Neoadjuvant Chemotherapy Without Routine Radiotherapy Shows Promise in Patients With Locally Advanced Rectal Cancer


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Deborah Schrag, MD, MPH

Neoadjuvant Chemotherapy in Rectal Cancer

For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes.

—Deborah Schrag, MD, MPH, and colleagues

In a pilot study reported in the Journal of Clinical Oncology, Deborah Schrag, MD, MPH, and colleagues from Memorial Sloan Kettering Cancer Center, New York, assessed outcomes with neoadjuvant FOLFOX (fluorouracil, leucovorin, oxaliplatin)/bevacizumab (Avastin) with selective use of chemoradiotherapy.1 They found that this strategy does not appear to compromise outcome; the strategy is being assessed in a phase III trial.

Study Details

In this phase II study, 32 patients with clinical stage II to III rectal cancer at Memorial Sloan Kettering Cancer Center who were candidates for low anterior resection with total mesorectal excision received six cycles of modified FOLFOX6, with bevacizumab in cycles 1 to 4.

Patients with stable or progressive disease were to have radiation before total mesorectal excision, and responders were to have immediate excision. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX for six cycles was recommended, but regimens were left to clinician discretion. The primary outcome measure was R0 resection rate.

Patients had a median age of 52 years, and 17 (53%) were women. Overall, 23 (72%) were clinically node-positive; 20 had T3, N+, 9 had T3, N–, and 3 had T2, N+ rectal tumors. At the cutoff date (April 15, 2003), patients had been followed for a mean of 53 months and a median of 54 months (range, 43–73 months).

All patients underwent R0 resection (100%), with 8 (25%) having pathologic complete response. Local recurrence has not been observed in any patient. Two patients (6%) did not complete preoperative chemotherapy due to cardiovascular toxicity, with both having preoperative chemoradiotherapy or radiotherapy followed by R0 resection. The remaining 30 patients (94%) completed four cycles of FOLFOX/bevacizumab and two cycles of FOLFOX alone.

Outcomes

All patients had evidence of clinical response to neoadjuvant chemotherapy at restaging and directly underwent total mesorectal excision, usually with a temporary diverting ostomy. One patient received postoperative radiotherapy. Four patients (12.5%) developed metastatic disease to the lung. Three patients (9%) died, two due to metastatic rectal cancer and one due to postoperative complications. Overall, the 4-year local recurrence rate was 0%, 4-year disease-free survival was 84%, and 4-year overall survival was 91%.

Patients Not Completing FOLFOX/Bevacizumab

Of the two patients who did not complete neoadjuvant chemotherapy, one was a 63-year-old woman with a cT3, N+ tumor who developed arrhythmia after one cycle of ­FOLFOX/bevacizumab. Study treatment was discontinued, and she received standard chemoradiotherapy, underwent R0 resection of a pathologic T3, N1 tumor, received postoperative ­FOLFOX, and remained free of rectal cancer at last follow-up.

The other was a 69-year-old man with a cT3, N+ tumor who developed angina after two cycles of FOLFOX/bevacizumab. The regimen was discontinued, and he was treated with neoadjuvant radiotherapy without chemotherapy and had an R0 resection with yT3, N1 disease. He subsequently developed metastatic lung disease and died from rectal cancer 57 months later.

Other Patient Outcomes

The patient who received postoperative radiotherapy was an 81-year-old woman with a cT3, N1 and yT3, N2 tumor with 14 of 16 lymph nodes positive and a radial margin with residual tumor within 3 mm of the surgical specimen. She underwent postoperative radiotherapy but developed pulmonary metastasis within 1 year of surgery and died from metastatic disease without local recurrence. Of the two surviving patients with metastatic disease, one had surgical resection of an isolated lung metastasis and was alive with no evidence of disease at last follow-up and one was alive with pulmonary metastases.

The patient who died from postoperative complications was a 64-year-old man with a cT3, N0 and yT1, N1 tumor who had syncope and renal failure that appeared to be due to dehydration from high-volume ileostomy output at 17 days after surgery. He died from renal failure with no evidence of infection, thromboembolism, or other precipitating event.

The investigators noted that they could not rule out a contribution of bevacizumab to cardiac complications during neoadjuvant FOLFOX/bevacizumab in two patients and the death that appeared to be attributable to dehydration. They stated, “Given the negative results of two large-scale trials of bevacizumab in the adjuvant setting in colon cancer, we do not believe that our favorable results are attributable to bevacizumab and do not plan to incorporate it into future studies.”

They concluded, “For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes.”

“Although this preliminary experience is promising, it must be corroborated in the multicenter setting,” Dr. Schrag told The ASCO Post. “To accomplish just that, PROSPECT or N1048 is a randomized phase II/III clinical trial that is evaluating standard pelvic neoadjuvant chemoradiation with induction FOLFOX and selective use of chemoradiation. This trial is endorsed by all of the NCI cooperative groups and is available at many practice sites in North America. We really need to determine whether consistent or selective use of chemoradiation is optimal. PROSPECT will carefully assess outcome metrics, including quality of life and local and distant recurrence rates.”

Leonard B. Saltz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article. (See his related commentary on page 86). ■

Disclosure: The study was funded by Genentech. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Schrag D, Weiser MR, Goodman KA, et al: Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: A pilot trial. J Clin Oncol. January 13, 2014 (early release online).


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