s senior vice president, Development and chief medical officer. “Tumors use different pathways to grow and these results showed that combining medicines targeting two of these pathways instead of one delayed disease progression.”
Earlier Trial
An earlier study, SATURN, showed erlotinib delayed disease progression when given as a single agent immediately following treatment with chemotherapy, compared to placebo. In ATLAS, patients were initially treated with bevacizumab plus chemotherapy followed by the addition of erlotinib to bevacizumab in the maintenance phase.
Bevacizumab is currently approved as first-line treatment in combination with carboplatin and paclitaxel chemotherapy for patients with locally advanced, non-squamous NSCLC, and erlotinib is currently approved as a treatment for patients with advanced NSCLC who have progressed following treatment with at least one prior chemotherapy regimen. Both therapies have been shown to improve overall survival in these indications.
“This is the second study to show that people with lung cancer who took the daily pill Tarceva following initial treatment lived longer without their cancer getting worse. We plan to discuss these data with the FDA to determine next steps,” said Hal Barron, MD, Genentech’s senior vice president, Development and chief medical officer. “Tumors use different pathways to grow and these results showed that combining medicines targeting two of these pathways instead of one delayed disease progression.”
Earlier Trial
An earlier study, SATURN, showed erlotinib delayed disease progression when given as a single agent immediately following treatment with chemotherapy, compared to placebo. In ATLAS, patients were initially treated with bevacizumab plus chemotherapy followed by the addition of erlotinib to bevacizumab in the maintenance phase.
Bevacizumab is currently approved as first-line treatment in combination with carboplatin and paclitaxel chemotherapy for patients with locally advanced, non-squamous NSCLC, and erlotinib is currently approved as a treatment for patients with advanced NSCLC who have progressed following treatment with at least one prior chemotherapy regimen. Both therapies have been shown to improve overall survival in these indications.
African Americans with proximal polyps and overweight or obese women are at higher risk for colorectal cancer: Researchers call for more screening
WASHINGTON—Cancer in the proximal colon, the right part of the colon closest to the small intestine, has been increasing in African-American men since the mid-1990s.
The rising incidence stands in marked contrast to the overall decrease in colorectal cancer rates seen over the past 20 years, said Ananya Das, MD, associate professor, Division of Gastroenterology, at the Mayo Clinic in Scottsdale, Arizona. Dr. Das presented the findings at the Digestive Disease Week 2007 conference (abstract 431).
Dr. Das and his colleagues analyzed millions of records from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, calculating sex-, race-, and site-specific incidence for all patients with confirmed, invasive, primary colorectal cancer between 1973 and 2003.
Overall colorectal cancer rates declined during this period in both blacks and whites and in both men and women, the researchers found. But when they looked at proximal colon cancer among African Americans, they "came up with a very startling observation," Dr. Das commented. Starting in the mid-1990s, rates began rising for African Americans, especially men.
Although the reason for the increase is unknown, it does suggest that screening among African Americans should include complete colonoscopies, Dr. Das said. Colonoscopy, in contrast to sigmoidoscopy, includes the proximal section of the colon.
"There are very convincing data that African Americans have lower rates of colonoscopy screening, even after having colon cancer," Dr. Das said. "That could help explain the findings."
The rising incidence stands in marked contrast to the overall decrease in colorectal cancer rates seen over the past 20 years, said Ananya Das, MD, associate professor, Division of Gastroenterology, at the Mayo Clinic in Scottsdale, Arizona. Dr. Das presented the findings at the Digestive Disease Week 2007 conference (abstract 431).
Dr. Das and his colleagues analyzed millions of records from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, calculating sex-, race-, and site-specific incidence for all patients with confirmed, invasive, primary colorectal cancer between 1973 and 2003.
Overall colorectal cancer rates declined during this period in both blacks and whites and in both men and women, the researchers found. But when they looked at proximal colon cancer among African Americans, they "came up with a very startling observation," Dr. Das commented. Starting in the mid-1990s, rates began rising for African Americans, especially men.
Although the reason for the increase is unknown, it does suggest that screening among African Americans should include complete colonoscopies, Dr. Das said. Colonoscopy, in contrast to sigmoidoscopy, includes the proximal section of the colon.
"There are very convincing data that African Americans have lower rates of colonoscopy screening, even after having colon cancer," Dr. Das said. "That could help explain the findings."
Newer Chemo Regimens Prolong Survival in Advanced Colorectal Cancer
Judith Groch
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
* Explain to patients who ask that this meta-analysis was based on group data, rather than individual patient information, so that conclusions about the value of certain regimens should be avoided for now.
* Explain that despite limited longer survival for patients treated with the newer drugs, toxicity and complication rates were high.
IOANNINA, Greece, Sept. 24 -- Today's newer chemotherapy drugs add months to the lives of patients with advanced colorectal cancer, but at a high cost in toxicity and complications, a meta-analysis showed.
For patients expected to live for a year when treated with fluorouracil and leucovorin (Welcovorin), the estimated absolute survival benefit of additional treatment with irinotecan (Camptosar) plus bevacizumab (Avastin) was an added eight months, John P.A. Ioannidis, M.D., Ph.D., of the University of Ioannina here, and colleagues, reported online in the Sept. 20 issue of The Lancet Oncology.
Survival benefits of an added 4.7 months were also noted for the addition of oxaliplatin (Eloxatin) plus bevacizumab or for irinotecan plus oxaliplatin, the researchers said.
Newer chemotherapy drugs, such as irinotecan and oxaliplatin, and molecularly targeted agents such as bevacizumab and cetuzimab (Erbitux) have shown effectiveness in trials of patients with advanced colorectal cancer, but these drugs are highly toxic and the size of the benefits have not been measured, the researchers wrote.
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
* Explain to patients who ask that this meta-analysis was based on group data, rather than individual patient information, so that conclusions about the value of certain regimens should be avoided for now.
* Explain that despite limited longer survival for patients treated with the newer drugs, toxicity and complication rates were high.
IOANNINA, Greece, Sept. 24 -- Today's newer chemotherapy drugs add months to the lives of patients with advanced colorectal cancer, but at a high cost in toxicity and complications, a meta-analysis showed.
For patients expected to live for a year when treated with fluorouracil and leucovorin (Welcovorin), the estimated absolute survival benefit of additional treatment with irinotecan (Camptosar) plus bevacizumab (Avastin) was an added eight months, John P.A. Ioannidis, M.D., Ph.D., of the University of Ioannina here, and colleagues, reported online in the Sept. 20 issue of The Lancet Oncology.
Survival benefits of an added 4.7 months were also noted for the addition of oxaliplatin (Eloxatin) plus bevacizumab or for irinotecan plus oxaliplatin, the researchers said.
Newer chemotherapy drugs, such as irinotecan and oxaliplatin, and molecularly targeted agents such as bevacizumab and cetuzimab (Erbitux) have shown effectiveness in trials of patients with advanced colorectal cancer, but these drugs are highly toxic and the size of the benefits have not been measured, the researchers wrote.
Cetuximab Improves Survival in Advanced Colorectal Cancer
A multicenter, open-label, randomized phase III trial recently published in the New England Journal of Medicine (357:2040-2048, 2007) demonstrated that cetuximab (Erbitux) as a single agent significantly improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to approved chemotherapy agents. The study compared cetuximab plus best supportive care (BSC) to BSC alone in patients with mCRC whose disease had progressed through treatment with all approved chemotherapy, including irinotecan (Camptosar), oxaliplatin (Eloxatin), and fluoropyrimidines.
The independent study, conducted by the National Cancer Institute of Canada Clinical Trials Group in collaboration with the Australasian Gastro-Intestinal Trials Group, involved 572 patients and demonstrated that treating patients with cetuximab monotherapy plus BSC significantly increased overall survival compared to BSC alone. BSC included palliative therapies designed to alleviate pain and treat other effects caused by mCRC.
"This is the first time an antibody used as a single agent in colorectal cancer has demonstrated an overall survival benefit. These outcomes add to the growing body of evidence supporting the significant clinical benefits of Erbitux," said Eric K. Rowinsky, MD, chief medical officer and senior vice president of ImClone, the drug's manufacturer.
Study Design
The study enrolled patients with epidermal growth factor receptor (EGFR)-expressing mCRC who had been previously treated. Cetuximab was administered at the recommended dose and schedule: 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity.
In this study, the median survival was 6.1 months for patients treated with cetuximab plus BSC vs 4.6 months for patients on BSC alone (hazard ratio [HR] = 0.77, P = .005). Treatment with cetuximab monotherapy resulted in a significant improvement in progression-free survival vs BSC alone (HR = 0.68, P < .001). A total of 23 patients (8.0%) treated with cetuximab and no patients on BSC alone had partial responses (P < .001).
Grade 3/4 adverse events (occurring in at least 10% of patients in either group) reported more frequently in the cetuximab-plus-BSC treatment arm compared with the BSC-only arm included fatigue (33% vs 26%), other pain (16% vs 7%), dyspnea (16% vs 12%), infection without neutropenia (13% vs 6%), rash/desquamantion (12% vs < 1%), and other gastrointestinal events (10% vs 8%).
The independent study, conducted by the National Cancer Institute of Canada Clinical Trials Group in collaboration with the Australasian Gastro-Intestinal Trials Group, involved 572 patients and demonstrated that treating patients with cetuximab monotherapy plus BSC significantly increased overall survival compared to BSC alone. BSC included palliative therapies designed to alleviate pain and treat other effects caused by mCRC.
"This is the first time an antibody used as a single agent in colorectal cancer has demonstrated an overall survival benefit. These outcomes add to the growing body of evidence supporting the significant clinical benefits of Erbitux," said Eric K. Rowinsky, MD, chief medical officer and senior vice president of ImClone, the drug's manufacturer.
Study Design
The study enrolled patients with epidermal growth factor receptor (EGFR)-expressing mCRC who had been previously treated. Cetuximab was administered at the recommended dose and schedule: 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity.
In this study, the median survival was 6.1 months for patients treated with cetuximab plus BSC vs 4.6 months for patients on BSC alone (hazard ratio [HR] = 0.77, P = .005). Treatment with cetuximab monotherapy resulted in a significant improvement in progression-free survival vs BSC alone (HR = 0.68, P < .001). A total of 23 patients (8.0%) treated with cetuximab and no patients on BSC alone had partial responses (P < .001).
Grade 3/4 adverse events (occurring in at least 10% of patients in either group) reported more frequently in the cetuximab-plus-BSC treatment arm compared with the BSC-only arm included fatigue (33% vs 26%), other pain (16% vs 7%), dyspnea (16% vs 12%), infection without neutropenia (13% vs 6%), rash/desquamantion (12% vs < 1%), and other gastrointestinal events (10% vs 8%).
FDA Clears Test for Monitoring Metastatic Colorectal Cancer
The US Food and Drug Administration (FDA) has granted an expanded clearance for the CellSearch System to be used as an aid in the monitoring of metastatic colorectal cancer. CellSearch is currently approved for monitoring metastatic breast cancer.
The CellSearch System identifies and counts circulating tumor cells (CTCs) in a blood sample to predict progression-free survival and overall survival in patients with metastatic colorectal or breast cancer, and can do so earlier than the current standard of care. The results of serial testing for CTCs with the CellSearch System, in conjunction with other clinical methods for monitoring, can help physicians assess disease progression, thereby guiding more informed care decisions earlier.
The CellSearch System is the first diagnostic test to automate the detection and enumeration of CTCs, cancer cells that detach from solid tumors and enter the blood stream, and is the standard in a new class of diagnostic tools. The system's specificity, sensitivity, and reproducibility allow for serial assessment of CTCs as early as the first cycle of treatment to help evaluate disease progression sooner.
Key Trial
A prospective, multicenter clinical trial was conducted to validate the expanded clearance for CellSearch. The study, which took place in 55 clinical centers in the United States and Europe, involved 430 metastatic colorectal patients about to enter first- or second-line therapy. Data showed that patients with less than three CTCs at baseline had significantly better survival rates vs patients with more than three CTCs—an overall finding consistent with metastatic breast cancer patients. Data also showed that CTCs are a strong independent predictor of progression-free survival and overall survival, and that the combination of CTC analysis and radiologic assessment may provide the most accurate assessment of prognosis.
The CellSearch test works by using antibodies that are joined to microscopic iron particles, called ferrofluid. These antibody/ferrofluid combinations attach very specifically to CTCs. Powerful magnets then "pull" the CTCs out of the blood sample. They are then stained with additional biomolecules and chemicals so that they can be positively identified as CTCs. The CellSearch test differs from the current standard of care because it can be used much earlier than traditional imaging (eg, CT scans), and is not subject to the variation observed with other serum tumor markers.
The CellSearch System identifies and counts circulating tumor cells (CTCs) in a blood sample to predict progression-free survival and overall survival in patients with metastatic colorectal or breast cancer, and can do so earlier than the current standard of care. The results of serial testing for CTCs with the CellSearch System, in conjunction with other clinical methods for monitoring, can help physicians assess disease progression, thereby guiding more informed care decisions earlier.
The CellSearch System is the first diagnostic test to automate the detection and enumeration of CTCs, cancer cells that detach from solid tumors and enter the blood stream, and is the standard in a new class of diagnostic tools. The system's specificity, sensitivity, and reproducibility allow for serial assessment of CTCs as early as the first cycle of treatment to help evaluate disease progression sooner.
Key Trial
A prospective, multicenter clinical trial was conducted to validate the expanded clearance for CellSearch. The study, which took place in 55 clinical centers in the United States and Europe, involved 430 metastatic colorectal patients about to enter first- or second-line therapy. Data showed that patients with less than three CTCs at baseline had significantly better survival rates vs patients with more than three CTCs—an overall finding consistent with metastatic breast cancer patients. Data also showed that CTCs are a strong independent predictor of progression-free survival and overall survival, and that the combination of CTC analysis and radiologic assessment may provide the most accurate assessment of prognosis.
The CellSearch test works by using antibodies that are joined to microscopic iron particles, called ferrofluid. These antibody/ferrofluid combinations attach very specifically to CTCs. Powerful magnets then "pull" the CTCs out of the blood sample. They are then stained with additional biomolecules and chemicals so that they can be positively identified as CTCs. The CellSearch test differs from the current standard of care because it can be used much earlier than traditional imaging (eg, CT scans), and is not subject to the variation observed with other serum tumor markers.
Biomarker CCSA-2 May Provide Accurate Blood Test for Colorectal Cancer
A blood-based marker called colon cancer–specific antigen-2 (CCSA-2) may be an accurate indicator of colorectal cancer, according to preliminary research led by Johns Hopkins University in collaboration with the University of Pittsburgh and presented at the 5th annual Gastrointestinal Cancers Symposium, held January 25–27 in Orlando, Florida.
The goal of this research was to find an accurate, simple and noninvasive method for the early detection of colorectal cancer, similar to the prostate-specific antigen (PSA) blood test for prostate cancer. Other markers for colorectal cancer, including the fecal occult blood test and the carcinoembryonic antigen (CEA) test, are also found in patients with conditions other than cancer, and therefore lack specificity, resulting in false-positives in about 85% to 90% of cases for the fecal occult blood test and about 40% to 60% for the CEA test.
May Also Detect High-Risk Precancers
"Our goal when researching colorectal cancer biomarkers was to take a step back and try to understand the fundamental properties of the cancer cell," said Eddy S. Leman, phd, an instructor in the department of urology at Johns Hopkins Hospital. "The theory was that there must be a set of proteins that correlate with the changes that are seen when a cell becomes cancerous and are specific to colorectal cancer. With CCSA-2, we've found a biomarker that not only better detects the presence of colon cancer, but also may accurately indicate whether a patient has a high-risk precancerous condition."
Investigators analyzed 135 blood samples from patients who had undergone colonoscopies and had been diagnosed as normal (24%), having potentially precancerous growths (polyps: 19%; nonadvanced adenomas: 29%; advanced adenomas: 14%), or having colorectal cancer (14%). A control population of 125 people, made up of individuals with benign diseases or other types of cancer, was also included.
Dr. Leman and his colleagues previously demonstrated that the proteins colon cancer–specific antigen-3 and -4 (CCSA-3 and CCSA-4) can indicate the presence of colorectal cancer. The CCSA-2 immunoassay, however, is unique because in addition to detecting cancer, researchers noted a direct correlation between the level of biomarker in the blood and the size of adenomas: The higher the level of biomarker in the blood, the larger the growth; the highest levels of the biomarker indicated the presence of colorectal cancer. The researchers could thus distinguish patients who had colorectal cancer or advanced adenomas from those who had nonadvanced adenomas, low-risk polyps or normal colons. CCSA-2 also had a lower rate of false-positives than CCSA-3 and CCSA-4.
The test had an overall specificity of about 80% and a sensitivity of 91%. Based on these results, the next step is to validate the findings with larger groups of patients at a greater number of research institutions.
The goal of this research was to find an accurate, simple and noninvasive method for the early detection of colorectal cancer, similar to the prostate-specific antigen (PSA) blood test for prostate cancer. Other markers for colorectal cancer, including the fecal occult blood test and the carcinoembryonic antigen (CEA) test, are also found in patients with conditions other than cancer, and therefore lack specificity, resulting in false-positives in about 85% to 90% of cases for the fecal occult blood test and about 40% to 60% for the CEA test.
May Also Detect High-Risk Precancers
"Our goal when researching colorectal cancer biomarkers was to take a step back and try to understand the fundamental properties of the cancer cell," said Eddy S. Leman, phd, an instructor in the department of urology at Johns Hopkins Hospital. "The theory was that there must be a set of proteins that correlate with the changes that are seen when a cell becomes cancerous and are specific to colorectal cancer. With CCSA-2, we've found a biomarker that not only better detects the presence of colon cancer, but also may accurately indicate whether a patient has a high-risk precancerous condition."
Investigators analyzed 135 blood samples from patients who had undergone colonoscopies and had been diagnosed as normal (24%), having potentially precancerous growths (polyps: 19%; nonadvanced adenomas: 29%; advanced adenomas: 14%), or having colorectal cancer (14%). A control population of 125 people, made up of individuals with benign diseases or other types of cancer, was also included.
Dr. Leman and his colleagues previously demonstrated that the proteins colon cancer–specific antigen-3 and -4 (CCSA-3 and CCSA-4) can indicate the presence of colorectal cancer. The CCSA-2 immunoassay, however, is unique because in addition to detecting cancer, researchers noted a direct correlation between the level of biomarker in the blood and the size of adenomas: The higher the level of biomarker in the blood, the larger the growth; the highest levels of the biomarker indicated the presence of colorectal cancer. The researchers could thus distinguish patients who had colorectal cancer or advanced adenomas from those who had nonadvanced adenomas, low-risk polyps or normal colons. CCSA-2 also had a lower rate of false-positives than CCSA-3 and CCSA-4.
The test had an overall specificity of about 80% and a sensitivity of 91%. Based on these results, the next step is to validate the findings with larger groups of patients at a greater number of research institutions.
Targeting Metastatic Colorectal Cancer in 2008: A Long Way From 5-FU
Alexandra Pohl, MD
Postdoctoral Research Fellow
Wu Ahang, MD
Research Scientist
Yan Ning, MD, PhD
Research Scientist
Philipp C. Manegold, MD
Postdoctoral Research Fellow
Georg Lurje, MD
Postdoctoral Research Fellow
Heinz-Josef Lenz, MD, FACP
Professor of Medicine and Preventive Medicine
Division of Medical Oncology
Sharon A. Carpenter Laboratory
USC/Norris Comprehensive Cancer Center
Keck School of Medicine
Los Angeles, California
ABSTRACT: Colorectal cancer is one of the leading causes of cancer-related death worldwide, with almost 20% of all patients presenting with metastatic disease at the time of their diagnosis. The treatment regimens and options of metastatic colorectal cancer have significantly changed in the last 10 years, leading to an improvement of response rates to about 50%, progression-free survival of about 10 months, and overall survival reaching over 2 years. Beside US Food and Drug Administration approval of the cytotoxic agents irinotecan (Camptosar), oxaliplatin (Eloxatin), and capecitabine (Xeloda), the increasing understanding of molecular pathways that comprise the cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy. The biologic agent bevacizumab (Avastin), an inhibitor against vascular endothelial growth factor, and cetuximab (Erbitux) and panitumumab (Vectibix), monoclonal antibodies to epidermal growth factor receptor, have demonstrated their efficacy in clinical trials. This article reviews the mechanisms of action and possible markers of resistance, and summarizes data on the clinical efficacy of targeting agents.
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. With an estimated 153,760 newly diagnosed cases and 52,180 cancer-related deaths in the United States for 2007, it will remain the second leading cause of cancer-related death.[1] Almost 20% of these patients will present at the time of diagnosis with metastatic disease (mCRC).[2] For nearly 35 years, the standard chemotherapeutic regimen for treating metastatic colorectal carcinoma consisted only of fluorouracil (5-FU), with an overall response rate of 10% and a median survival of 10 months.[3,4] With the addition of leucovorin to 5-FU, the response rate improved to 23%.[5] During the past 10 years, with the addition of the cytotoxic agents irinotecan (Camptosar) and oxaliplatin (Eloxatin), a substantial change in response rate, progression-free survival, and overall survival occurred.
Furthermore, the increasing understanding of molecular pathways that characterize the cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy.[6] The biologic agents bevacizumab (Avastin) as an inhibitor against vascular endothelial growth factor (VEGF), and cetuximab (Erbitux), a monoclonal antibody to the epidermal growth factor receptor (EGFR), received US Food and Drug Administration (FDA) approval for the treatment of metastatic CRC.
This article reviews the mechanisms of action, promising new agents, and markers of resistance, and summarizes data on the clinical efficacy of targeting agents.
Targeting VEGF
The revelation that tumor growth is angiogenesis-dependent identified new targets for anticancer treatment.[7,8] The promotion of new blood vessel formation is a tightly regulated complex, working via secretion of proangiogenic factors by tumor cells and adjacent stromal cells that activate endothelial cells.[9] Among these, the most prominent proangiogenic factors are VEGF, platelet-derived growth factor (PDGF), and angiopoietin-1.[9]
VEGF is a heparin-binding glycoprotein family that includes six members, referred to as VEGF-A through VEGF-E and PDGF.[10] VEGF is the most critical regulator for the development of neoangiogenesis and functions as an endothelial cell mitogen. It increases microvascular permeability, induces endothelial cell migration and division, reprograms gene expression, promotes endothelial cell survival, prevents senescence, and induces angiogenesis and lymphangiosis.[11]
VEGF-A through -E and PDGF act through specific binding to three different cell membrane receptors (VEGFR-1, -2, and-3), which consist of an extracellular domain, a transmembrane domain, and an intracellular region containing a tyrosine kinase domain. Binding of a ligand to its receptor induces the activation of the tyrosine kinase domain, which initializes the activation of intracellular signaling transduction pathways that are involved in regulation of cellular proliferation and survival, such as the raf/MEK, ERK, AKT, mTOR, IGFIR, and PI3K pathways.[12]
High VEGF serum levels have been found to be associated with poor outcome in cancer patients.[13,14] Numerous angiogenesis inhibitors (eg, bevacizumab, sunitinib [Sutent], vatalanib) have been developed in the clinic as antiangiogenic approaches to therapy. Inhibition of VEGF-A by bevacizumab in patients with mCRC appears to be the most promising such strategy so far.
Postdoctoral Research Fellow
Wu Ahang, MD
Research Scientist
Yan Ning, MD, PhD
Research Scientist
Philipp C. Manegold, MD
Postdoctoral Research Fellow
Georg Lurje, MD
Postdoctoral Research Fellow
Heinz-Josef Lenz, MD, FACP
Professor of Medicine and Preventive Medicine
Division of Medical Oncology
Sharon A. Carpenter Laboratory
USC/Norris Comprehensive Cancer Center
Keck School of Medicine
Los Angeles, California
ABSTRACT: Colorectal cancer is one of the leading causes of cancer-related death worldwide, with almost 20% of all patients presenting with metastatic disease at the time of their diagnosis. The treatment regimens and options of metastatic colorectal cancer have significantly changed in the last 10 years, leading to an improvement of response rates to about 50%, progression-free survival of about 10 months, and overall survival reaching over 2 years. Beside US Food and Drug Administration approval of the cytotoxic agents irinotecan (Camptosar), oxaliplatin (Eloxatin), and capecitabine (Xeloda), the increasing understanding of molecular pathways that comprise the cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy. The biologic agent bevacizumab (Avastin), an inhibitor against vascular endothelial growth factor, and cetuximab (Erbitux) and panitumumab (Vectibix), monoclonal antibodies to epidermal growth factor receptor, have demonstrated their efficacy in clinical trials. This article reviews the mechanisms of action and possible markers of resistance, and summarizes data on the clinical efficacy of targeting agents.
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. With an estimated 153,760 newly diagnosed cases and 52,180 cancer-related deaths in the United States for 2007, it will remain the second leading cause of cancer-related death.[1] Almost 20% of these patients will present at the time of diagnosis with metastatic disease (mCRC).[2] For nearly 35 years, the standard chemotherapeutic regimen for treating metastatic colorectal carcinoma consisted only of fluorouracil (5-FU), with an overall response rate of 10% and a median survival of 10 months.[3,4] With the addition of leucovorin to 5-FU, the response rate improved to 23%.[5] During the past 10 years, with the addition of the cytotoxic agents irinotecan (Camptosar) and oxaliplatin (Eloxatin), a substantial change in response rate, progression-free survival, and overall survival occurred.
Furthermore, the increasing understanding of molecular pathways that characterize the cell cycle, apoptosis, angiogenesis, and invasion has provided novel targets in cancer therapy.[6] The biologic agents bevacizumab (Avastin) as an inhibitor against vascular endothelial growth factor (VEGF), and cetuximab (Erbitux), a monoclonal antibody to the epidermal growth factor receptor (EGFR), received US Food and Drug Administration (FDA) approval for the treatment of metastatic CRC.
This article reviews the mechanisms of action, promising new agents, and markers of resistance, and summarizes data on the clinical efficacy of targeting agents.
Targeting VEGF
The revelation that tumor growth is angiogenesis-dependent identified new targets for anticancer treatment.[7,8] The promotion of new blood vessel formation is a tightly regulated complex, working via secretion of proangiogenic factors by tumor cells and adjacent stromal cells that activate endothelial cells.[9] Among these, the most prominent proangiogenic factors are VEGF, platelet-derived growth factor (PDGF), and angiopoietin-1.[9]
VEGF is a heparin-binding glycoprotein family that includes six members, referred to as VEGF-A through VEGF-E and PDGF.[10] VEGF is the most critical regulator for the development of neoangiogenesis and functions as an endothelial cell mitogen. It increases microvascular permeability, induces endothelial cell migration and division, reprograms gene expression, promotes endothelial cell survival, prevents senescence, and induces angiogenesis and lymphangiosis.[11]
VEGF-A through -E and PDGF act through specific binding to three different cell membrane receptors (VEGFR-1, -2, and-3), which consist of an extracellular domain, a transmembrane domain, and an intracellular region containing a tyrosine kinase domain. Binding of a ligand to its receptor induces the activation of the tyrosine kinase domain, which initializes the activation of intracellular signaling transduction pathways that are involved in regulation of cellular proliferation and survival, such as the raf/MEK, ERK, AKT, mTOR, IGFIR, and PI3K pathways.[12]
High VEGF serum levels have been found to be associated with poor outcome in cancer patients.[13,14] Numerous angiogenesis inhibitors (eg, bevacizumab, sunitinib [Sutent], vatalanib) have been developed in the clinic as antiangiogenic approaches to therapy. Inhibition of VEGF-A by bevacizumab in patients with mCRC appears to be the most promising such strategy so far.
Sorting Out the Targeted-Agent Combinations for Colorectal Cancer
David H. Ilson, MD, PhD
Attending Physician and Member
Memorial Sloan-Kettering Cancer Center
New York, New York
Dr. Pohl and colleagues have provided a comprehensive and well written overview of the current landscape of targeted agents and chemotherapy in advanced colorectal cancer. It is clear that we have made significant progress in the past decade, first with the development of oxaliplatin (Eloxatin)/irinotecan (Camptosar) combination chemotherapy, which has translated into a doubling and tripling of antitumor response rates in metastatic disease, and a near doubling of median survival in advanced disease. The advent of more active therapy in metastatic disease has also translated into a significant survival improvement in stage III disease, with the application of fluorouracil (5-FU)/oxaliplatin–based adjuvant chemotherapy.
These advances have been further extended with increases in response and survival demonstrated for the addition of agents targeting either the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) pathways. Whether the benefits for these targeted agents will extend to patients treated in the adjuvant setting, after curative surgery, awaits evaluation in ongoing trials in the United States and Europe.
Optimizing Treatment
We now have defined standards of care for the treatment of advanced colorectal cancer extending out to third-line therapies. Optimal treatment of each patient with metastatic colorectal cancer, however, needs to be individualized. Bevacizumab (Avastin) has emerged as an important component of all first-line chemotherapy, but it remains unclear if similar benefits are accrued with oxaliplatin- vs irinotecan-based first-line therapy, given the failure of the NO16966 trial to demonstrate response or overall survival benefits for the addition of bevacizumab to first-line oxaliplatin-based chemotherapy in advanced disease—despite an improvement in progression-free survival. Because efficacy in NO16966 may have been undercut by early termination of patient therapy due to oxaliplatin toxicity, this study underscores the care that must be used in first-line treatment of patients with oxaliplatin combination chemotherapy.
In particular, cumulative neurologic toxicity can be avoided by employing the strategy defined by the OPTIMOX-1 trial, in which patients had planned discontinuation of oxaliplatin after six cycles but continued with maintenance therapy with leucovorin/5-FU. This approach reduced neurologic toxicity and did not compromise therapeutic efficacy, indicating that a maintenance strategy of 5-FU alone (with bevacizumab) may be employed, after initial therapy with both 5-FU and oxaliplatin. At a minimum, patients treated with oxaliplatin in combination with 5-FU and bevacizumab who develop oxaliplatin toxicity should continue on therapy with 5-FU and bevacizumab alone, to optimize the potential benefit from treatment. Actual changes in therapy (to irinotecan or cetuximab [Erbitux]-based treatment) should be made only for disease progression.
Exploring Other Combinations
Data from the Eastern Cooperative Oncology Group (ECOG) E3200 trial, as well as retrospective data from the Bevacizumab Regimens Investigation of Treatment Effects and Safety (BRiTE) registry, provide compelling data to continue bevacizumab into second-line therapy. However, continuation of a costly agent into salvage therapy without demonstration of benefit from clearly designed clinical trials raises economic considerations.
The ongoing Intergroup SO600 trial addresses this issue. After progression on 5-FU/oxaliplatin/bevacizumab therapy, patients are treated with irinotecan-based chemotherapy, with or without the continuation of bevacizumab into second-line therapy. This trial is somewhat problematic, however, because all patients receive cetuximab as part of first-use irinotecan, based on the assumption that earlier use of cetuximab in this setting is justified. Although the small BOND 2 trial indicated that bevacizumab added to either cetuximab alone, or cetuximab in combination with irinotecan, resulted in improved response and progression-free survival, this approach has not been validated in a larger data set.
A possible negative interaction between EGFR and VEGF therapy has been shown by the PACCE trial, which indicated that the addition of the EGFR-targeted agent panitumimab (Vectibix) to 5-FU/oxaliplatin/bevacizumab resulted in inferior progression-free and overall survival, as well as greater toxicity. As we often learn from phase III trials, more is not always better, and sometimes it is worse.
Attending Physician and Member
Memorial Sloan-Kettering Cancer Center
New York, New York
Dr. Pohl and colleagues have provided a comprehensive and well written overview of the current landscape of targeted agents and chemotherapy in advanced colorectal cancer. It is clear that we have made significant progress in the past decade, first with the development of oxaliplatin (Eloxatin)/irinotecan (Camptosar) combination chemotherapy, which has translated into a doubling and tripling of antitumor response rates in metastatic disease, and a near doubling of median survival in advanced disease. The advent of more active therapy in metastatic disease has also translated into a significant survival improvement in stage III disease, with the application of fluorouracil (5-FU)/oxaliplatin–based adjuvant chemotherapy.
These advances have been further extended with increases in response and survival demonstrated for the addition of agents targeting either the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) pathways. Whether the benefits for these targeted agents will extend to patients treated in the adjuvant setting, after curative surgery, awaits evaluation in ongoing trials in the United States and Europe.
Optimizing Treatment
We now have defined standards of care for the treatment of advanced colorectal cancer extending out to third-line therapies. Optimal treatment of each patient with metastatic colorectal cancer, however, needs to be individualized. Bevacizumab (Avastin) has emerged as an important component of all first-line chemotherapy, but it remains unclear if similar benefits are accrued with oxaliplatin- vs irinotecan-based first-line therapy, given the failure of the NO16966 trial to demonstrate response or overall survival benefits for the addition of bevacizumab to first-line oxaliplatin-based chemotherapy in advanced disease—despite an improvement in progression-free survival. Because efficacy in NO16966 may have been undercut by early termination of patient therapy due to oxaliplatin toxicity, this study underscores the care that must be used in first-line treatment of patients with oxaliplatin combination chemotherapy.
In particular, cumulative neurologic toxicity can be avoided by employing the strategy defined by the OPTIMOX-1 trial, in which patients had planned discontinuation of oxaliplatin after six cycles but continued with maintenance therapy with leucovorin/5-FU. This approach reduced neurologic toxicity and did not compromise therapeutic efficacy, indicating that a maintenance strategy of 5-FU alone (with bevacizumab) may be employed, after initial therapy with both 5-FU and oxaliplatin. At a minimum, patients treated with oxaliplatin in combination with 5-FU and bevacizumab who develop oxaliplatin toxicity should continue on therapy with 5-FU and bevacizumab alone, to optimize the potential benefit from treatment. Actual changes in therapy (to irinotecan or cetuximab [Erbitux]-based treatment) should be made only for disease progression.
Exploring Other Combinations
Data from the Eastern Cooperative Oncology Group (ECOG) E3200 trial, as well as retrospective data from the Bevacizumab Regimens Investigation of Treatment Effects and Safety (BRiTE) registry, provide compelling data to continue bevacizumab into second-line therapy. However, continuation of a costly agent into salvage therapy without demonstration of benefit from clearly designed clinical trials raises economic considerations.
The ongoing Intergroup SO600 trial addresses this issue. After progression on 5-FU/oxaliplatin/bevacizumab therapy, patients are treated with irinotecan-based chemotherapy, with or without the continuation of bevacizumab into second-line therapy. This trial is somewhat problematic, however, because all patients receive cetuximab as part of first-use irinotecan, based on the assumption that earlier use of cetuximab in this setting is justified. Although the small BOND 2 trial indicated that bevacizumab added to either cetuximab alone, or cetuximab in combination with irinotecan, resulted in improved response and progression-free survival, this approach has not been validated in a larger data set.
A possible negative interaction between EGFR and VEGF therapy has been shown by the PACCE trial, which indicated that the addition of the EGFR-targeted agent panitumimab (Vectibix) to 5-FU/oxaliplatin/bevacizumab resulted in inferior progression-free and overall survival, as well as greater toxicity. As we often learn from phase III trials, more is not always better, and sometimes it is worse.
Building on the Foundation of 5-FU to Treat Metastatic Colorectal Cancer
Cathy Eng, MD
Assistant Professor
Department of GI Medical Oncology
The University of Texas
M.D. Anderson Cancer Center
Houston, Texas
Pohl and colleagues have provided a concise overview of current treatment options for metastatic colorectal cancer (mCRC). However, the authors do not provide personal insights as to what direction this burgeoning field will take next. Within the past decade, an abundance of treatment options have emerged. With all available therapies, the median overall survival is reportedly 31.8 months.[1] Yet the 5-year overall survival of a patient with surgically unresectable disease is < 10%, and the duration of treatment is indefinite.
Recent therapeutic development has focused primarily on biologic therapy, which is thought to result in fewer toxicities but has largely remained unproven, since combined treatment with chemotherapy continues to provide the most effective approach for the mCRC patient. Furthermore, single-agent or combined biologic therapy alone has no greater efficacy and may in fact result in significant toxicities.[2] Hence, treatment for the mCRC patient often carries a risk of toxicity, financial burden, and possible psychological strain. We need to identify key predictive and prognostic markers to optimally benefit our patients.
Bevacizumab, FOLFOX, and XELOX
Two signal transduction pathways mentioned by the authors involve the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Pohl and colleagues highlight the role of the VEGF inhibitor bevacizumab (Avastin) in first- and second-line bevacizumab-naive patients and discuss the original registration trials of AVF2107 and ECOG 3200.[3,4] They briefly mention the results of NO16966 but do not attempt to explain the confounding data.[5,6]
The NO16966 study was originally created as a 2 × 2 international phase III trial to establish noninferiority of FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin [Eloxatin]) vs XELOX (capecitabine [Xeloda], oxaliplatin). With the subsequent US Food and Drug Administration (FDA) approval of bevacizumab, NO16966 was amended to be a 2 × 2 placebo-controlled trial with primary endpoints of noninferiority for FOLFOX vs XELOX and superiority of bevacizumab when added to chemotherapy; each primary endpoint was fulfilled. However, when evaluating the benefit of bevacizumab to the specific chemotherapy regimen, the hazard ratio (HR) for progression-free survival was superior only for the XELOX regimen (7.4 vs 9.3 months; HR = 0.77 [97.5% confidence interval (CI) = 0.63–0.94]; P = .0026) in comparison to the FOLFOX regimen (8.6 vs 9.4 months; HR = 0.89 [97.5% CI = 0.73–1.08]; P = .1871). The preliminary findings from this trial resulted in significant concerns about bevacizumab in combination with FOLFOX.
The authors suggest that the response rate and overall survival are consequences of the discontinuation of all chemotherapy, but further elaboration is needed. Other reasons account for this outcome: First, the superior hazard ratio for XELOX/bevacizumab may be a result of the longer progression-free survival in the control arm of FOLFOX vs XELOX resulting in a greater measurable difference. Second, only 29% of bevacizumab patients received treatment until disease progression. Final details of NO16966 are to be published at a later date.
Other Anti-VEGF Therapies
Anti-VEGF therapies discussed by the authors include the oral tyrosine kinase inhibitors (TKI) sunitinib (Sutent) and vatalanib. Sunitinib is a multitargeted TKI currently in phase I/ II development for the treatment of mCRC. Pohl and coauthors state that the reason for the efficacy of sunitinib in metastatic renal cell carcinoma (mRCC), as opposed to less impressive results in mCRC, is unknown. However, they fail to mention the known association between anti-VEGF therapy and mRCC. The transcription factor known as hypoxia-inducible factor (HIF-1α) is normally degraded by the von Hippel-Landau (VHL) protein. However, in the presence of the VHL mutation, HIF-1α degradation is inhibited, resulting in increased VEGF expression, which is likely to account for the single-agent activity of sunitinib and bevacizumab.
The authors suggest that there is a future role for the oral VEGF receptor inhibitor vatalanib in mCRC. Furthermore, high levels of lactate dehydrogenase (LDH) correlated with progression-free survival. However, vatalanib has been extensively evaluated in the first- and second-line settings, failing to fulfill the primary endpoint of progression-free survival. Furthermore, correlation with elevated LDH and progression-free survival was noted on post ad hoc analysis. Elevated LDH levels are nonspecific and not classically viewed as a prognostic indicator in mCRC. Hence, it is unlikely that vatalanib will have a future role in mCRC.
Assistant Professor
Department of GI Medical Oncology
The University of Texas
M.D. Anderson Cancer Center
Houston, Texas
Pohl and colleagues have provided a concise overview of current treatment options for metastatic colorectal cancer (mCRC). However, the authors do not provide personal insights as to what direction this burgeoning field will take next. Within the past decade, an abundance of treatment options have emerged. With all available therapies, the median overall survival is reportedly 31.8 months.[1] Yet the 5-year overall survival of a patient with surgically unresectable disease is < 10%, and the duration of treatment is indefinite.
Recent therapeutic development has focused primarily on biologic therapy, which is thought to result in fewer toxicities but has largely remained unproven, since combined treatment with chemotherapy continues to provide the most effective approach for the mCRC patient. Furthermore, single-agent or combined biologic therapy alone has no greater efficacy and may in fact result in significant toxicities.[2] Hence, treatment for the mCRC patient often carries a risk of toxicity, financial burden, and possible psychological strain. We need to identify key predictive and prognostic markers to optimally benefit our patients.
Bevacizumab, FOLFOX, and XELOX
Two signal transduction pathways mentioned by the authors involve the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Pohl and colleagues highlight the role of the VEGF inhibitor bevacizumab (Avastin) in first- and second-line bevacizumab-naive patients and discuss the original registration trials of AVF2107 and ECOG 3200.[3,4] They briefly mention the results of NO16966 but do not attempt to explain the confounding data.[5,6]
The NO16966 study was originally created as a 2 × 2 international phase III trial to establish noninferiority of FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin [Eloxatin]) vs XELOX (capecitabine [Xeloda], oxaliplatin). With the subsequent US Food and Drug Administration (FDA) approval of bevacizumab, NO16966 was amended to be a 2 × 2 placebo-controlled trial with primary endpoints of noninferiority for FOLFOX vs XELOX and superiority of bevacizumab when added to chemotherapy; each primary endpoint was fulfilled. However, when evaluating the benefit of bevacizumab to the specific chemotherapy regimen, the hazard ratio (HR) for progression-free survival was superior only for the XELOX regimen (7.4 vs 9.3 months; HR = 0.77 [97.5% confidence interval (CI) = 0.63–0.94]; P = .0026) in comparison to the FOLFOX regimen (8.6 vs 9.4 months; HR = 0.89 [97.5% CI = 0.73–1.08]; P = .1871). The preliminary findings from this trial resulted in significant concerns about bevacizumab in combination with FOLFOX.
The authors suggest that the response rate and overall survival are consequences of the discontinuation of all chemotherapy, but further elaboration is needed. Other reasons account for this outcome: First, the superior hazard ratio for XELOX/bevacizumab may be a result of the longer progression-free survival in the control arm of FOLFOX vs XELOX resulting in a greater measurable difference. Second, only 29% of bevacizumab patients received treatment until disease progression. Final details of NO16966 are to be published at a later date.
Other Anti-VEGF Therapies
Anti-VEGF therapies discussed by the authors include the oral tyrosine kinase inhibitors (TKI) sunitinib (Sutent) and vatalanib. Sunitinib is a multitargeted TKI currently in phase I/ II development for the treatment of mCRC. Pohl and coauthors state that the reason for the efficacy of sunitinib in metastatic renal cell carcinoma (mRCC), as opposed to less impressive results in mCRC, is unknown. However, they fail to mention the known association between anti-VEGF therapy and mRCC. The transcription factor known as hypoxia-inducible factor (HIF-1α) is normally degraded by the von Hippel-Landau (VHL) protein. However, in the presence of the VHL mutation, HIF-1α degradation is inhibited, resulting in increased VEGF expression, which is likely to account for the single-agent activity of sunitinib and bevacizumab.
The authors suggest that there is a future role for the oral VEGF receptor inhibitor vatalanib in mCRC. Furthermore, high levels of lactate dehydrogenase (LDH) correlated with progression-free survival. However, vatalanib has been extensively evaluated in the first- and second-line settings, failing to fulfill the primary endpoint of progression-free survival. Furthermore, correlation with elevated LDH and progression-free survival was noted on post ad hoc analysis. Elevated LDH levels are nonspecific and not classically viewed as a prognostic indicator in mCRC. Hence, it is unlikely that vatalanib will have a future role in mCRC.
Nonprofit Group Formed to Promote Safe Colorectal Cancer Screenings and Care
The National Coalition for Quality Colorectal Cancer Screening and Care, a 501(c)(6) not-for-profit association, recently announced the formation of a broad-based coalition dedicated to reducing the incidence of colorectal cancer through educational programs aimed at promoting colonoscopy screening and care options for patients in a safe and comfortable setting.
The Coalition, comprised of gastroenterologists, surgeons, primary care physicians, oncologists, anesthesiologists, patient advocacy groups, and concerned individuals, will support a sustained effort of advocacy, collaboration, research, and education geared toward key stakeholders, including the public.
Coalition Goals
"A primary goal of the new organization is to promote evidence-based standards of care in a variety of medical practices that yield better clinical outcomes," notes Steven J. Morris, MD, facp, facg, chairperson of the Coalition and CEO of Atlanta Gastroenterology Associates. In addition, Dr. Morris adds that "the Coalition wants to ensure that quality is never compromised by minimizing physician input or by the arbitrary efforts of insurers to save dollars at the expense of human lives."
Stanford Plavin, MD, vice chairperson of the Coalition and managing partner of Ambulatory Anesthesia of Atlanta, states: "It is tragic that many people avoid colorectal cancer screening due to fear or anxiety. Colorectal cancer screening can be achieved in an effective manner without discomfort. I encourage patients and providers to join us in this most important effort to maintain all effective options for colorectal cancer screening that will enable us to achieve higher screening rates and make a positive impact on cancer survival."
"In order to achieve a higher colorectal cancer screening rate, physicians must be able to choose optimal forms of sedation to encourage patients to undergo screening colonoscopies," elaborates Dr. Morris. He observes further that "75% of new colon cancer cases occur in persons with no known risk factors, regular colorectal cancer screenings are crucial to the prevention, early detection, and successful treatment of this disease."
The Coalition will work from a broad perspective to establish public policy consensus on the importance of physician and patient choice necessary for sustained improvement in colorectal cancer screening rates. One of the first written comments submitted by the Coalition relates to a proposed medical policy by Blue Cross and Blue Shield of Tennessee regarding the use of anesthesia services for routine gastrointestinal endoscopy.
To learn more about the activities of the National Coalition for Quality Colorectal Cancer Screening and Care, visit www.preventingcolorectalcancer.org, or contact the Coalition toll-free at (866) 461-9296 or at info@preventingcolorectalcancer.org.
The Coalition, comprised of gastroenterologists, surgeons, primary care physicians, oncologists, anesthesiologists, patient advocacy groups, and concerned individuals, will support a sustained effort of advocacy, collaboration, research, and education geared toward key stakeholders, including the public.
Coalition Goals
"A primary goal of the new organization is to promote evidence-based standards of care in a variety of medical practices that yield better clinical outcomes," notes Steven J. Morris, MD, facp, facg, chairperson of the Coalition and CEO of Atlanta Gastroenterology Associates. In addition, Dr. Morris adds that "the Coalition wants to ensure that quality is never compromised by minimizing physician input or by the arbitrary efforts of insurers to save dollars at the expense of human lives."
Stanford Plavin, MD, vice chairperson of the Coalition and managing partner of Ambulatory Anesthesia of Atlanta, states: "It is tragic that many people avoid colorectal cancer screening due to fear or anxiety. Colorectal cancer screening can be achieved in an effective manner without discomfort. I encourage patients and providers to join us in this most important effort to maintain all effective options for colorectal cancer screening that will enable us to achieve higher screening rates and make a positive impact on cancer survival."
"In order to achieve a higher colorectal cancer screening rate, physicians must be able to choose optimal forms of sedation to encourage patients to undergo screening colonoscopies," elaborates Dr. Morris. He observes further that "75% of new colon cancer cases occur in persons with no known risk factors, regular colorectal cancer screenings are crucial to the prevention, early detection, and successful treatment of this disease."
The Coalition will work from a broad perspective to establish public policy consensus on the importance of physician and patient choice necessary for sustained improvement in colorectal cancer screening rates. One of the first written comments submitted by the Coalition relates to a proposed medical policy by Blue Cross and Blue Shield of Tennessee regarding the use of anesthesia services for routine gastrointestinal endoscopy.
To learn more about the activities of the National Coalition for Quality Colorectal Cancer Screening and Care, visit www.preventingcolorectalcancer.org, or contact the Coalition toll-free at (866) 461-9296 or at info@preventingcolorectalcancer.org.
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