Rethinking Adjuvant Chemotherapy in Rectal Cancer

Neil Osterweil

May 07, 2015

Don't automatically assume that a patient with locally advanced rectal cancer is going to need or benefit from postoperative chemotherapy.

That's the message of a provocative opinion piece published May 4 in the Journal of Clinical Oncology by Theodore S. Hong, MD, and David P. Ryan, MD, from the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston.

But another academic clinician countered that it is better to err on the side of caution and typically administer the adjuvant therapy in this setting.

The Harvard pair expect debate.

They point to long-term results from the European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy Group 22921 trial, which showed that the addition of adjuvant chemotherapy made no difference in 10-year overall survival (OS), disease-free survival (DFS), or cumulative incidence of distant metastases in patients with clinical stage II or III rectal cancer who had undergone preoperative radiation or chemoradiation.

The results of EORTC 22921, along with those of smaller, more recent studies (, "argue against the routine use of chemotherapy for patients with clinical stage II or III disease who are undergoing preoperative chemoradiotherapy," the essayists write.

Current rectal cancer guidelines from the National Comprehensive Cancer Network recommend routine adjuvant use of the FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin) regimens for patients with stage II or III rectal cancer treated with neoadjuvant chemoradiotherapy or short-course radiation and total mesorectal excision (TME).

But current recommendations are based on older evidence and do not take into account changes in clinical practice, the authors point out. Improved surgical techniques, especially TME, combined with routine use of neoadjuvant chemoradiotherapy and better staging through advanced imaging studies, helps clinicians identify and treat accordingly those patients who are most likely to need the additional assurance of postoperative therapy, the authors contend.

Trial on Trial

Initial results of EORTC 22921 were published in 2006. In the study, patients had clinical stage T3 or T4 resectable rectal cancer and underwent preoperative radiotherapy, 45 Gy over 5 weeks; these patients served as controls.

Three other groups (with 253 patients in each) received chemotherapy in addition to radiation. Chemotherapy consisted of fluorouracil and leucovorin at 350 mg and 20 mg, respectively, per square meter of body surface per day. The preoperative group received two courses of chemotherapy, on week 1 and week 5 of radiotherapy. The postoperative group started chemotherapy 3 to 10 weeks after surgery and received four courses delivered every 3 weeks. A third group of patients received chemotherapy both before and after surgery.

As reported at the time by Medscape Medical News , there were no significant differences between the groups in survival. The 5-year overall survival rate was 65.8% vs 64.8% in the groups with and without preoperative chemotherapy ( P = .84), respectively, and 67.2% vs 63.2% in those with and without postoperative chemotherapy (P = .12). The 5-year disease-free survival rates were 56.1% vs 54.4% for the groups with and without preoperative chemotherapy (P = .52) and 58.2% vs 52.2% for those with and without postoperative chemotherapy (P = .13).

Ten-year follow-up results, published in 2014, showed that after a median 10.4 years there were no significant differences in either OS (51.8% with adjuvant chemotherapy vs 48.4% without chemotherapy), DFS (47.0% vs 43.7%), or cumulative incidence of distant metastases.

Dr Hong and Dr Ryan note that the incidence of local recurrences was decreased in all three study arms where patients received chemotherapy vs those who had received radiotherapy alone, but this did not result in OS advantage for chemotherapy, possibly because the trial was underpowered to detect an absolute survival advantage smaller than 10%.

"Despite the lack of evidence, the US national clinical trials network efforts have assumed that chemotherapy, and specifically oxaliplatin-based chemotherapy, should be given to all patients with locally advanced rectal cancer," they write.

A Different Opinion

In addition, the toxicities of oxaliplatin-based regimens such as FOLFOX or CAPEOX must be considered, they point out. For example, in the MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in The Adjuvant Treatment of Colon Cancer) study, nearly one-fourth of all patients had peripheral sensory neuropathy of any grade at 18 months, and 15.4% still had some degree of neuropathy at 48 months.

"Clearly, better predictors of those who actually need either chemotherapy or radiation are necessary. Perhaps the use of adjuvant chemotherapy can be tailored to the clinical situation. For instance, many patients with early-stage disease by imaging could be treated with as little as short-course radiation alone, and use of FOLFOX could be restricted to patients who have node-positive disease," they write.

But a medical oncologist who treats patients with rectal cancer says that he would be reluctant to stop providing chemotherapy to patients with stage II or III rectal cancer, regardless of clinical nodal status at the time of diagnosis.

"In our center we make that decision at the time of diagnosis," said Preet Singh, MD, assistant professor of medicine in the division of oncology at Washington University School of Medicine in St Louis, Missouri.

"Seldom do we change our decision about postoperative chemotherapy based on what the pathology shows. We base the decision on the clinical stage at the time of diagnosis, and most patients with stage II and III will get adjuvant chemotherapy with FOLFOX or another oxaliplatin-based regimen," he said in an interview with Medscape Medical News.

He acknowledged that, in patients diagnosed with early-stage disease with no nodal involvement, he and his colleagues may consider a short course of radiation and surgery, and reassess the patient after surgery. However, given that approximately 20% of patients with T3N0 disease based on clinical staging end up with lymph node metastases, they prefer to err on the side of caution, with caution in this case meaning adjuvant chemotherapy.

"I would be really concerned about not giving patients with this T3NO-type disease chemotherapy, especially since some of them will have node-positive disease," he said.

Dr Hong, Dr Ryan, and Dr Singh have reported no relevant financial relationships.

J Clin Oncol. Published ahead of print, May 4, 2015. Full text


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