New agents. Both cytotoxic and targeted chemotherapeutic agents have been incorporated into phase I/II preoperative CMT regimens. Most of the regimens report higher pCR rates compared with 5-FU alone.
Four randomized trials have examined the impact that adding oxaliplatin(Drug information on oxaliplatin) to 5-FU- or capecitabine(Drug information on capecitabine)-based CMT has on response rates and acute toxicity in patients with cT3-4 and/or N+ rectal cancer. The STAR (Studio Terapia Adiuvante Retto)-01 trial randomized 747 patients to preoperative CMT with 50.4 Gy plus CI 5-FU with or without oxaliplatin. There was a significant increase in grade 3+ toxicity with oxaliplatin (24% vs 8%, P < .001), with no improvement in pCR (15% vs 16%).
In the ACCORD (Action Clinique Coordonnées en cancérologie Digestive) trial, 598 patients were randomized to preoperative CMT with 50 Gy plus capecitabine plus oxaliplatin (CAPOX) vs 45 Gy plus capecitabine. There was a similar significant increase in grade 3+ toxicity with oxaliplatin (25% vs 11%, P < .001), with no improvement in pCR (19% vs 14%).
NSABP R-04 was a four-arm investigation (2 × 2 comparison) of CI 5-FU vs capecitabine-based preoperative CMT (50.4 Gy) with or without oxaliplatin. A total of 1606 patients with cT3 and/or N+ disease were randomized. Addition of oxaliplatin (to either 5-FU or capecitabine) was associated with significantly more grade 3+ diarrhea (15% vs 7%, P = .0001), with no improvement in pCR (21% vs 19%) or sphincter-sparing surgery (60% vs 64%).
The German CAO/ARO/AIO-04 trial randomized 1265 patients with cT3-4 and/or N+ disease to the pre-operative arm of CAO/ARO/AIO-94 (50.4 Gy + 5-FU) vs 50.4 Gy/5-FU + oxaliplatin (at 50 mg/m2 weekly). In contrast with the STAR-01, ACCORD, and NSABP R-04 trials, patients who received oxaliplatin-based CMT had a significant improvement in pCR (17% vs 13%, P = .045), with no corresponding increase in acute grade 3+ toxicity (23% vs 22%). The results of a similar trial (PETACC-6) are pending.
Since three of four randomized trials reveal an increase in acute toxicity with no benefit in the pCR rate, the current standard is not to include oxaliplatin in preoperative CMT regimens. Data from these trials on local control and survival are not available, however, and this recommendation may need to be modified once these data are reported.
The role of targeted biological agents such as bevacizumab(Drug information on bevacizumab) is being tested. Preliminary phase I trials using pre-operative CMT with CAPOX plus bevacizumab have reported pCR rates of 18% to 24%.[39,40] However, given the lack of a survival benefit in the NSABP C-08 adjuvant colon cancer trial, the ultimate role of bevacizumab in rectal cancer therapy remains unclear.
Although the report from Heidelberg of capecitabine–irinotecan (CAPEIRI)-based CMT cited a pCR rate of 25%, other trials with 5-FU, capecitabine, or CAPOX reported more limited rates of 5% to 12%.[43,44] It is unknown whether the benefit of patient selection based on K-ras expression seen in patients with metastatic disease will be helpful in the adjuvant setting for patients with rectal cancer.
Induction chemotherapy. The Spanish Granada Cancer Registry (GCR)-3 randomized phase II trial compared induction chemotherapy followed by CMT with conventional preoperative CMT followed by surgery and postoperative chemotherapy. A total of 108 patients received 50.4 Gy plus CAPOX preoperatively and were randomized to receive 4 months of CAPOX either by induction or adjuvant (postoperative) therapy. Although the pCR rates were not different (14% vs 13%), grade 3+ toxicity was lower (17% vs 51%, respectively, P = .00004) and the ability to receive all four chemotherapy cycles was higher (93% vs 51%, P = .0001) with induction.
Radiation techniques and dose
The clinical utility of routine 3-D and intensity-modulated radiation therapy (IMRT) planning techniques is being investigated.[46,47] The most important contributions of 3-D treatment planning are the ability to plan and localize the target and normal tissues at all levels of the treatment volume and to obtain dose-volume histogram data. An analysis of 3-D treatment planning techniques suggests that the volume of small bowel in the radiation field is decreased with protons as compared with photons. IMRT treatment planning techniques can further decrease the volume of small bowel in the field, but the clinical benefit of IMRT compared with 3-D or conventional treatment delivery remains to be determined.Guidelines for the definition and delineation of the clinical target volumes are available from a number of investigators.[50,51]
The Radiation Therapy Oncology Group (RTOG) R-0012 phase II randomized trial compared twice-a-day preoperative CMT up to 60 Gy (1.2 Gy to 45.6 Gy, with a boost of 9.6 Gy to 14.4 Gy) with conventional fractionation (1.8 Gy to 45 Gy, with a boost of 5.4 Gy to 9.0 Gy) plus 5-FU/irinotecan. Both regimens resulted in a 28% pCR rate but were also associated with a greater than 40% rate of grade 3/4 acute toxicity.
Historically, adjuvant chemotherapy was administered in combination with CMT after surgical resection for stage II and III rectal adenocarcinoma. The introduction of preoperative CMT for clinical stage II and III rectal cancer as the preferred standard of care has resulted in variation in the use of adjuvant chemotherapy after neoadjuvant CMT and surgery. Some potential reasons for failure to administer adjuvant chemotherapy include uncertainty as to whether adjuvant chemotherapy is necessary for patients who demonstrated a pCR after neoadjuvant CMT and concerns that patients who have undergone CMT and surgery may not be able to tolerate additional therapy after surgery. A question of significant importance is whether the relatively brief exposure to chemotherapy in combination with preoperative radiation therapy (which generally includes infusion 5-FU or capecitabine) is truly sufficient to improve survival, particularly for high-risk rectal cancer patients. Survival rates in rectal cancer are a persistent problem; only about one-third of patients with stage IIC and IIIC rectal cancer, for example, survive 5 years. The 5-year-survival rates of stage II A (64.5%) and IIB (51.6%) rectal cancer are also suboptimal. An extrapolation from colon cancer clinical trials would strongly suggest that approximately 6 months of adjuvant chemotherapy with FOLFOX is the optimal current strategy to improve survival for individuals at risk for recurrence (eg, those with stage III colon cancer). Unfortunately, two randomized National Cancer Institute Gastrointestinal Intergroup stage II/III rectal cancer adjuvant clinical trials (E3201, E5204) closed prematurely because of insufficient accrual. As similar trials mature, however, they will provide some information about toxicity of combination therapy, sites of recurrence, and progression-free survival, as well as limited data on overall survival.
Two randomized trials (Table) address whether postoperative chemotherapy is beneficial following preoperative therapy. The European Organisation for Research and Treatment of Cancer (EORTC) trial 22921 was a four-arm randomized study of 1011 patients who received 45 Gy preoperatively, with or without concurrent bolus 5-FU/leucovorin, followed by surgery with or without 4 cycles of postoperative 5-FU/leucovorin. Only 37% of patients had a TME. The FFCD (Fédération Francophone de la Cancérologie Digestive) 9203 was a two-arm trial of 742 patients randomized to preoperative 45 Gy with or without concurrent bolus 5-FU/leucovorin. However, all patients were scheduled to receive postoperative chemotherapy and 73% did receive it.
The EORTC trial demonstrated a significant decrease in local recurrence among patients who received CMT vs radiation (8% to 10% vs 17%, P < .001) but no difference in 5-year survival (65%). Only 43% of patients received 95% or more of the planned postoperative chemotherapy, however, which may explain the negative results. Furthermore, a subset analysis of the EORTC trial revealed that patients who responded to preoperative CMT had a survival benefit from postoperative chemotherapy. This retrospective analysis included the group of 785 patients with cT3-4 tumors who underwent a R0 resection; only those who had tumor downstaging to ypT0-2 disease demonstrated improved 5-year disease-free survival (76.7% vs 65.6%, respectively; P = .013). The FFCD trial reported a similar decrease in local recurrence (8% vs 17%, P < .05) and a corresponding increase in pCR (11% vs 4%, P < .05) with preoperative CMT, but no survival benefit (68% vs 67%).
A pooled analysis of the two trials with a median follow-up of 5.6 years confirmed that patients who received preoperative CMT vs radiation had a significant decrease in local recurrence (11% vs 15%, P = .0001), however there was no difference in 5-year overall survival (66%) for both groups). Other retrospective analyses have indicated that patients who experience pathologic downstaging after treatment with neoadjuvant CMT and surgery were most likely to receive additional benefit from adjuvant chemotherapy.[58-60] For example, two separate retrospective series from MD Anderson including clinical stage II or III rectal cancer patients (117 and 407 patients, respectively) who underwent R0 resection showed improved disease-free survival if significant downstaging was noted and patients received adjuvant chemotherapy.[58,59] A small Canadian retrospective study also showed that those achieving significant downstaging with neoadjuvant CMT had improved progression-free and cause-specific survival.
These results need to be placed in perspective. Given that most patients did not receive adequate doses of postoperative chemotherapy in the EORTC trial, and the FFCD trial only tested the impact of concurrent chemotherapy with preoperative radiation, preoperative CMT followed by surgery and 4 months of postoperative adjuvant chemotherapy remains the standard practice in North America. However, there is still considerable controversy in some European countries regarding the use of postoperative adjuvant chemotherapy.
As mentioned, adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer has resulted in significant improvement in overall survival. Currently, no prospective data are available on patients with stage II and III rectal cancer, to determine the efficacy of adjuvant oxaliplatin combination chemotherapy. Two Intergroup randomized clinical trials that included adjuvant FOLFOX chemotherapy closed prematurely because of lack of accrual (E3201, E5204), and a third phase II study by the Eastern Cooperative Oncology Group (ECOG) does not have mature data at this time (E3204). The German Rectal Cancer Study Group recently reported safety data from their randomized phase III rectal cancer study of 1265 patients (CAO/ARO/AIO-04), comparing neoadjuvant CMT, surgery, and adjuvant 5-FU vs neoadjuvant CMT with 5-FU and oxaliplatin, surgery, and FOLFOX adjuvant chemotherapy. This study is designed to demonstrate whether oxaliplatin-based chemotherapy will improve 3-year disease-free survival.
Most investigators believe that it is reasonable to use the same chemotherapy for adjuvant treatment of colon and rectal cancer. For patients selected to receive postoperative adjuvant chemotherapy, treatment with 4 to 6 months (8 to 12 cycles) of mFOLFOX6 is recommended.
Treatment for patients with locally advanced, resectable rectal cancer has clearly evolved, with significant refinements in preoperative assessment, surgical technique, and use of preoperative CMT. These have improved patient outcomes, including fewer patients requiring a permanent colostomy, preservation of postoperative and sexual function leading to improved quality of life, and declining incidence of local recurrence. Care of patients with locally advanced, resectable rectal cancer must be further optimized. Important issues include the need for surgical and radiation quality control, increasing the use of TME, proper evaluation and careful implementation of emerging surgical technology, decreasing the rate of long-term sequelae of CMT (eg, sexual dysfunction), defining the optimal radiation schedule for individual patients (eg, short course vs long course), defining a select population of patients who may not require radiation, determining the significance of pCR on outcome and integration of adjuvant therapy, and investigating adjuvant therapy strategies to improve the overall survival of rectal cancer patients.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.