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Experts weigh in on adjuvant chemotherapy for stage II colon cancer
Use of adjuvant therapy in patients with stage II colon cancer remains controversial.
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Determining whether a patient with stage II colon cancer should receive adjuvant therapy is far from a simple decision — for the clinician or the patient. Choosing a therapeutic path for a patient with stage II disease presents complicated issues.
“From my perspective, patients with stage II colon cancer are among the most complicated initial consultations,” said Leonard B. Saltz, MD, professor of medicine at the Weill Medical College of Cornell University and attending physician at Memorial Sloan-Kettering Cancer Center. “With stage I disease, everyone agrees that no adjuvant therapy is indicated and we routinely follow patients expectantly. And all clinicians agree that patients with stage III colon cancer should undergo adjuvant therapy. Stage II is that complex area where the data are inconclusive, and we’re really forced to individualize treatment and think carefully,” Saltz told HemOnc Today.
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Photo by Memorial Sloan-Kettering Cancer Center |
“In general, for stage II colon cancer, there is no definitive recommendation regarding initiation of adjuvant chemotherapy,” said Cathy Eng, MD, assistant professor of gastrointestinal medical oncology at The University of Texas M.D. Anderson Cancer Center. A dominant stance does not exist because the existing trial data are inconclusive and insufficient for the high-risk stage II patient.
“Any adjuvant trial requires thousands of patients to demonstrate a small improvement in disease-free survival,” Eng said, adding that it is particularly challenging to enroll a strictly stage II patient population.
“If you have an 80% curability rate without doing anything, you have to be clear that you are not doing an unsafe intervention,” said Alan Venook, MD, professor of clinical medicine at the University of California, San Francisco. “You have to think twice about trying new agents in clinical trials, because if you have complications, then you haven’t done the patient any favors.”
The last study to assess strictly stage II patients was in 1999: the IMPACT B2 study, or the International Multicentre Pooled Analysis of B2 Colon Cancer Trials. IMPACT B2 researchers conducted a pooled analysis of 1,016 patients who were randomly assigned to 5-FU/leucovorin or observation. After a median follow-up of 5.75 years, patients receiving 5-FU/LV did not experience a statistically significant increase in event-free (HR=0.83; 90% CI, 0.72-1.07) or overall survival (HR= 0.86; 90% CI, 0.68-1.07). Therefore, the data did not support the routine use of adjuvant 5-FU/LV in all patients with stage II colon cancer, the researchers reported in The Journal of Clinical Oncology.
“We know that it is very difficult to conduct a large enough study to show differences in no treatment vs. treatment in stage II patients,” Saltz said. “The QUASAR study has suggested a modest but statistically significant difference in outcome for patients who receive 5-FU–based chemotherapy.”
“After median follow-up of about five and a half years, the researchers found that the relative risk for recurrence was 0.78 (P=.001) and the relative risk for death from 5-FU-based chemotherapy vs. observation alone was 0.82 with a P-value of .008,” Eng said. “The researchers concluded that chemotherapy with 5-FU and LV could improve survival. So again, it’s not definitive.”
Trial data pose new questions
The QUASAR study included some patients with rectal cancer and stage III disease in addition to the majority with stage II disease. Saltz considers the results of the trial meaningful, regardless of the mixed population. “I don’t think there were enough stage III patients to be the drivers of the finding. It’s pretty convincing. Most studies that have failed to show a benefit have simply been underpowered to address the question,” he said.
Another study that further examined the use of adjuvant chemotherapy in stage II and III patients was the MOSAIC trial. Aimery de Gramont, MD, presented the six-year results at the 43rd American Society of Clinical Oncology Annual Meeting in 2007. De Gramont and colleagues randomly assigned 2,246 patients to 5-FU–based chemotherapy or FOLFOX4 (5-FU/LV plus oxaliplatin). Sixty percent of the patients had stage III colon cancer, and the remaining 40% had stage II disease. There was a nonsignificant 3.8% improvement in disease-free survival (HR=0.84; 95% CI, 0.62-1.14) among all stage II patients receiving FOLFOX vs. 5-FU/LV. This was, however, a trial of three drugs vs. two; there was no observation-only arm.
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“When you are talking about a patient population receiving adjuvant chemotherapy, we are well aware that oxaliplatin has some significant toxicities,” Eng said, referring to the FOLFOX regimen employed in the MOSAIC trial. “The development of peripheral neuropathy is a difficult issue, so for a general stage II patient, there is no additional benefit, and we would likely not provide adjuvant FOLFOX in that setting.” De Gramont came to the same conclusion, stating that the average-risk stage II patient does not benefit from oxaliplatin.
“If you have a high-risk patient, that is a different story,” Eng continued. “These patients probably do derive benefit.” In the MOSAIC trial, de Gramont and colleagues demonstrated a significant 7.2% improvement in disease-free survival (HR=0.74; 95% CI, 0.52-1.06) associated with FOLFOX compared with 5-FU/LV.
Saltz concurred with de Gramont’s conclusions. “My routine practice is to offer FOLFOX therapy to high-risk stage II patients and to favor 5-FU/LV alone or capecitabine for average-risk stage II patients.”
According to Eng, the QUASAR and MOSAIC trials are not empirically changing clinical practice. “The MOSAIC and QUASAR studies have brought the controversy back into light and we need to recruit these patients into clinical trials,” she said.
This is a controversy that Venook, a HemOnc Today Editorial Board member, stressed is not to be taken lightly. “The controversy is that it is taking 100 patients to help a couple, and this treatment is not without risk,” he said.
Saltz, however, believes that the benefit of adjuvant therapy is worth the apparent risks. “I tell most of my patients that I’m convinced that there is a small, but real, benefit to therapy. If a person has a disease for which there may be 3% survival benefit, 97 out of 100 patients aren’t going to get benefit. The majority of those 97 will do well in spite of not receiving treatment, and a small percentage of those 97 are going to experience disease recurrence even if they are treated. But for three out of 100, it makes all the difference,” Saltz said.
Current recommendations
Al B. Benson III, MD, associate director for clinical investigations at the Robert H. Lurie Comprehensive Cancer Center and professor of medicine Northwestern University Feinberg School of Medicine in Chicago, co-chaired the ASCO panel that authored the current recommendations. In The Journal of Clinical Oncology, the panel concluded that “direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. … The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences.”
“The ASCO guidelines basically confirm what the QUASAR trial states, which is you should discuss it, but it is a very gray area,” Eng said.
“Every stage II patient deserves a medical oncology consultation for frank discussion of the risks and benefits, pros and cons of receiving adjuvant therapy or not,” Saltz said.
“Prior studies have demonstrated that the general population of stage II patients does not appear to derive any additional benefit from the use of 5-FU earlier on,” Eng said. “However, there are high-risk stage II patients. And those are the patients you want to consider for adjuvant therapy. Patients with high-risk stage II disease are those who present with poorly differentiated histology, T4 disease, bowel perforation, lymphovascular invasion or suboptimal lymph-node dissection,” she explained. “Ideally, most surgeons would prefer that patients have at least 14 lymph nodes dissected.”
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Ongoing Research Effort
“Certainly, ASCO strongly supports clinical trial participation,” Benson told HemOnc Today. “One of our challenges is how do we best define risk and benefit from adjuvant therapy. Again, we do not have solid data to do that at this time.” Benson hopes that his currently enrolling venture, the ECOG 5202 study, will be a step in the right direction. Benson and colleagues plan to enroll 3,600 patients; current accrual is more than 1,100.
“This trial is unique because it is an attempt to use molecular biology to determine a treatment decision for patients,” he began. “These particular markers were chosen based on a number of retrospective analyses of patients who received 5-FU. The data suggested that 18q LOH [heterozygosity of chromosome 18q] and MSI [microsatellite instability] can be strong prognostic factors in stage II colon cancer, and we decided to use these factors to determine treatment.
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“The low-risk patients would be assigned to observation. If our hypothesis is correct, the survivorship for this group would be nearly 90%. … The high-risk individuals, based on 18q LOH/MSI status, would be randomized to receive FOLFOX or FOLFOX with bevacizumab (Avastin, Genentech),” Benson said. “If the trial confirms that these molecular features can demonstrate the low-risk population convincingly, that would be a huge step forward.” Over the long term, Benson and colleagues hope to study additional molecular factors and integrate pathologic factors to conduct multivariate analyses to see if different patterns emerge based on various factors. “In addition, we hope to create microarrays to conduct further genetic profile analyses for these patients,” he said.
Venook agreed that the ECOG 5202 study is a conceptually important trial and hopes that microarray initiatives will eventually be put into practice. “There are publications looking at microarrays that have important signatures. In the next five to 10 years, I would expect the technology to evolve to give us a handle on stage II colon cancer being a basket of entities that are subdivided based on their molecular signature. … Furthermore, if you determine that someone has a prognosis that you would use chemotherapy, the next step would be further analyzing the tumor to determine which chemotherapy,” he said.
Axel Grothey, MD, of the Mayo Clinic in Rochester, Minnesota, echoed this notion. “These molecular markers [18q LOH and MSI] came from analyses of trials conducted in the 1980s and 1990s. … We’ll probably go beyond these molecular markers and hope to see what’s happening in breast cancer already with array gene profiling. It is probably a better tool to identify some high-risk and low-risk features than just looking at two markers. It takes some time before these biomarkers can make it into clinical practice.”
Current state of care
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Though it never hurts to predict future directions, current disease strategies are highly relevant to clinicians who manage these difficult-to-treat patients. “In the end, if a patient is willing to undergo six months of therapy for a marginal benefit, I am more than happy to accommodate this patient and treat,” Grothey said. “This individualized medicine is not only assessing markers and individualized therapy, but sitting down with a patient, identifying risk and goals, and then developing a strategy.”
“I’m shifting my thinking as time goes on,” said Saltz. “If you asked me 10 years ago whether I treated most stage II patients, my answer was no. If you ask me today, my answer is yes. I am aware of the relatively modest benefit that we’re talking about, but I think it’s appropriate.
“If you look at what is very comfortably accepted practice in the breast cancer community — treating with far more aggressive chemotherapy with more side effects for very small 2% and 3% survival benefits — it’s absolutely routine, and it’s done without question,” Saltz continued. “Frankly, we’re catching up. Historically, there is a sense of therapeutic nihilism in gastrointestinal oncology — that gastrointestinal tumors are chemoresistant, that all we have is 5-FU, and that treatment is sort of pointless. Those are outdated thoughts.”
Syma Iqbal, MD, assistant professor of clinical medicine at the University of Southern California, Los Angeles, echoed Saltz’s view. “In the breast cancer community, it is actually standard of care to administer chemotherapy for a 2% to 5% benefit. But in colon cancer, the recommendation is to have a discussion with a patient to see if they are willing to accept that benefit. … To go over the risks and benefits of treatment with the absolute benefit at this point can be complicated for a patient to internalize.
“When I give treatment for stage II disease, I talk about all of the studies. If a patient elects to be treated, I lean toward treating with FOLFOX. There are no data that actually support giving combination chemotherapy in a stage II patient,” Iqbal said. She refers to the MOSAIC trial, which demonstrated a nonsignificant benefit with FOLFOX vs. standard chemotherapy.
According to Saltz, if clinicians do not recognize these positive trends, no one stands to benefit. “In the current adjuvant environment where we have multiple drugs, relatively high activity levels, and a significant potential to benefit people with chemotherapy, we have to reset our thermostat and recognize that small victories are better than no victory at all.” – by Rebekah Cintolo
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Do current data support adjuvant treatment for stage II colon cancer?
For more information:
- De Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4007.
- Benson III AB, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408-3419.
- Gray RG, Barnwell J, Hills R, et al. QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. Proc Am Soc Clin Oncol. 2004;22:14S (abstr 3501).
- International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999;17:1356-1363.