A Multimodality Approach to the Initial Management of Stage IV Rectal Cancer
Abstract & Commentary
By Bindu Kanapuru, MD
Hematology/Oncology Division, IASIA-Falls Church, Falls Church, VA
Dr. Kanapuru reports no financial relationships relevant to this field of study.
Synopsis:In this Phase 2, single-arm, multicenter clinical trial conducted in the Netherlands, 50 patients with metastatic rectal cancer were treated with 5 days of 5 Gy RT followed by six cycles of intravenous bevacizumab (7.5 mg/kg) and oxaliplatin (130 mg/m2) on D1 and capecitabine (1000 mg/m2) orally on D1-D14. Thereafter, resection of the primary tumor and metastatic disease (when possible) was undertaken. Efficacy and tolerability was assessed as percentage of patients who underwent radical resection, survival at 2 years, and recurrence rates, as well as treatment-related toxicity. Nearly three-fourths of the patients underwent curative resection, and 2-year overall survival was 84%. Treatment was well tolerated with no treatment-related deaths.
Source:van Dijk TH, et al. Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer. Ann Oncol 2013;24:1762-1769.
The best treatment for primary metastatic rectal cancer is not established. In selected patients undergoing resection of metastatic disease, studies have shown prolonged survival and, for some, potential cures. But such an approach is often difficult because primary rectal tumors are frequently locally advanced and require prompt treatment. Neoadjuvant chemotherapy or chemo radiotherapy (RT) has been used to potentially downstage tumors and convert unresectable disease to resectable. However, the prolonged periods without systemic therapy for those with metastatic disease and the added toxicity of radiation may reduce the benefits of surgical resection in patients who are known to have metastatic disease at presentation. Short-course RT has been shown to produce similar rates of distant failure, overall survival, and late radiation toxicity when compared to long duration chemo-RT. However, chemotherapy with short-course RT has not yet been tested.
In this study, to overcome the logistical issues in treatment sequence, the investigators used a preoperative short-course pelvic radiotherapy including five fractions of 5 Gy each (5 × 5 Gy), followed by capecitabine and oxaliplatin (CapeOx) given in combination with bevacizumab prior to surgical resection. Systemic chemotherapy with bevacizumab/CapeOX was started 2 weeks after completion of short-course RT. The RT was delivered by linear accelerator and the clinical target volume included the primary tumor, mesorectum, and internal iliac nodes. Six to 8 weeks after completion of chemotherapy, total mesorectal resection of the primary tumor was performed. Surgical treatment of metastases included partial liver or lung resection, radiofrequency ablation (RFA) of liver metastases, or a combination of resection and RFA.
Fifty patients ≥ 18 years of age with resectable hepatic or lung metastasis with adequate organ function and hematological parameters were enrolled from seven centers in the Netherlands in this single-arm, Phase 2, open-label study between April 2006 and December 2010. Patients who received previous pelvic radiotherapy and 5 fluorouracil-based chemotherapy for any disease were excluded. Baseline imaging of the primary tumor and preoperative assessment was by CT or MRI. Distant metastatic disease at baseline, after two cycles, and upon completion of therapy was assessed by CT imaging. Following completion of therapy, patients were followed every 3 months with clinical examination, carcino-embryonic antigen (CEA) levels, and imaging studies. The primary endpoint was the percentage of patients receiving radical surgical treatment of all tumor sites (R0). Secondary endpoints were 2-year survival, 2-year recurrence rate, and treatment-related toxicity. Pathologic complete response after neoadjuvant treatment (ypCR) was defined as the absence of residual tumor cells in the primary tumor and lymph node specimens (ypT0N0). Down staging was assessed by comparing pathologic stage (ypT) with baseline clinical T-stage. Radical (R0) RFA was assessed by 1-week post-procedural CT scan with an ablation zone with tumor-free margins ≥ 5 mm. Toxicity was graded according to NTCAE version 3.0 and surgical complications were also compiled.
All patients had an ECOG performance status ≤ 1. Eighty-four percent of the patients had liver metastasis and 64% had cT3N1-2 disease. All 50 patients received RT and 49 patients received preoperative chemotherapy, with 84% of the patients receiving all six cycles of the planned therapy. Ninety-six percent of the patients (48/50) were scheduled for surgery by curative intent, and 72% of patients underwent R0 resection of all surgical sites. Ninety percent of the patients were able to undergo resection of their primary rectal cancer. Pathological complete response was seen in 26% of the patients. Simultaneous resection of primary and metastatic disease was carried out in 26 patients. There were no grade 3 or 4 toxicity-related events observed before or after RT. Six percent of the patients discontinued bevacizumab, and the most common grade 1 or 2 toxicities observed were neuropathy, fatigue, and nausea. The median time from completion of chemotherapy to surgery was 39 days. No patient deaths were observed within 90 days after surgery. The 2-year overall survival rate was 80% (40 of 50 patients) in the intent-to-treat group, and the 2-year recurrence rate after R0 resection was 64% (23 of 36 patients). Median time to recurrence was 13 (range 7-20) months.
COMMENTARY
The authors have clearly demonstrated that short-course RT followed by chemotherapy is a safe and efficacious therapy for patients with metastatic rectal cancer. The complete pathological responses seen in this trial (26%) are similar to response rates observed in patients receiving concurrent chemo-radiotherapy regimens. In addition, 47% down staging was observed from clinical to pathological stage similar to what has been observed with long-course RT. The 2-year recurrence rates and survival rates were also comparable to other studies enrolling patients with similar disease severity.
However, although the rate of surgical morbidity was comparable to other studies, the need for additional surgical intervention for postoperative complications was more frequent. The Hartmann procedure was the most common surgical procedure performed (53%) rather than immediate anastomosis to avoid complications. The rates of sphincter preservation were not reported as an endpoint.
This was a relatively small, single-arm study and, thus, the generalizability of results is limited. Yet, this aggressive approach for the management of metastatic rectal cancer was shown to be feasible and the results are clearly sufficient to form a basis for a randomized controlled trial in patients with resectable metastatic disease.
References
1.Verhoef C, et al. The "liver-first approach" for patients with locally advanced rectal cancer and synchronous liver metastases. Dis Colon Rectum 2009;52:23-30.
2.Bujko K, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomized trial comparing short-term radiotherapy vs conventionally fractionated radio chemotherapy. Radiother Oncol 2004;72:15-24.
3.Bosset JF, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: Preliminary results-EORTC 22921. J Clin Oncol 2005;23:5620-5627.
4.Scappaticci FA, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005;91:173-180.
5.Willett CG, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J Clin Oncol 2009;27:3020-3026.
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