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DR HALLER: Since the 1991 consensus conference, the American model for the management of rectal cancer had generally consisted of surgery followed by postoperative chemoradiation therapy for patients with Stage II or Stage III disease, but I now believe that preoperative chemoradiation therapy is the gold standard for patients with rectal cancer.

Currently, both adjuvant and neoadjuvant chemoradiation therapy are acceptable options, but based on the German Rectal Cancer trial comparing preoperative and postoperative chemoradiation therapy, more people will be switching to the preoperative model. In the United States, preoperative or postoperative radiation therapy alone would be an unacceptable option.

We are mostly using neoadjuvant chemoradiation therapy, so I believe a standard regimen would consist of infusional 5-FU and radiation therapy. According to Joel Tepper’s presentation of the Intergroup-0114 trial results, the bolus 5-FU regimens have more toxicity and equal efficacy compared to the infusional regimen; however, patients who are confounded by infusional therapy might choose one of the bolus regimens. In patients who do not want infusional therapy, the cumulative data for capecitabine suggest that it could be substituted. I’m not willing to simply say capecitabine can be substituted in every patient, but I believe it’s an option.

DR LOVE: What is your general approach for neoadjuvant chemotherapy for patients with rectal cancer?

DR GROTHEY: The Mayo Clinic is a conservative institution, and we are using continuous-infusion 5-FU in this situation, but I think the data are compelling that capecitabine can be used as a substitute. Outside of clinical trials, we shouldn’t be afraid to use capecitabine. Having said that, this is currently being investigated in NSABP-R-04, which compares radiation therapy with either capecitabine or infusional 5-FU.

A second randomization will evaluate the addition of oxaliplatin. The future involves increasing the efficacy of neoadjuvant chemotherapy because in the end, patients eventually succumb to distant metastases.

Adding more effective chemotherapy up front in combination with radiation therapy will allow us to maintain systemically active chemotherapy, which might attack micrometastases as early as possible.

I’m sure it will enhance the pathologic complete response rate following chemoradiation therapy, which is a predictor for overall survival. Hence, we’ll have local control improvement, and with the use of combination chemotherapy early on, we might have an impact on distant metastases.

DR LOVE: Can you describe a rectal cancer case where you would not recommend neoadjuvant therapy?

DR GROTHEY: In a situation where the lesion is high — 12 centimeters from the anal verge — I would recommend resection followed by chemotherapy. However, the majority of respondents selected neoadjuvant radiochemotherapy. The decision not to utilize neoadjuvant therapy is determined by the location of the lesion. The higher the tumor is located, the less important radiation becomes.

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In discussing neoadjuvant strategies, the key issue is the radiation component, and if we want to extrapolate, we have some data from the Dutch trial looking at the location of the tumor relative to the risk of recurrence. For a patient who has a tumor located 12 centimeters from the anal verge, recurrence rates — even without radiation — are less than five percent.

DR LOVE: In terms of the general recommendation for neoadjuvant therapy in patients with rectal cancer, most physicians use intravenous 5-FU as opposed to capecitabine. What is your opinion on that?

DR GROTHEY: This is clearly because we don’t have any Phase III neoadjuvant data with capecitabine in rectal cancer available yet. I was actually surprised that for older-age patients, the recommendation for capecitabine increased to almost one fourth of patients. This is interesting, and it shows potential for this drug because apparently it’s perceived as more tolerable for elderly patients. If we are able to document that capecitabine is equally effective — which is a matter of ongoing trials — then it could be a nice replacement for intravenous 5-FU. I think in the future we will see more usage of CAPOX.

The primary reason we use capecitabine is patient convenience. I believe that 5-FU and capecitabine are interchangeable in terms of efficacy. In dosing capecitabine, I tend to use capecitabine twice a day Monday through Friday during radiation as a radiosensitizer. We tell patients not to use multivitamins while they are taking capecitabine.

DR LOVE: How about CAPOX in the neoadjuvant setting?

DR GROTHEY: To be honest, I thought it would have been used more. We do have published data on that, including results published in the Journal of Clinical Oncology over two years ago. So, you could use it with the idea that oxaliplatin adds significant efficacy in terms of the systemic recurrence. However, based on this survey, it does not appear that CAPOX is utilized in the neoadjuvant setting for rectal cancer.

DR LOVE: What do you think about NSABP-R-04, evaluating preoperative radiotherapy with capecitabine versus 5-FU and the second randomization to add oxaliplatin?

DR PHILIP: I have mixed thoughts with respect to the first randomization in NSABP-R-04 of infusional 5-FU or capecitabine because I already use capecitabine with radiation therapy. We started using this at our institution several years ago when there weren’t any protocols available. We reviewed and published our experience confirming the safety of this approach; therefore, we have been using capecitabine routinely in these patients in the clinical setting.

I am interested in the second randomization in the trial using oxaliplatin. I have started using that in combination with radiation therapy in some, but not all, patients. For example, I have used oxaliplatin in healthier patients with a better performance status and in patients with whom I have special concerns about not being able to preserve the sphincter, where I want to obtain a maximum pathologic response.

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DR CHRISTOPHER CRANE: The NSABP designed R-04 to compare capecitabine with venous infusional fluorouracil in patients receiving preoperative radiotherapy for locally advanced rectal cancer, but I don’t believe such a trial is necessary. The study design has now been changed to incorporate oxaliplatin, which I believe is our only opportunity to understand whether that drug will benefit such patients. The final design is a two-by-two randomization of infusional 5-FU versus capecitabine with a second randomization to oxaliplatin or not.

I believe everyone will agree that the amended design is better. If I had to guess what this trial would show, my guess would be that capecitabine will be equally effective but less toxic than infusional 5-FU and that oxaliplatin will improve response but not longterm outcome.

DR LOVE: What about the role of neoadjuvant bevacizumab in the treatment of rectal cancer?

DR CRANE: Bevacizumab has been proven in many disease sites to improve the effects of chemotherapy. Approximately three years ago, before it was approved with radiation therapy, we had the opportunity to investigate this agent. We conducted a Phase I trial of 50 patients with pancreatic cancer (ID02-146) who received capecitabine, radiation therapy and bevacizumab, and the results were very exciting. In the patients who received five mg/kg of bevacizumab every two weeks, which was the final recommended dose, we saw a 50 percent partial response rate. Six of the 12 patients had their tumors shrink by 50 percent, which is a “high bar” endpoint for pancreatic cancer.

The regimen was well tolerated, and the RTOG is now conducting a Phase II study with bevacizumab, capecitabine and radiation therapy in patients with locally advanced pancreatic cancer that cannot be surgically excised (RTOG-0411).

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At MD Anderson, we currently have a neoadjuvant Phase II study with the same regimen in patients presenting with locally advanced rectal cancer. Investigators at Mass General published a Phase I trial in Nature Medicine and presented it at ASCO in 2004. In this trial, patients with primary rectal cancer received neoadjuvant bevacizumab, 5-FU and radiotherapy.

It was initially reported that five out of six patients had either microscopic residual or complete pathologic responses to the preoperative regimen, and I know from personal communication that these results are holding up, and now 11 out of 12 patients have had this response. In addition, no surgical catastrophes have been encountered following this regimen as long as six weeks elapse before the patient undergoes surgery.

These data open a lot of doors for the future of these patients and chemoradiation in general. In clinical trials, we will be evaluating bevacizumab’s ability to enhance the effect of radiation therapy.

One of our focuses at MD Anderson is organ preservation, and with bevacizumab, instead of removing radiation therapy from the neoadjuvant treatment equation, this agent, when used with radiation therapy, may lessen how radical a surgery needs to be. I want to stress that this is investigational, but the responses are better, and I believe they will also translate into better local control.

DR VENOOK: Bevacizumab obviously has great potential in the rectal cancer setting. Chris Willett’s paper in Nature Medicine was a very clever and interesting development. These were patients with primary or locally advanced rectal cancer who received a single dose of bevacizumab and, in 12 days, were reevaluated with imaging and biopsy and then received 5-FU/radiotherapy. Blood flow, blood volume and tumor vasculature all were impacted by a single dose of bevacizumab to these tumors that were in situ. So certainly, there’s biological activity of bevacizumab alone, and I think this really needs to be looked at in neoadjuvant studies.

DR HOFF: We try to put these patients on protocol as much as possible. Right now, we have a preoperative Phase II protocol with capecitabine, bevacizumab and radiation therapy. If patients cannot participate in this study, we usually use preoperative capecitabine with radiation therapy.

DR LOVE: What are your thoughts regarding bolus 5-FU, infusional 5-FU and capecitabine for the adjuvant treatment of rectal cancer?

DR WOLFF: In the adjuvant setting, when infusional 5-FU rather than bolus 5-FU is combined with radiation therapy, disease-free and overall survival are improved. Infusional 5-FU is a better radiosensitizing agent. The advantage of infusional 5-FU with radiation therapy is probably more of a systemic than a local control benefit.

An Intergroup trial published in The New England Journal of Medicine demonstrated a trend toward better local control using infusional 5-FU compared to bolus 5-FU. That study is proof of the principle that infusional 5-FU is a superior treatment modality when combined with radiation therapy.

Capecitabine is an interesting alternative to infusional 5-FU for several reasons. With infusional 5-FU, catheterrelated problems can develop, such as thrombosis and infection. Additionally, patients are required to carry an ambulatory pump. When the pump is on for a couple of weeks it’s no big deal, but generally by the fifth week of radiation therapy, patients are tired of it. Capecitabine is a nicer route of administration.

Additionally, capecitabine is a prodrug, and it has to be converted to 5-FU at the intracellular level. One of the enzymes responsible for that conversion is thymidine phosphorylase (TP), which is expressed in higher concentrations in the rectal mucosa.

At the biological level, that may mean that the rectum, the rectal mucosa and the tumor cells have a higher intracellular concentration of 5-FU, leading to both an active cytotoxic benefit and more radiosensitization. We have therefore been interested in evaluating capecitabine as a radiosensitizer compared to infusional 5-FU.

In the future, we will combine capecitabine with bevacizumab. That trial is not yet open, but we will pursue not only conventional cytotoxic agents with radiation but also utilize biologic agents such as bevacizumab for this group of patients.

DR LOVE: What is your opinion of the survey findings related to locoregional therapy for rectal cancer?

DR GROTHEY: The number of patients who have undergone total mesorectal resection — 50 percent — seems to be quite low. Interestingly, the number of patients who have undergone APR seems a little bit high — it should be under 20 percent.

Of course, this could be due in part to the definition of what qualifies as rectal cancer. Is the 12-centimeter tumor still rectal cancer, or is it sigmoid cancer? This should be factored into the equation; when the oncologists answered the question, were they only thinking of low rectal cancers? We define rectal cancer as a lesion located between the anal verge and up to 12 centimeters from the anal verge. Our goal is to reduce the need for APR to less than 20 percent.

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