Adjuvant Systemic Therapy for Colon Cancer

Colorectal Cancer Update 2005 (2)

DR JOHN MARSHALL: It is interesting that we tend to back away from adjuvant therapy in patients who have a lower risk, when it may be more appropriate to do exactly the opposite. I think that those are the patients with whom we should be the most aggressive. In the Stage II subset analysis of the MOSAIC study, the patients who received FOLFOX had a three-year disease-free survival of 87 percent. To my knowledge, that’s the highest number ever reported for Stage II patients.

In breast cancer we are accustomed to utilizing adjuvant chemotherapy for relatively small gains, meaning two to four percent absolute gain. I believe we should be equally aggressive when treating patients with colon cancer, and we should incorporate these adjuvant therapies as often as possible. By adopting these new therapies, we’re going to cure more patients of this disease.

Interview, August 2005

DR LOVE: What are your thoughts on these patterns of data related to the risk of recurrence and the use of adjuvant chemotherapy in breast and colon cancer (Figure 7)?

DR AXEL GROTHEY: This is very interesting and reflects what we see in practice, particularly in terms of the 10 percent risk of recurrence. When the categories of very likely and more likely than unlikely are combined, more than 65 percent of the breast cancer patients would receive chemotherapy, while approximately 40 percent of the colon cancer patients would receive chemotherapy. That is a significant difference, and this is relevant.

DR LOVE: In a recent colorectal cancer think tank, Peter Ravdin mentioned that the number of people utilizing the colon cancer Adjuvant! model is about one tenth the number who utilize the breast cancer Adjuvant! model.

What was your take in this survey on the number of oncologists utilizing the Adjuvant! model for both breast and colon cancer risk estimates?

DR GROTHEY: I thought that it was very interesting that the oncologists appear to be using the models so much more in breast cancer. I believe that the oncologists’ predictions for recurrence and mortality in the adjuvant setting for Stage II and Stage III patients are also quite accurate (Figures 10-12).

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DR LOVE: According to the survey data, adverse risk factors such as angiolymphatic invasion, obstruction and microsatellite instability have significant impacts on whether or not doctors choose to recommend chemotherapy (Figures 10- 12); do you support this observation?

DR GROTHEY: Yes, if an adverse risk factor can be identified, it clearly shifts toward the recommendation of chemotherapy. That is exactly what has happened with this data — risk factors were identified and chemotherapy was recommended.

I was surprised that the molecular risk factor — the microsatellite-stable patient with 18q deletion — actually shifted practice as much as some of the clinical factors.

Furthermore, I was a little bit concerned about the magnitude of difference in the shift toward treating for an obstructing tumor compared to treatment for a tumor that had an inadequate sample size of lymph nodes — zero of eight lymph nodes.

The awareness of the importance of lymph-node dissection, which is a very, very strong prognostic factor, is not as large as it should be. That factor is as important as obstruction or other clinical risk factors.

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Colorectal Cancer MTP September 2005

DR LOVE: In general, for Stage II disease, which regimen do you generally utilize when you treat a patient in their sixties?

DR GEORGE FISHER: For patients in good health, I would have no real concerns about the safety of administering chemotherapy. It is a question of how much discomfort that person would be willing to tolerate for six months. In a patient with high-risk disease who wanted to receive a regimen that offered the highest absolute benefit, then that would be a FOLFOX regimen. And if that person was shy of doctors’ visits, IVs, needles, 48-hour infusions, or had catheter contraindications, I believe that CAPOX is certainly a suitable alternative.

Colorectal Cancer Update 2005 (4)

DR LOVE: What are your thoughts about adjuvant chemotherapy for patients with Stage II colon cancer?

DR ROBERT DIASIO: Typically, patients with no evidence of lymph node involvement, no matter how deeply the tumor appears to extend, do not receive chemotherapy for Stage II disease. However, increasing data suggest that some patients with penetration of the intestinal wall, who would not have been treated in the past, may benefit from chemotherapy.

The ASCO committee published an aggressive position paper stating that perhaps Stage II patients should be offered adjuvant therapy. While we don’t have any convincing objective data to validate the use of adjuvant therapy in Stage II disease, subsets within that population may benefit. The ultimate proof of the benefit in such patients will come from ongoing adjuvant studies.

One reason it may be difficult to demonstrate a benefit from adjuvant therapy in Stage II disease is that fewer events occur. However, the MOSAIC trial and some of the earlier Intergroup studies have suggested certain patients can benefit from chemotherapy.

Colorectal Cancer Update 2005 (3)

DR LOVE: In general, what is your approach to adjuvant therapy in patients with high-risk Stage II colon cancer?

DR AIMERY de GRAMONT: I would certainly offer adjuvant FOLFOX to patients with Stage III or high-risk Stage II disease.

In patients with a very good prognosis, the potential risks and benefits of an adjuvant regimen must be weighed in a discussion that should occur between the patient and physician.

We presented data from the patients with Stage II disease in the MOSAIC adjuvant trial. In an analysis of the patients with high-risk Stage II disease (eg, T4, bowel obstruction, tumor perforation, venous invasion or fewer than 10 lymph nodes analyzed), the difference in disease-free survival in favor of FOLFOX was over five percent.

In patients with high-risk Stage II disease, adjuvant FOLFOX should be considered.

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Colorectal Cancer Update 2005 (3)

DR PAULO HOFF: For those patients who present with Stage II disease, the decision about the use of adjuvant chemotherapy is complicated. Obviously, we have to discuss the potential benefits and toxicities of chemotherapy. I tend to suggest adjuvant chemotherapy more strongly if their disease has a high-risk feature (eg, obstruction, perforation or lymphovascular invasion).

Once I explain all the options, even some patients in whom I would prefer to use FOLFOX surprisingly ask to receive capecitabine. They feel attracted to the oral agent. Also, for patients with severe comorbid conditions or the very frail elderly patients, I tend to use adjuvant capecitabine instead of FOLFOX.

Colorectal Cancer Update 2005 (4)

DR LOVE: Do you think that capecitabine can be utilized in the adjuvant setting as a substitute for 5-FU?

DR PHILIP PHILIP: In situations in which a single-agent fluoropyrimidine is being used or contemplated, capecitabine should be used. I don’t believe at this time that, if given the option, a patient will opt for intravenous treatment unless an issue arises regarding who will pay for the capecitabine. Capecitabine should be the drug of choice for patients who will receive a single-agent fluoropyrimidine because it’s easier to administer and doesn’t interfere much with the patient’s daily routine. It has side effects, and we have to pay attention to them. But overall, it’s a treatment that patients will prefer.

In which patients should we use single-agent therapy? In patients with Stage III disease, the data on adjuvant FOLFOX have completely transformed my practice. I use FOLFOX in patients with Stage III disease, except in those who refuse the combination, cannot take a neurotoxic drug or are too old for such a combination. Those patients who don’t receive adjuvant FOLFOX receive single-agent capecitabine. The next question becomes, Can we combine capecitabine with oxaliplatin? Adjuvant CAPOX is still experimental, and it should be used as part of a clinical trial. We still have to wait for the head-to-head comparison with FOLFOX.

Interview, August 2005

DR LOVE: In general, what adjuvant chemotherapy would you be most likely to recommend to a patient with Stage III colon cancer who had a T2 tumor and one of 25 positive lymph nodes?

DR GROTHEY: I would recommend FOLFOX for a 38-, 65- or 75-year-old patient. In an 85-year-old patient I would more than likely utilize capecitabine.

DR LOVE: The survey shows that in the adjuvant setting for the 85-yearold patient with lower-risk disease, the frequency of using 5-FU monotherapy is approximately the same as the amount of capecitabine being given.

DR GROTHEY: Yes, and this is happening based on extensive experience with 5-FU regimens and the fact that the dosing of capecitabine has not been completely established in the United States. There is concern about the toxicity associated with capecitabine. However, there is clear advantage with capecitabine in terms of convenience. There’s no doubt about that. I would prefer to see more patients on capecitabine than on bolus 5-FU.

DR LOVE: What therapy should be recommended to a Stage III patient who is concerned about oxaliplatin-associated neuropathy and would prefer not to take an oxaliplatin-containing regimen?

DR GROTHEY: In that situation capecitabine should be recommended. However, most patients can tolerate some oxaliplatin. Cumulative toxicity does not occur within the first three or four months. Whatever regimen you choose to combine with oxaliplatin — whether you utilize FLOX or FOLFOX — there is evidence that a little bit of oxaliplatin is better that none. We assume that the same holds true for combining oxaliplatin with capecitabine-based regimens.

Colorectal Cancer Update 2005 (5)

DR LOVE: What is your opinion of the NSABP-C-07 trial comparing Roswell Park 5-FU versus FLOX?

DR GROTHEY: The results from NSABP-C-07 were more positive than most experts expected. NSABP-C-07 randomly assigned patients with Stage II or III colon cancer to receive the Roswell Park regimen of 5-FU/leucovorin (three cycles of an eight-week regimen) with or without oxaliplatin 85 mg/m2 administered at weeks one, three and five (FLOX).

Compared to the FOLFOX4 regimen used in the MOSAIC adjuvant trial, the FLOX regimen in NSABP-C-07 had the same duration of therapy but a lower cumulative dose of oxaliplatin (765 mg/m2 versus 1,020 mg/m2). Although the dose intensity of oxaliplatin was lower and a bolus 5-FU regimen was used as the backbone for the FLOX regimen, they found an increase in the three-year disease-free survival that was almost identical to that in the MOSAIC trial: about a five percent absolute increase. This suggests that the addition of oxaliplatin to any 5-FU-based regimen is of benefit in the adjuvant setting. Secondly, it shows we probably have two alternatives to choose from: FOLFOX or FLOX.

Colorectal Cancer Update 2005 (3)

DR LOVE: How has the X-ACT trial impacted your utilization of capecitabine in the adjuvant setting?

DR MICHAEL O’CONNELL: The X-ACT trial established the principle that oral chemotherapy could be effective in the adjuvant setting, compared to intravenous chemotherapy. Capecitabine offers the patient the advantage of not requiring IV injections. The dosage level that was used is a bit higher than most oncologists in the United States have been able to administer to their patients, and it raises some interesting questions about possible pharmacogenetic differences between the populations in Europe and the United States.

I believe the data are very compelling and suggest that there might be an advantage for capecitabine over the Mayo Clinic method of administering 5-FU and leucovorin in the primary endpoint of disease-free survival, which practically reached statistical significance in favor of the capecitabine. The primary goal of the study was to demonstrate noninferiority. They certainly accomplished that. I now believe that in clinical practice, for a patient in whom fluoropyrimidine therapy is considered appropriate, capecitabine is a viable option.

Colorectal Cancer Update 2004 (5)

DR HOCHSTER: The X-ACT trial was a comparison of adjuvant capecitabine to the Mayo Clinic 5-FU regimen. We now know adjuvant capecitabine is equal to or perhaps slightly better than the Mayo Clinic regimen. I think that’s a very important observation, and adjuvant capecitabine is a reasonable option for a well-educated patient who can be relied upon to take pills on a regular basis.

This requires a highly motivated patient who will call you or come in when they start to develop diarrhea, handfoot syndrome or any of the toxicities. I don’t have a hesitation to use adjuvant capecitabine, based on the clinical data at this point in the adjuvant setting.

Colorectal Cancer Update 2005 (3)

DR LOVE: In general, what is your treatment approach in the adjuvant setting for a patient with Stage III colon cancer?

DR LEONARD SALTZ: I’m pretty comfortable with the MOSAIC data, so I generally use FOLFOX in the adjuvant setting for patients with Stage III disease. When I have a patient who is particularly dependent on their fine-motor skills, I discuss with them whether we want to include oxaliplatin in their treatment because the neurotoxicity might compromise their quality of life. If I’m concerned about a patient’s ability to tolerate combination chemotherapy, I might consider using one of several schedules of 5-FU/leucovorin or capecitabine.

Colorectal Cancer Update 2005 (1)

DR CHRIS TWELVES: In the MOSAIC trial, the addition of oxaliplatin resulted in a significant reduction in the risk of recurrence in the adjuvant setting.

I believe the MOSAIC data are the new gold standard. Only time will tell what that means for individual patients. A gold standard doesn’t necessarily mean the therapy applies to all patients. There are toxicities related to oxaliplatin, such as myelosuppression and neurotoxicity, and I don’t believe oxaliplatin-based adjuvant therapy will replace single-agent treatment across the board.

I anticipate a rapid move towards oxaliplatin-based treatments, especially in the younger, fitter and higher-risk patients. However, I believe a single-agent fluoropyrimidine will still be an appropriate option for a substantial proportion of older, more frail patients or patients at lower risk of disease recurrence.

Colorectal Cancer Update 2005 (1)

DR LOVE: Can you discuss the ongoing NSABP trial investigating the addition of bevacizumab to FOLFOX in the adjuvant setting?

DR NORMAN WOLMARK: The NSABPC-08 trial opened in October 2004. The trial design is simple and straightforward — modified FOLFOX-6 with or without one year of bevacizumab. The eligibility criteria include patients with Dukes’ B or C colon cancer.

Originally, we wanted to make this trial as broad-based as possible and include FLOX (bolus
5-FU/leucovorin/oxaliplatin). The FDA didn’t particularly embrace that idea; their response was justified because we didn’t have data from NSABP-C-07. In view of the MOSAIC adjuvant trial data with a FOLFOX regimen, I think a FOLFOX-inspired regimen is reasonable. So we eliminated the possibility of having FLOX as a control arm. Also, we were thinking of including a capecitabine/oxaliplatin (CAPOX) arm, but the sample size would have been much greater.

We really wanted to address a pivotal question — whether the benefits associated with bevacizumab as first-line therapy for metastatic colorectal cancer can be translated to the adjuvant setting. Once we came to grips with that as our unequivocal principal aim, the trial was structured to address it.

The sample size is manageable at about 2,600 patients. Theoretically, we hope bevacizumab will be more effective in the adjuvant setting. We hope the prolongation in time to progression seen in patients with advanced disease, if translated to the adjuvant setting, will result in lives saved.

Colorectal Cancer Update 2005 (2)

DR ALAN VENOOK: In my opinion, the flaw in treating patients with Stage II disease in the NSABP C-08 trial evaluating FOLFOX with and without bevacizumab is the accumulating evidence that a subset of patients with Stage II disease should not be subjected to the risk of chemotherapy.

ECOG is addressing that issue with a clever trial design that risk stratifies patients with node-negative disease. This stratification is based on the molecular features of the tumors.

For example, patients who have normal 18q are observed without therapy, based on retrospective data from a number of studies suggesting that those patients do well, while patients in the study who have deletion of 18q are randomly assigned to chemotherapy.

A relative risk reduction occurs with colorectal cancer chemotherapy, so the issue lies in identifying the baseline risk. FOLFOX causes neuropathy, so in a patient with node-negative disease who may have an 82 percent likelihood of being alive and disease free five years later, you have to balance the benefit with the long-term consequence.

Colorectal Cancer Update 2005 (4)

DR PHILIP: The specific question that is being asked by NSABP-C-08 relates to whether there is a benefit to adding bevacizumab to FOLFOX. The duration of therapy with bevacizumab is also of interest in this study because it continues after adjuvant chemotherapy for another six months.

We also have to evaluate the toxicity associated with this regimen because of what we’ve seen with bevacizumab. NSABP-C-08 is a good trial because the best use of bevacizumab might be early in the natural history of the disease. This may be the way to go, but one of the concerns with the regimen is, obviously, toxicity. We’ll need to see what happens.

Colorectal Cancer MTP September 2005

DR LOVE: Is there a role for irinotecan in the adjuvant setting, for example, in a patient with neuropathy or who cannot tolerate oxaliplatin?

DR PETER ENZINGER: The PETACC trial investigated infusional 5-FU/ leucovorin with or without irinotecan. In that trial the primary endpoint was not statistically significant.

However, I believe that there is some borderline benefit for using irinotecan in the adjuvant setting. You could argue that in a patient who has high-risk Stage III disease but for some reason upon receiving the first dose of FOLFOX has an allergic reaction to oxaliplatin, that may be a patient in whom you could use the FOLFIRI regimen.

The ACCORD study specifically looked at high-risk colon cancer patients and did not identify a difference between the patients who received irinotecan and those who did not. That being said, it was clear that investigators removed their patients — or the patients removed themselves — from the study, if they were randomized to receive only 5-FU and leucovorin. The bottom line, in my mind, is that FOLFIRI may be an option in a patient who wishes to receive aggressive therapy and who cannot, for some reason or another, tolerate oxaliplatin.

Interview, August 2005

DR LOVE: In your experience, what percent of patients on oxaliplatin-containing regimens develop acute neuropathy?

DR GROTHEY: Approximately 90 percent of patients develop cold-induced symptoms. The mean response to the question regarding oxaliplatin-related neuropathy (Figure 15) is considerably less than I would have expected. Perhaps the physicians are not aware of this — so this may define an educational need.

When you ask a patient a subjective question, such as whether they have experienced side effects, it is a very dynamic process. If you do not ask, the patients may not forward the information. However, when you ask a patient directly, “So, did you have any side effects from the treatment?” I would expect that more than 70 percent of patients would respond, “Yes, I experienced some nerve problems.” This is completely underrepresented, and it may be due to confusion identifying acute and chronic neuropathy — which is important for clinical management.

DR LOVE: In terms of chronic neuropathy, do you agree with the mean response of 36 percent?

DR GROTHEY: This question is left open in terms of severity. In the end, it’s a matter of how you define chronic neuropathy. I would say this is more likely what the physicians perceive. Almost every patient experiences some form of neuropathy, although it might not affect activities of daily living. So perhaps a better question would be, What percentage of your patients develops chronic neuropathy that affects the activities of daily living?

DR LOVE: Do you agree with the survey response that patients are able to tolerate an average of eight cycles of an oxaliplatin-containing regimen?


Colorectal Cancer Update 2004 (4)

DR LOVE: Do you find that most patients are able to tolerate oxaliplatin-related neuropathy?

DR FISHER: Certainly the toxicity seems tolerable. In the MOSAIC trial, about 18 percent of the participants had Grade III neuropathy during or shortly after the study. At one-year follow-up, that decreased to one percent. Grade III neuropathy is no fun, but patients have been living with cisplatin neurotoxicity for years. I think adjuvant FOLFOX is finding believers, not only in academic circles but also in the community. In particular, it’s being used for young patients with high-risk Stage III disease.

Interview, August 2005

DR LOVE: Do you use calcium and magnesium to prevent oxaliplatin-related neuropathy?

DR GROTHEY: We utilize these agents within a clinical trial. We currently have a placebo-controlled trial — calcium/magnesium versus placebo in the adjuvant setting — that we proposed to run through the NCCTG. However, one of the comments that we have received was that physicians were reluctant to enroll patients in the placebo arm because they are using calcium/magnesium in their clinical practice.

Seventy-eight percent of the physicians surveyed who use magnesium and calcium believe it is effective. This is higher than I would have expected, but on the other hand, physicians wouldn’t use it if they didn’t see any effectiveness.

Colorectal Cancer Update 2005 (1)

DR LOVE: What are your thoughts on the role of CAPOX in the adjuvant and metastatic settings?

DR TWELVES: As one who participates in clinical trials, I prefer to wait for evidence from randomized studies before using new combinations off protocol in the adjuvant and metastatic settings. However, with CAPOX I’m torn because everything we’ve seen to date from the clinical trials suggests that 5-FU can be substituted with capecitabine in these clinical settings. In addition, I would be very surprised if CAPOX doesn’t emerge as being equivalent to the FOLFOX regimen, alone or in combination with bevacizumab. I do believe CAPOX, off protocol, is a reasonable option at this time.

Colorectal Cancer Update 2005 (3)

DR HOFF: There is great interest, especially in the community, in having an oral chemotherapy-based regimen, and the CAPOX regimen is very attractive in that regard. Given the opportunity, patients tend to choose oral agents. We have the X-ACT adjuvant study showing that capecitabine was equivalent and had a hint of being better than bolus 5-FU/leucovorin. I think the data from the Phase II CAPOX trials in the advanced setting are intriguing enough to say that it’s at least equivalent to FOLFOX.

I wouldn’t recommend CAPOX as my first option in the adjuvant setting, because obviously we prefer to use evidence-based medicine. However, I would not necessarily find it incorrect to use CAPOX in the adjuvant setting. Scientifically, it makes sense.

Colorectal Cancer MTP September 2005

DR LOVE: Can you outline the design of the international AVANT trial?

DR WOLFF: The AVANT trial investigates adjuvant therapy for patients with Stage III colon cancer. There are three arms to that trial, and there are two questions being asked. The first question being addressed is, Are CAPOX and FOLFOX equivalent? The second question is, Does bevacizumab add to adjuvant therapy?

Patients on the first arm will receive FOLFOX alone. Patients on the second arm will receive FOLFOX plus bevacizumab. And patients in the third arm will receive CAPOX plus bevacizumab. However, there is not an arm directly comparing CAPOX versus FOLFOX. My belief is that bevacizumab will work with both the CAPOX and FOLFOX. What we will learn from this study is whether or not bevacizumab adds to standard adjuvant chemotherapy and whether CAPOX and FOLFOX are equivalent in terms of efficacy as adjuvant chemotherapy.

This study is very nicely done. I do not believe that the toxicity is going to be unmanageable based on our experience with these regimens in the past.

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