Treatment Option Overview
The management of rectal cancer varies somewhat from that of colon cancer because of the increased risk of local recurrence and a poorer overall prognosis. Differences include surgical technique, the use of radiation therapy, and the method of chemotherapy administration. In addition to determining the intent of rectal cancer surgery (i.e., curative or palliative), it is important to consider therapeutic issues related to the maintenance or restoration of normal anal sphincter, genitourinary function, and sexual function.[1,2]
The approach to the management of rectal cancer is multimodal and involves a multidisciplinary team of cancer specialists with expertise in gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology.
|Stage (TNM Staging Criteria)||Standard Treatment Options|
|Stage 0 Rectal Cancer||Polypectomy or surgery|
|Stage I Rectal Cancer||Surgery with or without chemoradiation therapy|
|Stages II and III Rectal Cancer||Surgery|
|Preoperative chemoradiation therapy|
|Short-course preoperative radiation therapy|
|Postoperative chemoradiation therapy|
|Stage (TNM Staging Criteria)||Treatment Options|
|Stage IV and Recurrent Rectal Cancer||Surgery with or without chemotherapy or radiation therapy|
|First-line chemotherapy and targeted therapy|
Primary Surgical Therapy
The primary treatment for patients with rectal cancer is surgical resection of the primary tumor. The surgical approach to treatment varies according to the following:
- Tumor location.
- Stage of disease.
- Presence or absence of high-risk features (i.e., positive margins, lymphovascular invasion, perineural invasion, and poorly differentiated histology).
- Polypectomy for select T1 cancers.
- Transanal local excision and transanal endoscopic microsurgery for select clinically staged T1/T2 N0 rectal cancers.
- Total mesorectal excision with autonomic nerve preservation techniques via low-anterior resection.
- Total mesorectal excision via abdominoperineal resection for patients who are not candidates for sphincter-preservation, leaving patients with a permanent end-colostomy.
Local excision of clinical T1 tumors is an acceptable surgical technique for appropriately selected patients. For all other tumors, a mesorectal excision is the treatment of choice. Very select patients with T2 tumors may be candidates for local excision. Local failure rates in the range of 4% to 8% after rectal resection with appropriate mesorectal excision (total mesorectal excision for low/middle rectal tumors and mesorectal excision at least 5 cm below the tumor for high rectal tumors) have been reported.[6-10]
For patients with advanced cancers of the mid- to upper rectum, low-anterior resection followed by the creation of a colorectal anastomosis may be the treatment of choice. For locally advanced rectal cancers for which radical resection is indicated, however, total mesorectal excision with autonomic nerve preservation techniques via low-anterior resection is preferable to abdominoperineal resection.[1,2]
The low incidence of local relapse after 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.
Preoperative chemoradiation therapy
Neoadjuvant therapy for rectal cancer, using preoperative chemoradiation therapy, is the preferred treatment option for patients with stages II and III disease. However, postoperative chemoradiation therapy for patients with stage II or III rectal cancer remains an acceptable option.[Level of evidence: 1iA]
Preoperative chemoradiation therapy has become the standard of care for patients with clinically staged T3–T4 or node-positive disease (stages II/III), based on the results of several studies:
Multiple phase II and III studies examined the benefits of preoperative chemoradiation therapy, which include the following:
- Tumor regression and downstaging of the tumor.
- Improved tumor resectability.
- Higher rate of local control.
- Improved toxicity profile of chemoradiation therapy.
- Higher rate of sphincter preservation.
Complete pathologic response rates of 10% to 25% may be achieved with preoperative chemoradiation therapy.[15-22] However, preoperative radiation therapy is associated with increased complications compared with surgery alone; some patients with cancers at a lower risk of local recurrence might be adequately treated with surgery and adjuvant chemotherapy.[23-26]
Postoperative chemoradiation therapy
Preoperative chemoradiation therapy is the current standard of care for stages II and III rectal cancer. However, before 1990, the following studies noted an increase in both disease-free survival (DFS) and overall survival (OS) with the use of postoperative combined-modality therapy:
Subsequent studies have attempted to increase the survival benefit by improving radiation sensitization and by identifying the optimal chemotherapeutic agents and delivery systems.
Fluorouracil (5-FU): The following studies examined optimal delivery methods for adjuvant 5-FU:
(Refer to the Stages II and III Rectal Cancer section of this summary for detailed information about these study results.)
Acceptable postoperative chemoradiation 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 leucovorin (LV).
Findings from the NSABP-R-01 trial compared surgery alone with surgery followed by chemotherapy or radiation therapy. Subsequently, the NSABP-R-02 study, addressed whether adding postoperative radiation therapy to chemotherapy would enhance the survival advantage reported in R-01.[Level of evidence: 1iiA]
In the NSABP-R-02 study, the addition of radiation therapy significantly reduced local recurrence at 5 years (8% for chemotherapy and radiation vs. 13% for chemotherapy alone, P = .02) but failed to demonstrate a significant survival benefit. Radiation therapy appeared to improve survival among patients younger than 60 years and among patients who underwent abdominoperineal resection.
While this trial has initiated discussion in the oncologic community about the proper role of postoperative radiation therapy, omission of radiation therapy seems premature because of the serious complications of locoregional recurrence.
Table 8 describes the chemotherapy regimens used to treat rectal cancer.
|Regimen Name||Drug Combination||Dose|
|5-FU = fluorouracil; IV = intravenous; LV = leucovorin.|
|Arbeitsgemeinschaft Internistische Onkologie (AIO) or German AIO||Folic acid, 5-FU, and irinotecan||Irinotecan (100 mg/m2) and LV (500 mg/m2) administered as 2-hour infusions on day 1, followed by 5-FU (2,000 mg/m2) IV bolus administered via ambulatory pump weekly over 24 hours, 4 times a year (52 weeks).|
|CAPOX||Capecitabine and oxaliplatin||Capecitabine (1,000 mg/m2) twice daily on days 1 through 14, plus oxaliplatin (70 mg/m2) on days 1 and 8 every 3 weeks.|
|Douillard||Folic acid, 5-FU, and irinotecan||Irinotecan (180 mg/m2) administered as a 2-hour infusion on day 1, LV (200 mg/m2) administered as a 2-hour infusion on days 1 and 2, followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump over 22 hours every 2 weeks on days 1 and 2.|
|FOLFIRI||LV, 5-FU, and irinotecan||Irinotecan (180 mg/m2) and LV (400 mg/m2) administered as 2-hour infusions on day 1, followed by a loading dose of 5-FU (400 mg/m2) IV bolus administered on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump over 46 hours every 2 weeks.|
|FOLFOX4||Oxaliplatin, LV, and 5-FU||Oxaliplatin (85 mg/m2) administered as a 2-hour infusion on day 1, LV (200 mg/m2) administered as a 2-hour infusion on days 1 and 2, followed by a loading dose of 5-FU (400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump over 22 hours every 2 weeks on days 1 and 2.|
|FOLFOX6||Oxaliplatin, LV, and 5-FU||Oxaliplatin (85–100 mg/m2) and LV (400 mg/m2) administered as 2-hour infusions on day 1, followed by a loading dose of 5-FU (400 mg/m2) IV bolus on day 1, then 5-FU (2,400–3,000 mg/m2) administered via ambulatory pump over 46 hours every 2 weeks.|
|FOLFOXIRI||Irinotecan, oxaliplatin, LV, 5-FU||Irinotecan (165 mg/m2) administered as a 60-minute infusion, then concomitant infusion of oxaliplatin (85 mg/m2) and LV (200 mg/m2) over 120 minutes, followed by 5-FU (3,200 mg/m2) administered as a 48-hour continuous infusion.|
|FUFOX||5-FU, LV, and oxaliplatin||Oxaliplatin (50 mg/m2) plus LV (500 mg/m2) plus 5-FU (2,000 mg/m2) administered as a 22-hour continuous infusion on days 1, 8, 22, and 29 every 36 days.|
|FUOX||5-FU plus oxaliplatin||5-FU (2,250 mg/m2) administered as a continuous infusion over 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin (85 mg/m2) on days 1, 15, and 29 every 6 weeks.|
|IFL (or Saltz)||Irinotecan, 5-FU, and LV||Irinotecan (125 mg/m2) plus 5-FU (500 mg/m2) IV bolus and LV (20 mg/m2) IV bolus administered weekly for 4 out of 6 weeks.|
|XELOX||Capecitabine plus oxaliplatin||Oral capecitabine (1,000 mg/m2) administered twice daily for 14 days plus oxaliplatin (130 mg/m2) on day 1 every 3 weeks.|
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 after 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. Patients treated with radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than do patients who undergo surgical resection alone.[24,32-37]
An analysis of patients treated with postoperative chemotherapy and radiation therapy suggests that these patients may have more chronic bowel dysfunction than do patients who undergo surgical resection alone. A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with radiation therapy.
- The use of high-energy radiation machines.
- The use of multiple pelvic radiation fields.
- Prone patient positioning.
- Customized patient molds (belly boards) to exclude as much small bowel as possible from the radiation fields and immobilize patients during treatment.
- Bladder distention during radiation therapy to exclude as much small bowel as possible from the radiation 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 3-dimensional or other advanced radiation planning techniques.
In Europe, it is common to deliver preoperative radiation therapy alone in one week (5 Gy × five daily treatments) followed by surgery one week later, rather than the long-course chemoradiation approach used in the United States. One reason for this difference is the concern in the United States for heightened late effects when high radiation doses per fraction are given.
A Polish study randomly assigned 316 patients to preoperative long-course chemoradiation therapy (50.4 Gy in 28 daily fractions with 5-FU and LV) or short-course preoperative radiation therapy (25 Gy in five fractions). 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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