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Colorectal Cancer: Trials of Adjuvant Chemo Raise More Questions than Answers

Tuma, Rabiya S PhD

doi: 10.1097/01.COT.0000396082.05320.85

SAN FRANCISCO—Cancer drug development usually follows a pattern with novel agents tested in the sickest patients first and then moved gradually to patients with less-advanced disease. That approach has worked in many disease settings and with numerous agents. However, two presentations here at the Gastrointestinal Cancer Symposium demonstrate that the approach may not work so well in colorectal cancer.

Results from the AVANT trial (Abstract 362) show that adding bevacizumab to FOLFOX or XELOX does not increase disease-free survival in patients with Stage III cancer, even though the drug is active in the metastatic setting.

Conversely, data from the Intergroup trial N0147 (Abstract 363) suggest that FOLFIRI and cetuximab may have a synergistic effect in early disease, even though neither agent works on its own in that setting.

“It is unclear why are we seeing these contradictory findings in adjuvant therapy,” said the chair of the session, Richard M. Goldberg, MD, Associate Director of Clinical Research at the University of North Carolina Lineberger Comprehensive Cancer Center. “There is great concern that we now have tested three drugs—bevacizumab, cetuximab, and irinotecan—and found that there is overall no benefit,” despite evidence that they are active in the metastatic setting.”

Noted the Discussant for the abstracts, Johanna Bendell, MD, Associate Director of Drug Development and Director of Gastrointestinal Cancer Research at Sarah Cannon Research Institute in Nashville, “What we have learned is that we can't think we know what we are doing until we have seen the trial results. We've seen in these studies that common paradigms are not holding true: What works in the metastatic setting does not necessarily work in the adjuvant setting.”

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AVANT: No Gain with Bevacizumab

Randomized clinical trials demonstrated that adding bevacizumab to chemotherapy improves outcomes for patients with metastatic colorectal cancer. However, when researchers tested bevacizumab plus FOLFOX in patients with Stage II or III disease in the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 trial, they saw no improvement in disease-free survival, relative to patients treated with chemotherapy alone. An ad hoc analysis, though, suggested that there might be an early benefit with bevacizumab, but the benefit disappeared after one year.

Now, Aimery de Gramont, MD, PhD, Head of Internal Medicine in Oncology and Professor of Oncology at Hôpital Saint-Antoine in Paris, and colleagues report similar findings from the AVANT trial.

A total of 3,451 patients with Stages II or III colorectal cancer were assigned to treatment with FOLFOX4, FOLFOX4 plus bevacizumab, or XELOX plus bevacizumab. Of those, 2,867 patients had Stage III disease and were included in the primary analysis of disease-free survival, which showed a hazard ratio of 1.17 for FOLFOX plus bevacizumab compared with FOLFOX alone, and a hazard ratio of 1.07 for XELOX plus bevacizumab.

The three-year disease-free survival rates were 76% for patients treated with FOLFOX4, 73% for patients treated with FOLFOX4 plus bevacizumab, and 75% for patients treated with XELOX plus bevacizumab.

Moreover, the team saw a trend for poorer overall survival in patients treated with the bevacizumab combinations compared with chemotherapy alone, with hazard ratios of 1.31 and 1.27 in the FOLFOX plus bevacizumab and XELOX plus bevacizumab arms, respectively.

Although cautioning that the overall survival data are still immature and need longer follow-up to be definitive, Dr. de Gramont said that despite these overall negative results, the investigators did see an early trend that initially favored the bevacizumab combinations. “We have observed the same effect as in the NSABP trial—an early benefit for XELOX or FOLFOX with bevacizumab, but this is lost after one year.”

He said that looking for an explanation for the unusual pattern and overall negative results, he and his colleagues first considered the possibility that bevacizumab-related toxicities were a problem. “In the AVANT trial it is certainly not the case,” he said.

Ten percent of patients in the bevacizumab arms developed Grade 3 or higher hypertension, but there were smaller increases in bleeding, proteinuria, gastrointestinal perforations, and thrombotic events. Moreover, the median duration of therapy was similar in all three arms, ranging from 4.9 to 5.3 months for oxaliplatin and 5.3 to 5.6 for capecitabine and 5-FU.

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No Suggestion of Rebound Effect

Nor do the results appear to suggest a rebound effect following bevacizumab therapy because the disease recurrence patterns were similar in all three arms. For example, the percentage of patients with more than one involved site was between 5% and 6% in the three trial arms.

Following disease recurrence, 68% to 69% of the patients in each arm received additional drug therapy, with irinotecan and fluorouracil used most frequently. Slightly more patients in the control arm received bevacizumab after recurrence than those in the experimental arms (35% vs 16% and 21% in the FOLFOX4 plus bevacizumab and XELOX plus bevacizumab arms, respectively).

Dr. de Gramont speculated that this difference might have contributed to a slight advantage for patients in the control arm in terms of median time between recurrence and death, although the difference did not reach statistical significance and did not account for the overall negative results.

Finally, Dr. de Gramont, like Dr. Goldberg, noted that bevacizumab was now the third agent to fail in the adjuvant setting after showing activity in advanced disease. “This is an important question: Why is active therapy in the advanced setting not active in the adjuvant setting?” Notably, all three agents—bevacizumab, cetuximab, and irinotecan—inhibit the vascular endothelial growth factor pathway signaling. (Cetuximab and irinotecan block the pathway though HIFα.)

Because previous work suggests that blocking angiogenesis can trigger tumor dormancy, and tumor dormancy protects cancer cells from chemotherapy in preclinical models, Dr. de Gramont hypothesized that this may be what these three agents have in common.

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Goals of Therapy Not the Same?

Dr. Goldberg, though, took a different view. He speculated that what bevacizumab does is allow chemotherapy to kill the bulk of the tumor but that it has little or no effect on cancer stem cells that drive new metastases. In that case, therapy would be effective in advanced disease where tumor bulk is causing patient symptoms and disability, but it would be ineffective in early disease where the goal is to prevent disease recurrence.

In other words, it may be that bevacizumab works in one setting but not the other because the goals of therapy are not the same in the two settings. “They may well be different,” he said. “I think we are beginning to understand that. It is certainly no longer true that activity in the advanced setting can be expected to translate into incremental improvements in the adjuvant setting.”

Regardless of the reasons for failure, Dr. Bendell was clear that bevacizumab should not be tested further in the adjuvant setting. “What we have seen with adjuvant bevacizumab is that it shows no improvement in these trials, either NSABP, C-08, or AVANT, in disease-free or overall survival. Prolonging bevacizumab therapy may hold down disease for some period of time but, really, at what cost? Both in terms of toxicity and in terms of financial.

“I think we need to stop development of adjuvant bevacizumab for now,” Dr. Bendell concluded. “Maybe we can look at it in the adjuvant metastatic setting, or look for proof of concept that it works as single-agent maintenance therapy.”

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Irinotecan and Cetuximab May Have Synergy

Intergroup trial N0147 was initially designed to compare two chemotherapy regimens—FOLFOX and FOLFIRI—with and without cetuximab. However, when other trials indicated that FOLFIRI was inactive in the adjuvant setting in colorectal cancer, researchers stopped enrolling patients in the FOLFIRI arms. Results from the FOLFOX arms, reported last year, showed no improvement in disease-free or overall survival with the addition of cetuximab.

Now, a previously unreported analysis of patients enrolled in the FOLFIRI arms suggests that Stage III patients do benefit from the addition of cetuximab to FOLFIRI. In fact, the results hint that FOLFIRI plus cetuximab may be better than FOLFOX, even though neither irinotecan nor cetuximab work on their own in the adjuvant setting.

Of the 146 patients enrolled and evaluable, 106 received FOLFIRI alone and 40 received FOLFIRI plus cetuximab. Median three-year disease-free survival was 66.7% in the patients treated with chemotherapy alone and 86.6% in patients treated with chemotherapy plus cetuximab, which was a statistically significant difference.

By comparison, the median three-year disease-free survival was 75.8% for patients treated with FOLFOX and 72.3% for patients treated with FOLFOX plus cetuximab.

When the researchers divided patients into those with KRAS wild-type tumors and those with KRAS mutant tumors, there was a trend for benefit in both groups with the addition of cetuximab. Specifically, patients with wild-type KRAS had a median three-year disease-free survival rate of 69.8% when treated with FOLFIRI and 92.3% when treated with FOLFIRI plus cetuximab, which was a statistically significant difference.

Unexpectedly, patients with KRAS-mutant tumors also showed a non-significant trend for benefit, with a median three-year disease free survival of 56.3% with FOLFIRI and 82.5% with FOLFIRI plus cetuximab.

The researchers also saw a trend for a benefit in overall survival with the addition of cetuximab to FOLFIRI, which was not seen in the FOLFOX arms of the trial. Two-year overall survival was 84.4% in patients treated with FOLFIRI compared with 91.8% with FOLFIRI plus cetuximab, which was statistically significant.

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Addition of Cetuximab Increased Grade 3-4 Toxicities

The addition of cetuximab, however, substantially increased the rate of Grade 3-4 toxicities from 53% in the chemotherapy-alone arm to 68% in the combination arm. Major toxicities included acne, paresthesias, and infarction. Moreover, the rates of discontinuation and refusal due to adverse events doubled, from 16% with chemotherapy alone to 33% in the combination arm.

Although the increases in disease-free survival with the FOLFIRI-cetuximab combination are intriguing, Jocelin Huang, MD, a hematology/oncology fellow at the Mayo Clinic, who presented the data, cautioned that there were too few patients to allow any firm conclusions. “Nevertheless, given these trends we have observed, the question arises whether a different synergist effect exists between FOLFIRI and cetuximab than with FOLFOX and cetuximab.”

Dr. Goldberg agreed that the data are provocative. “The trial suggests, perhaps, that the interactions between chemotherapy and cetuximab are different when that chemotherapy is irinotecan- versus oxaliplatin-based,” he told OT. “The question is, is that worthy of further testing or have we written off irinotecan forever in the adjuvant setting? I don't know the answer to that. I just think we ought to raise the question.”

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Meeting Cosponsors

The Gastrointestinal Cancers Symposium is cosponsored by the American Society of Clinical Oncology, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

© 2011 Lippincott Williams & Wilkins, Inc.
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