Axel Grothey: Yes
Yes, of course there is a role for oxaliplatin in rectal cancer, said Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, who was also Co-Chair (with David Ilson, MD, PhD) of the meeting.
Grothey started by highlighting the results of the EORTC Radiation Oncology Group 22931 trial (Lancet Oncology 2014;15:184-190)—which was designed to answer the questions of (1) whether adding chemotherapy to preoperative radiotherapy augments the local effect of the radiotherapy and the overall survival of the patients; and (2) whether pre- or post-operative chemotherapy, or both, can improve overall and progression-free survival.
The 1,011 patients with stage T3 or T4 resectable rectal cancer were randomly assigned to receive one of four treatments:
- Preoperative radiotherapy;
- Preoperative chemo-radiotherapy;
- Preoperative radiotherapy and postoperative chemotherapy; or
- Preoperative chemoradiotherapy and postoperative chemotherapy.
As Grothey summarized in his talk, the results showed that the addition of fluorouracil-based chemotherapy to preoperative radiotherapy had no statistically significant effect on the overall survival of patients with resectable rectal cancer. The addition of postoperative chemotherapy did not significantly improve progression-free or overall survival (OS). There was a trend towards improvement in both survival endpoints, starting two to five years after treatment initiation, and preoperative chemotherapy and/or postoperative chemotherapy were associated with a significant increase in local control.
“The conclusions of the EORTC 22921 trial were that adjuvant fluorouracil (5-FU)-based chemotherapy after pre-operative radiotherapy—with or without chemotherapy—does not affect disease-free survival [DFS] or OS,” he said.
He did, though, raise some criticisms of the trial:
- There were only 250 patients per arm;
- Pre-treatment lymph node staging was not documented; and
- The regimen—four cycles of a dose-reduced, abbreviated Mayo Clinic bolus (5-FU)/leucovorin, led to less than 43 percent of patients receiving the planned dose.
More recently, two clinical trials presented at the 2014 American Society of Clinical Oncology Annual Meeting show the advantages of adding oxaliplatin in adjuvant chemotherapy combinations: The German CAO/ARO/AIO-04 randomized Phase III trial (Abstract 3500) showed that adding oxaliplatin to 5-FU-based neoadjuvant chemo-radiation therapy and adjuvant chemotherapy in locally advanced rectal cancer significantly improved DFS.
In addition, the Korean ADORE randomized Phase II trial (Abstract 3502) found that adjuvant FOLFOX produced improved three-year disease-free survival in curatively resected rectal cancer patients with postoperative stage II/III disease after preoperative chemo-radiation.
“Conclusions from rectal cancer studies show that adjuvant therapy in rectal cancer should be guided by the same principles as in colon cancer,” Grothey said. “Adjuvant oxaliplatin-based therapy is superior to fluoropyrimidines alone in stage III assessed before neoadjuvant therapy. This is supported by similarities in biology between colon and rectal cancer in The Cancer Genome Atlas.”
Oxaliplatin does not provide benefit as a radiation sensitizer in the neoadjuvant setting, he added. “Complete response rates are not increased in four out of five 5 studies. This validates current clinical practice,” he said.
Grothey noted that the current National Comprehensive Cancer Network guidelines “strongly state that FOLFOX or CapeOx are preferred for any N2 patients.”
And, with a twinkle in his eye, he pointed out that his debate opponent was vice-chair of these guidelines (Grothey is also on the guidelines committee.)
Alan P. Venook: No
Alan P. Venook, MD, admitted that “we agree on everything in the field. Our slides are the same. But it is how you look at the data and the bias you bring to the table that makes a difference.”
A seminal paper by Rolf Sauer et al for the German Rectal Cancer Study Group published in the New England Journal of Medicine 11 years ago (2004;351:1731-1740) concluded that preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity, but did not improve overall survival.
“This established chemoradiation as standard therapy for rectal cancer,” Venook said. “Other studies have since found that oxaliplatin is inappropriate.”
As an example, he cited the National Surgical Adjuvant Breast and Bowel Project R-04 clinical trial of pre-operative oxaliplatin included as neoadjuvant therapy for rectal cancer (ASCO 2014 Annual Meeting, Abstract 390).
The authors suggested that oral capecitabine be considered a new standard of care in this setting, and that the addition of oxaliplatin provided no improvement in outcomes, but did add significant toxicity.” Neoadjuvant oxaliplatin just adds more toxicity, with no change in pathological complete response,” Venook said.
He also mentioned the ADORE trial, but in a different light, noting that DFS improved slightly from 63 percent in the postoperative 5FU-plus-leucovorin group to 72 percent in the FOLFOX group. “This showed the benefit in that DFS was slightly higher, suggesting a trend toward improvement. But this was a very small, underpowered study,” Venook said.
In contrast, The EORTC 22921, which Grothey had criticized, showed a benefit to the cumulative incidence of local recurrence as a first event with chemotherapy and radiation therapy. Venook noted that the conclusion included a lack of support for the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy.
“Chemotherapy, in general, does not show a clear benefit. We don't need to use adjuvant chemotherapy, much less adjuvant oxaliplatin,” he said.
As for postoperative chemotherapy use following neoadjuvant chemoradiation, Venook noted that about 40 percent of rectal cancer patients from 1998 to 2007 did not receive chemotherapy. “It is not clear that the toxicity of chemotherapy is worth it,” he said.
And regarding the NCCN guidelines, Venook noted with a smile that “since the guidelines committee has included a member from the Mayo Clinic, there have been many changes between 2009 and 2015.”
He suggested that paradigm-changing studies of FOLFOX to spare radiation, such as the PROSPECT clinical trial, are appropriate to perhaps define new treatment regimens. This ongoing Phase II/III trial is comparing neoadjuvant FOLFOX with selective use of combined-modality chemoradiation against preoperative combined-modality chemoradiation for locally advanced rectal cancer patients undergoing low anterior resection with total mesorectal excision.
Before the debate, the vast majority of the audience (88%) voted in favor of using adjuvant oxaliplatin in rectal cancer. After the debate, even more (91%) were convinced that was the best course of therapy.
In response to a question about overtreating patients, Venook responded that the NCCN guidelines are “too forgiving and open in indications.”
“If we look at the data, it does not follow that FOLFOX is the right therapy in rectal cancer,” he said. “We tend to err on the side of overtreating patients. To get local and systemic control in rectal cancer, clinicians hate to leave something on the table.”
He also noted that although it would be ethical to do a Phase III trial of adjuvant oxaliplatin, it would not be appropriate: The bias would be too strongly opposed to doing such a study with a no-adjuvant-therapy arm.”