Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a series of consecutive patients with locally advanced rectal cancer, a novel treatment regimen was studied that involved "induction chemotherapy" followed by chemoradiotherapy prior to total mesorectal excision. The investigators found a high local control rate and promising disease-free and overall survival outcomes.
Source: Schou JV, et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Ann Oncol 2012;23:2627–2633.
Approximately 50% of patients with rectal cancer present with locally advanced disease, and for these patients the current standard of care includes preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME).1,2 The addition of preoperative CRT has resulted in improved rates of local control but not disease-free survival (DFS) or overall survival (OS).3,4 CRT as it is currently configured has limited effect on the rates of distant recurrence. Thus, an effort to eliminate distant metastatic disease as a component of the initial treatment plan would seem worthwhile.
To this end, Schou and colleagues from Herlev Hospital in Copenhagen developed a modified CRT program that included initial capecitabine/oxaliplatin (CAPEOX) chemotherapy followed by CRT all prior to TME.
A total of 84 consecutively admitted patients with T4 tumors, T3N+ tumors, or T3 tumors involving or with a distance ≤ 1 mm to the mesorectal fascia were included. Initial chemotherapy was with capecitabine at 2000 mg/m2 administered in divided doses twice a day for 14 days followed by 7 days of rest. Oxaliplatin was given every 3 weeks at a dose of 130 mg/m2 for two cycles. Radiation therapy (RT) was given with 54 Gy in 27 fractions (five fractions/week). Capecitabine (1650 mg/m2 in divided doses) was continued through the radiation therapy and administered on the days of RT.
Of 84 consecutively admitted patients starting induction CAPEOX, 77 patients underwent surgery. R0 resection was achieved in 94% and T downstaging in 69%. In the intention-to-treat group, pathological complete response was seen in 23%. Five-year DFS and OS were 63% (95% confidence interval [CI], 52.2%-73.7%) and 67% (95% CI, 56.1%-77.3%), respectively.
As expected, nodal status assessed from the TME specimen proved to be an important predictor of both DFS and OS. Twenty-one patients (28%) had malignant lymph nodes in the resected specimen. For patients without malignant lymph nodes, the 5-year OS was 85% (95% CI, 75.3%-94.9%) compared with 44% (95% CI, 20.7%-66.7%) in patients with malignant lymph nodes and a hazard ratio of 4.5 (95% CI, 1.8-11.1) was seen. The 5-year DFS was 86% (95% CI, 75.9%-95.1%) for patients without malignant lymph nodes compared with 29% (95% CI, 8.8%-48.4%) in patients with malignant lymph nodes and the hazard ratio was 7.5 (95% CI, 3.1-18).
Grade 3/4 toxicity was seen in 18%, and four deaths occurred within 2 months of therapy. Of the four deaths, one had colitis, leading to sepsis. The second developed acute renal dysfunction, bilateral bronchopneumonia, and several minor pulmonary embolisms as determined by autopsy. The third died of ileus and the autopsy report also showed signs of heart failure. The fourth patient died of unknown cause after two series of CAPEOX. Two incidents of cerebral vascular accident were observed, one after a single cycle of CAPEOX and the second halfway through CRT, respectively. One patient had a resectable tumor after finishing both induction chemotherapy and chemoradiation but was considered unfit for surgery. Morbidity within 30 days of surgery was fistula formation (n = 3), anastomotic leak (n = 3), pelvic abscess (n = 2), and local infection (n = 7).
Presurgery RT and CRT have proven effective in reducing local recurrence.3 In a recent pooled analysis of 2795 patients receiving either RT or CRT prior to TME, it was noted that for those receiving CRT there was an apparent benefit in terms of distant metastases and overall survival.5 Yet, distant recurrence in liver, lung, or in other organs remains a fairly common occurrence even in those receiving CRT. The currently reported approach in which an initial chemotherapy "induction" was given prior to CRT was founded on the rationale that more intensive early chemotherapy might successfully eliminate existing microscopic metastases and result in fewer late recurrences. The results were encouraging, particularly because no distant recurrences were identified after 36 months (through 56 months of follow-up).
Nonetheless, there are some precautionary concerns. Although consecutive patients were treated according to protocol, this was a single-institution, retrospective analysis and such treatment outcomes may not be generalized. Furthermore and importantly, there was significant toxicity during the chemotherapy induction precluding the application of CRT/TME in a few patients. Thus, the observed excellent local control rate and promising DFS and OS data need to be confirmed by prospective, randomized clinical trial before "induction chemotherapy" becomes a community standard.
1. Bosset JF, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114-1123.
2. Gerard JP, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 2006;24:4620-4625.
3. Kapiteijn E, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-646.
4. Peeters KC, et al. The TME trial after a median follow-up of 6 years: Increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007;246:693-701.
5. Valentini V, et al. Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol 2011;29:3163-3172.