Complete Neoadjuvant Chemotherapy May Offer New Framework for Treating Rectal Cancer

Kimberly Perez, MD

Complete neoadjuvant treatment with mFOLFOX6 (oxaliplatin, 85 mg/m², and folinic acid, 200 mg/m² IV on day 1; followed by 5-fluorouracil [5-FU], 400 mg/m² IV bolus and then 5-FU 2400 mg/m² IV over 46 hours) has thus far been administered safely prior to chemoradiation and surgery in 90% of patients with rectal cancer in the phase II CONTRE study. Complete neoadjuvant treatment, therefore, may represent a well-tolerated alternative to the current standard treatment sequence of adjuvant chemotherapy following chemoradiation and surgery, said Kimberly Perez, MD, at the 2013 Gastrointestinal Cancers Symposium.

The CONTRE study is examining the feasibility of administering all chemotherapy prior to surgery, and its impact on pathologic complete response and complete resection in clinical stage II-III rectal cancer.

The conventional paradigm for rectal cancer management is radiation with fluoropyrimidine followed by primary resection with a temporary ostomy, fluoropyrimidine-based systemic therapy for 4 months, and ostomy closure, said Perez, a gastroenterology oncologist at Brown University in Providence, Rhode Island.

This paradigm has several potential disadvantages. “Compliance with adjuvant chemotherapy is sometimes suboptimal after neoadjuvant chemoradiation and surgery, historically with rates of 40% to 60%. Pathologic complete response rates to chemoradiation alone have been 10% to 25%,” she said. “Also, the timing of ileostomy reversal has been problematic. If ostomy closure occurs before FOLFOX, effective systemic therapy can be delayed for two to three months or longer, or if FOLFOX is given before ileostomy reversal, it increases the length of time that patients have the temporary ostomy in place, affecting quality of life.”

Complete neoadjuvant treatment before surgery could potentially improve compliance, decrease the rate of systemic recurrence if all chemotherapy was administered, and increase the pathologic complete response, she said.

Investigators have enrolled 39 patients thus far in the multicenter CONTRE study. Patients have stage II or III adenocarcinoma of the rectum by transrectal ultrasound and/or pelvic MRI. All but five patients are younger than 75 years.

Neoadjuvant Chemotherapy Compliance

Patients are being treated with mFOLFOX6 every 2 weeks for eight cycles, and are being followed by repeat MRI and proctoscopy to assess response. Following mFOLFOX6, patients receive 50.4 Gy of intensity-modulated radiation therapy with 5-FU, 225 mg/m²/d, or capecitabine, 825 mg/m² twice a day, 5 days per week during radiation, followed by surgery 4 to 8 weeks later.Compliance to neoadjuvant chemotherapy in the first 32 patients has been excellent, said Perez. Ninety percent of neoadjuvant mFOLFOX6 has been delivered. Twenty-nine of the first 32 patients received all eight cycles of mFOLFOX6. All but one of the 27 patients (96%) younger than 75 years completed all eight cycles. Of the five patients aged ≥75 years, 60% completed the intended treatment.

Doses were reduced or delayed in nine patients; seven required treatment delays and two required dose reductions for neutropenia, diarrhea, or vomiting/abdominal pain.

Chemoradiation Compliance

Grade 3 toxicities during chemotherapy include three cases of neutropenia, two cases of thrombocytopenia, two cases of fatigue, and two cases of abdominal pain, plus single cases of diarrhea, nausea, dehydration, incontinence, renal failure, emesis, anorexia, and acid reflux. There were two grade 4 toxicities (neutropenia and diarrhea).Compliance to chemoradiation in the 29 patients who completed mFOLFOX6 was >90%. Three patients required capecitabine dose reduction and two required treatment breaks.

Response Rates

There was one grade 4 toxicity (neutropenia) during chemoradiation. Grade 3 diarrhea was reported by seven patients.Ten of the first 30 (33%) had a pathologic complete response after neoadjuvant chemotherapy and chemoradiation. Of the five patients with a clinical complete response after induction mFOLFOX6, all had a pathologic complete response at surgery.

Perez K, Pricolo V, Vrees M, et al. A phase II study of complete neoadjuvant therapy in rectal cancer (CONTRE): The Brown University Oncology Group. J Clin Oncol 30: 2012 (suppl 34; abstr 335).

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