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Rectal Cancer Treatment (Professional) (cont.)

Treatment Option Overview

Primary Surgical Therapy

The primary treatment for patients with rectal cancer is surgical resection of the primary tumor. Local excision of clinical T1 tumors is an acceptable surgical technique for appropriately selected patients. For all but T1 tumors, a mesorectal excision is the treatment of choice. Very selected patients with T2 tumors may be candidates for local excision. Local failure rates in the range of 4% to 8% following rectal resection with appropriate mesorectal excision (total mesorectal excision [TME] for low/middle rectal tumors and mesorectal excision at least 5 cm below the tumor for high rectal tumors) have been reported.[1,2,3,4,5]

The low incidence of local relapse following meticulous mesorectal excision has led some investigators to question the routine use of adjuvant radiation therapy. Because of an increased tendency for first failure in locoregional sites only, the impact of perioperative radiation therapy is greater in rectal cancer than in colon cancer.[6]

Preoperative Chemoradiation Therapy

Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3–T4 or node-positive disease, based on the results of several studies.

German Rectal Cancer Study Group

Multiple phase II studies of preoperative chemoradiation suggested that administering radiation therapy prior to surgery improved the toxicity profile of chemoradiation and enhanced the possibility of sphincter-sparing surgery. The German Rectal Cancer Study Group randomly assigned 823 patients with ultrasound (US)-staged T3–T4 or node-positive rectal cancer to either preoperative chemoradiation therapy or postoperative chemoradiation therapy (50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional 5-fluorouracil (5-FU) 1,000 mg/m2 daily for 5 days during the first and fifth weeks of radiation therapy).[7] All patients received a TME and an additional four cycles of 5-FU–based chemotherapy postoperatively.

The overall 5-year survival rates were 76% and 74% for preoperative and postoperative chemoradiation, respectively (P = .80). The 5-year cumulative incidence of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% in the postoperative treatment group (P = .006). Grade 3 or grade 4 acute toxic effects occurred in 27% of the patients in the preoperative treatment group as compared with 40% of the patients in the postoperative treatment group (P = .001); the corresponding rates of long-term toxic effects were 14% and 24%, respectively (P = .01).[7][Level of evidence: 1iA] There was no difference in the number of patients receiving an abdominoperineal resection in each arm. However, among the 194 patients with tumors that were determined by the surgeon before randomization to require an abdominoperineal excision, a statistically significant increase in sphincter preservation was achieved among patients who received preoperative chemoradiation (P = .004).

These results have now been updated with a median follow-up of 11 years.[8] The 10-year overall survival (OS) is equivalent in both arms (10-year OS, 59.6% vs. 59.9%, respectively P = .85). However, a local-control benefit persists among patients treated with preoperative chemoradiation compared with postoperative chemoradiation (10-year cumulative of local relapse, 7.1% vs. 10.1%, respectively; P = .048). There were no significant differences detected for a 10-year cumulative incidence of distant metastases or disease-free survival (DFS). Among the patients assigned to the postoperative chemoradiation treatment arm, 18% actually had pathologically determined stage I disease and were overestimated by endorectal US to have T3 or T4 or N1 disease. A similar number of patients were possibly overtreated in the preoperative treatment group.[8]

National Surgical Adjuvant Breast and Bowel Project (NSABP)

The NSABP R-03 trial similarly compared preoperative with postoperative chemoradiation therapy for patients with clinical T3 or T4 or node-positive rectal cancer. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.4 Gy boost. Although the intended sample size was 900 patients, the study closed early because of poor accrual, with 267 patients. With a median follow-up of 8.4 years, preoperative chemoradiation was found to confer a significant improvement in 5-year DFS (64.7% vs. 53.4% for postoperative patients, P = .011). Similar to the German Rectal Study, there was no significant difference seen in OS between treatment arms (74.5% vs. 65.6%, P = .065 for preoperative vs. postoperative chemoradiation).[9][Level of evidence: 1iiA]

Postoperative Chemoradiation Therapy

Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy with radiation therapy, as well as redefining the techniques for both modalities. The efficacy of postoperative radiation therapy and 5-FU-based chemotherapy for stage II and III rectal cancer was established by a series of prospective, randomized clinical trials from the Gastrointestinal Tumor Study Group (GITSG-7175), the Mayo/North Central Cancer Treatment Group (NCCTG-794751), and the National Surgical Adjuvant Breast and Bowel Project (NSABP-R-01).[10,11,12][Level of evidence: 1iiA] These studies demonstrated an increase in both disease-free survival (DFS) interval and OS when radiation therapy was combined with chemotherapy after surgical resection. Following publication of the results of these trials, experts at a National Cancer Institute-sponsored Consensus Development Conference in 1990 concluded that postoperative combined-modality treatment is recommended for patients with stage II and III rectal carcinoma.[13]

Chemotherapy

Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems. The agents associated with the first successful combined-modality treatments were 5-FU and semustine. Semustine is not commercially available, and previous studies have associated this drug with the potential for increased risks of renal toxic effects and leukemia.

A follow-up randomized trial from GITSG demonstrated that semustine does not produce an additive survival benefit to radiation therapy and 5-FU.[14][Level of evidence: 1iiA] The Intergroup 86-47-51 trial (NCCTG-864751 [MAYO-864751]) showed a 10% improvement in OS with the use of continuous-infusion 5-FU (225 mg/m2 /day) throughout the course of radiation therapy when compared with bolus 5-FU (500 mg/m2 times three injections in the first and fifth weeks of radiation).[15][Level of evidence: 1iiA]

Subsequently, several studies attempted to determine the optimal way to deliver adjuvant 5-FU. The final results of Intergroup 0114 (INT-0114 [CLB-9081]) demonstrated no survival or local control benefit with the addition of leucovorin (LV), levamisole, or both to 5-FU administered postoperatively for stage II and III rectal cancers at a median follow-up of 7.4 years.[16][Level of evidence: 1iiA] Another study, Intergroup 0144 (SWOG-9304 [NCT00002551]), was a three-arm randomized trial designed to determine whether continuous-infusion 5-FU throughout the entire standard six-cycle course of adjuvant chemotherapy was more effective than continuous 5-FU only during pelvic radiation.[17]

  • Arm 1 received bolus 5-FU in two 5-day cycles before (500 mg/m2 /day) and after (450 mg/m2 /day) radiation therapy, with protracted venous infusion 5-FU (225 mg/m2 /day) during radiation therapy.
  • Arm 2 received continuous infusion 5-FU before (300 mg/m2 /day for 42 days), after (300 mg/m2 / day for 56 days), and during (225 mg/m2 /day) radiation therapy.
  • Arm 3 received bolus 5-FU plus LV (5-FU/LV) in two 5-day cycles before (5-FU 425 mg/m2 /day; LV 20 mg/m2 /day) and after (5-FU 380 mg/m2 /day; LV 20 mg/m2 /day) radiation therapy, and bolus 5-FU/LV (5-FU 400 mg/m2 /day; leucovorin 20 mg/m2 /day; days 1 to 4, every 28 days) during radiation therapy. Levamisole (150 mg/day) was administered in 3-day cycles every 14 days before and after radiation therapy.

Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 55% and 49% of patients in the two bolus arms, respectively (i.e., arms 1 and 3) versus 4% of patients in the continuous-infusion arm. No DFS, OS, or locoregional failure (LRF) difference was detected (across all arms: 3-year DFS, 67% to 69%; 3-year OS, 81% to 83%; LRF, 4.6% to 8%).[17][Level of evidence: 1iiA]

Addition of radiation therapy

Although the above data demonstrate a benefit with postoperative radiation therapy and 5-FU chemotherapy for patients with stage II and III rectal cancer, a follow-up study to the NSABP-R-01 trial, the NSABP-R-02 study, addressed whether the addition of radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[18][Level of evidence: 1iiA] The addition of radiation, while significantly reducing local recurrence at 5 years (8% for chemotherapy and radiation vs. 13% for chemotherapy alone, P = .02), demonstrated no significant benefit in terms of survival. The interpretation of the interaction of radiation therapy with prognostic factors, however, was challenging. Radiation appeared to improve survival among patients younger than 60 years, as well as among patients who received abdominoperineal resection. This trial has initiated discussion in the oncologic community as to the proper role of postoperative radiation therapy. Omission of radiation therapy seems premature, since locoregional recurrence remains a clinically relevant problem.

Using current surgical techniques, including TME, it may be possible to identify subsets of patients whose chance of pelvic failure is low enough to omit postoperative radiation. A trial conducted by the Dutch Colorectal Cancer Group (DUT-KWF-CKVO-9504) randomly assigned patients with resectable rectal cancers (stages I–IV) to a short course of radiation (5 Gy × 5 days) followed by TME compared with TME alone and demonstrated no difference in OS at 2 years (82% for both arms).[19][Level of evidence: 1iiA] Local recurrence rates were significantly reduced in the radiation therapy plus TME arm (2.4%) as compared with the TME only arm (8.2%, P < .001).

At present, acceptable postoperative therapy for patients with stage II or III rectal cancer not enrolled in clinical trials includes continuous-infusion 5-FU during 45 Gy to 55 Gy pelvic radiation and four cycles of adjuvant maintenance chemotherapy with bolus 5-FU with or without modulation with LV.

An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction compared with those who undergo surgical resection alone.[20] Improved radiation planning and techniques can be used to minimize treatment-related complications. These techniques include the use of multiple pelvic fields, prone positioning, customized bowel immobilization molds (belly boards), bladder distention, visualization of the small bowel through oral contrast, and the incorporation of three-dimensional or comparative treatment planning.[21,22]

The Role of Oxaliplatin for Localized Disease

Based on the results of several studies, oxaliplatin does not appear to add any benefit in terms of primary tumor response, but it has been associated with increased acute treatment-related toxicity.

Adjuvant oxaliplatin

Oxaliplatin has significant activity when combined with 5-FU-LV in patients with metastatic colorectal cancer. In the randomized Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study, the toxic effects and efficacy of FOLFOX4 (a 2-hour infusion of 200 mg/m2 LV, followed by a bolus of 400 mg/m2 5-FU, and then a 22-hour infusion of 600 mg/m2 5-FU on 2 consecutive days every 14 days for 12 cycles, plus a 2-hour infusion of 85 mg/m2 oxaliplatin on day 1, given simultaneously with the LV) were compared with the same 5-FU-leucovorin regimen without oxaliplatin when administered for 6 months.[23] Each arm of the trial included 1,123 patients.

Preliminary results of the study, with 37 months of follow-up, demonstrated a significant improvement in DFS at 3 years (77.8% vs. 72.9%; P = .01) in favor of FOLFOX4. When initially reported, there was no difference in OS.[24][Level of evidence: 1iiDii] Further follow-up at 6 years demonstrated that the OS for all patients (both stage II and stage III) entered into the study was not significantly different (OS = 78.5% vs. 76.0%; HR, 0.84; 95% CI, 0.71–1.00). On subset analysis, the 6-year OS in patients with stage III colon cancer was 72.9% in the patients receiving FOLFOX and 68.9% in the patients receiving 5-FU/LV (HR, 0.80; 95% CI, 0.65–0.97, P = .023).[24][Level of evidence: 1iiA] Patients treated with FOLFOX4 experienced more frequent toxic effects, consisting mainly of neutropenia (41% >grade 3) and reversible peripheral sensory neuropathy (12.4% >grade 3). These results are still preliminary, and additional information with regard to OS is anticipated. Nevertheless, these data suggest that FOLFOX4 may be a therapeutic option for patients with resected stage III colon cancer.[25]

The results of the now completed NSABP C-07 study confirmed and extended the results of the MOSAIC trial.[26] In NSABP C-07, 2,492 patients with stage II or III colon cancer were randomly assigned to receive either FLOX (2-hour intravenous infusion of 85 mg/m2 oxaliplatin on days 1, 15, and 29 of each 8-week treatment cycle, followed by a 2-hour intravenous infusion of 500 mg/m2 LV plus bolus 500 mg/m2 5-FU 1 hour after the start of the LV infusion on days 1, 8, 15, 22, 29, and 36, followed by a 2-week rest period, for a total of three cycles [24 weeks]) or the same chemotherapy without oxaliplatin (Roswell Park regimen). The 3- and 4-year DFS rates were 71.8% and 67% for the Roswell Park regimen and 76.1% and 73.2% for FLOX, respectively. The hazard ratio was 0.80 (95% confidence interval [CI], 0.69–0.93), a 20% risk reduction in favor of FLOX (P <.004).

Adjuvant chemotherapy following chemoradiation therapy and surgery

Many academic oncologists recommend that FOLFOX be considered the standard for adjuvant chemotherapy in rectal cancer. However, there are no data in rectal cancer to support this consideration. FOLFOX has become the standard arm in the latest Intergroup study evaluating adjuvant chemotherapy in rectal cancer. An Eastern Cooperative Oncology Group trial (ECOG-E5202 [NCI-2009-00562]) randomly assigned patients with stage II or III rectal cancer who have received preoperative or postoperative chemoradiation therapy to 6 months of FOLFOX with or without bevacizumab.

Oxaliplatin with chemoradiation therapy

Oxaliplatin has also been shown to have radiosensitizing properties in preclinical models;[27] and phase II studies combining this agent with fluoropyrimidine-based chemoradiation have reported pathologic complete response (pCR) rates ranging from 14% to 30%.[28,29,30,31,32] Data from multiple studies have demonstrated a correlation between rates of pCR and endpoints including distant metastasis-free survival, DFS, and OS.[33,34,35]

pCR was the primary endpoint (albeit never validated as a true surrogate of OS) in the ACCORD 12/0405-Prodige 2 trial, which randomly assigned 598 patients with clinically staged T2 or T3 or resectable T4 rectal cancer accessible to digital rectal examination to either preoperative radiation (45 Gy in 25 fractions over 5 weeks) with capecitabine (800 mg/m2 twice daily five of every 7 days) or to a higher dose of radiation (50 Gy in 25 fractions over 5 weeks) with the same dose of capecitabine and oxaliplatin (50 mg/m2 weekly).[36] TME was performed in 98% of both groups at a median interval of 6 weeks after chemoradiation was completed. Although a higher percentage of patients achieved a pCR in the oxaliplatin-treated group (19.2% vs. 13.9%), the difference did not reach statistical significance (P = .09). Moreover, the rate of grade 3 or 4 toxicity was significantly higher in the oxaliplatin-treated group (25% vs. 11%, P < .001), and there was no difference in sphincter-sparing surgery (75% vs. 78%). Therefore, there is no current role for off-trial use of concurrent oxaliplatin and radiation in the treatment of patients with rectal cancer.

The STAR-01 trial similarly investigated the role of oxaliplatin combined with 5-FU chemoradiation for locally advanced rectal cancer.[37] This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary endpoint was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported. The rate of pCR was equivalent at 16% in both arms (OR 0.98; 95% CI, 0.66–1.44, P = .904). Additionally, there was no difference noted in the rate of pathologically positive lymph nodes, tumor infiltration beyond the muscularis propria, or the rate of circumferential margin positivity. Again, an increase in grades 3 to 4 treatment-related acute toxicity was noted with the addition of oxaliplatin (24% vs. 8%, P <.001). Longer-term outcomes including OS have not yet been reported.[37][Level of evidence: 1iiA]

The NSABP-R-04 trial randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:

  1. Intravenous continuous infusion (IVCI) 5-FU with radiation therapy.
  2. Capecitabine with radiation therapy.
  3. IVCI 5-FU plus weekly oxaliplatin with radiation therapy.
  4. Capecitabine plus weekly oxaliplatin with radiation therapy.

The primary objective of this study is locoregional disease control.

Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated that there was no significant difference in the rates of pCR, sphincter-sparing surgery, or surgical downstaging between the 5-FU and capecitabine regimens or between the regimens with and without oxaliplatin. However, similar to the other studies, patients treated with oxaliplatin had significantly higher rates of grade 3 and 4 acute toxicity (15.4% vs. 6.6%, P < .001).[38][Level of evidence: 1iiD]

The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation with 5-FU (week 1 and week 5) or concurrent chemoradiation with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2).[39] In contrast to the previous studies, a significantly higher rate of pCR was achieved in patients who received oxaliplatin (17% vs. 13%, P = .038). There was no significant difference in rates of overall grades 3 and 4 toxicity, however, diarrhea and nausea and vomiting were more common among those treated with oxaliplatin. The 5-FU schedules in this study differed between the two arms, which may have contributed to the difference in outcomes noted. Longer follow-up will be necessary to determine the effect on the primary endpoint of the study, DFS.[39][Level of evidence: 1iiD]

Treatment Toxicity

The acute side effects of pelvic radiation therapy for rectal cancer are mainly the result of gastrointestinal toxicity, are self-limiting, and usually resolve within 4 to 6 weeks of completing treatment. Of greater concern is the potential for late morbidity following rectal cancer treatment. Patients who undergo aggressive surgical procedures for rectal cancer can have chronic symptoms, particularly if there is impairment of the anal sphincter.[40] Patients treated with adjuvant radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than those who undergo surgical resection alone.[41,42,43,44,45,46,47]

A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with adjuvant therapy.[40] Improved radiation planning and techniques may minimize these acute and late treatment-related complications. These techniques include:[48,49,50]

  • The use of high-energy radiation machines.
  • The use of multiple pelvic fields.
  • Prone patient positioning.
  • Customized patient molds (belly boards) to exclude as much small bowel as possible from the fields and immobilize patients during treatment.
  • Bladder distention during radiation therapy to exclude as much small bowel as possible from the fields.
  • Visualization of the small bowel through oral contrast during treatment planning so that when possible, the small bowel can be excluded from the radiation field.
  • The use of three dimensional or other advanced radiation planning techniques.

In Europe, it is common to deliver preoperative radiation therapy alone in one week (5 Gy x 5 daily treatments) followed by surgery one week later, as compared to the long-course chemoradiation approach in the United States. One reason for this difference is the concern in the U.S. for heightened late effects with high radiation doses per fraction.

A Polish study randomly assigned 316 patients between preoperative long course chemoradiation (50.4 Gy in 28 daily fractions with 5-FU and LV) and short-course preoperative radiation therapy (25 Gy in 5 fractions).[47] Although the primary endpoint was sphincter preservation, late toxicity was not statistically significantly different between the two treatment approaches (7% long course vs. 10% short course). Of note, data on anal sphincter and sexual function were not reported, and toxicity was physician determined, not patient reported.

Ongoing clinical trials comparing preoperative and postoperative adjuvant chemoradiation therapy should further clarify the impact of either approach on bowel function and other important quality-of-life issues (e.g., sphincter preservation) in addition to the more conventional endpoints of DFS and OS.

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