You are here: Home: CCU 3 | 2007: Christopher Willett, MD

Tracks 1-8

Track 1 Bevacizumab as a potential radiation sensitizer in rectal cancer Track 2 Clinical trial of bevacizumab alone and concurrent with chemoradiation therapy in rectal cancer Track 3 Direct evidence of antivascular effects of bevacizumab in rectal cancer Track 4 Clinical response to neoadjuvant chemoradiation with bevacizumab in rectal cancer Track 5 Capecitabine versus infusional 5-FU as neoadjuvant therapy in rectal cancer Track 6 Pathologic complete response with neoadjuvant combined chemoradiation and targeted therapies Track 7 Addition of oxaliplatin to neoadjuvant chemoradiation therapy for rectal cancer Track 8 American College of Surgeons trial of local excision in patients with T2 rectal cancer

Select Excerpts from the Interview

Track 1

DR WILLETT: Dr Rakesh Jain had been interested in a hypothesis called “normalization” (Jain 2001; [3.1]), which he examined in preclinical models.

The hypothesis is that the tumor vasculature is highly inefficient and is associated with high levels of interstitial pressure and hypoxia. So if you administer anti-angiogenic agents — specifically agents targeting VEGF — these agents may work not only through direct blood vessel killing but also by improving the efficiency of the remaining tumor vasculature.

DR LOVE: What was known about bevacizumab and radiation sensitization?

DR WILLETT: The preclinical work (Lee 2000; Yuan 1996) in a variety of mouse models demonstrated that if bevacizumab was administered with radiation therapy, the amount of radiation needed to control the tumors was less than with radiation therapy alone.

Track 2

DR WILLETT: We wanted to observe the effect of bevacizumab as a single agent on rectal cancer before introducing radiation therapy and 5-FU.

According to the trial design (Willett  2004), patients received a single infusion of bevacizumab prior to the introduction of 5-FU and radiation therapy with concurrent bevacizumab. We were keenly interested in what would be happening at a relatively short period after the first bevacizumab infusion.

At day 12, typically, after the first bevacizumab infusion, evaluations (flexible sigmoidoscopies, biopsies, interstitial fluid pressure, functional imaging, serum/blood assays) were repeated in terms of the correlative studies.

So it provided an opportunity to observe a human malignancy in vivo after bevacizumab treatment, and it allowed an opportunity to see the resulting types of effects.

DR LOVE: How long did patients receive the chemoradiation therapy and bevacizumab?

DR WILLETT: The protocol design was as follows: An infusion of bevacizumab was administered on day one, and two weeks later a second infusion of bevacizumab was followed by the introduction of pelvic irradiation and continuous infusion 5-FU.

We administered a standard course of radiation therapy — 50.4 Gray over 5.5 weeks. A seven-day continuous infusion of 5-FU at 225 mg/m² was administered throughout the course of radiation therapy.

Bevacizumab was administered every other week for a total of four infusions of bevacizumab with 50 Gray of radiation and 5-FU during the course of external-beam radiation therapy. Surgery was performed seven to nine weeks after completion of the bevacizumab to allow for clearance of the drug, considering the half-life of bevacizumab.

Track 3

DR WILLETT: The initial Phase I portion (Willett  2004) of the trial included six patients who received the first dose of bevacizumab in the trial, which was 5 mg/kg. At day 12, after the first infusion of bevacizumab, our first patient underwent a flexible sigmoidoscopy and appeared to show a response with the monotherapy alone.

We did not run into any dose-limiting toxicity. However, when we began to put the data together for the correlative studies, we noted some interesting findings (3.2).

One such finding was that the interstitial fluid pressure in these patients had dropped from baseline to day 12, a finding that perfectly matched the results that Dr Jain had observed in the xenograft models.

DR LOVE: You mentioned what happened to the first patient after two weeks — what about the other five patients?

DR WILLETT: Essentially, disease remained in the other five patients. Tumors seemed, in terms of response, about the same in size — no big changes. It is interesting that some of the tumors became perhaps a little more pale on gross visualization. We did see a drop in the tumor blood flow with perfusion CT scans.

According to the 18-fluorodeoxyglucose PET scans, essentially no difference had appeared in standardized uptake values between pretreatment and day 12. We also saw a drop in microvessel density between baseline and day 12, consistent with preclinical work.

You might ask whether a drop in tumor blood flow goes against the normalization hypothesis. Probably not — remember, the perfusion CT is a relatively gross measure. Even with a drop in blood flow, the level of tumor metabolic activity remained the same, which, in fact, suggested some element of normalization.

Track 4

DR WILLETT: In five of the six patients, we saw a flat ulcer in the surgical specimen with no exophytic or macroscopic disease. One patient had gross disease remaining. When these specimens were sectioned and examined histologically, we typically observed a nest of cells admixed into a deep fibrous tissue.

DR LOVE: In those five patients, if you had to make a guess, what fraction of the tumor do you think was destroyed?

DR WILLETT: That is a hard question. We used various grading scales to try to correlate the amount of residual disease with what one would have expected pretreatment. The clinical responses were excellent, with an ulcer remaining, and microscopic disease remained.

The next cohort of patients received bevacizumab at a higher dose level of 10 mg/kg. Five patients were assigned to that dose level. Two of the five patients who received the higher dose level showed complete pathological responses — that is, absolutely no malignant cells were left in the surgical specimens.

The other three patients also showed good responses, but again, microscopic disease remained. Note that these 11 patients were assessed by one pathologist, who “bread-loafed” the specimens individually, so the stringency of the pathological examination of these specimens was probably as tight as could be.

Track 5

DR WILLETT: The need to address the question in a Phase III trial as neoadjuvant treatment for rectal carcinoma is clear. Many clinicians have adopted capecitabine as an alternative to infusional 5-FU regimens, and not only for rectal carcinoma.

The data from Phase I and II studies (Chau 2006; Glynne-Jones 2005) of capecitabine and radiation therapy (3.3) suggest that it is as beneficial as 5-FU infusions, with a slightly different toxicity profile. We have used it, but we also discuss the option carefully with the patient.

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