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Adjuvant Therapy
Postoperative
The problem of unacceptably high local recurrence after surgery has led to many studies exploring the potential benefit of postoperative adjuvant therapy (12,40). One of the advantages of postoperative radiation is the ability to selectively treat patients at high risk of local failure on the basis of pathologic stage. Disadvantages include a potentially hypoxic postsurgical bed, making radiation less effective and potentially higher complications due to increased small bowel in the radiation field, and a larger treatment volume, especially if the patient undergoes an APR and the perineal scar needs to be covered.
There have been several large trials of postoperative radiation with or without chemotherapy (3,94,138). In general, surgery alone has resulted in a 25% local failure rate and 40% to 50% overall survival for T3 or T4 or node-positive patients, while radiation with the addition of chemotherapy has yielded a lower local failure rate of 10% to 15% and higher overall survival rate of 50% to 60%.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-01study randomized 555 patients into three arms after surgery: (a) observation, (b) postoperative chemotherapy of eight cycles of MOF (5FU, CCNU [semustine], and vincristine), and (c) postoperative radiation treatment alone of 46 to 47 Gy (49). Postoperative chemotherapy improved disease-free survival but not overall survival. The benefit of improved overall survival with MOF was restricted to men in subset analysis. Postoperative radiation treatment trended toward improved local control but not overall survival.
The NSABP R-02 study (182) enrolled 694 stage B and C patients and asked two questions in its study design: (a) Does the addition of radiation to chemotherapy improve outcome? and (b) Is MOF superior to 5-FU/LV in men? There were four treatment arms for males and two treatment arms for females. Five cycles of MOF were compared to six cycles of 5-FU/LV with or without radiation for the men. For women, 5-FU/LV was compared against additional radiation. The radiation dose was 50.4 Gy. At 5 years, the locoregional failure was 13% for the chemotherapy only arm as compared to 8% with the addition of radiation and chemotherapy. Additionally, 5-FU/LV showed better relapse-free survival and disease-free survival but not overall survival as compared to MOF. The conclusions of the two NSABP trials were that while postoperative radiation treatment did not appear to improve overall survival, there was an improvement in local control.
Two trials that did show an improvement in survival were the Gastrointestinal Tumor Study Group (GITSG) and North Central Cancer Treatment Group (NCCTG) studies. GITSG study was a four-arm trial of 227 patients with stage B2 and C rectal cancer who were randomized to either (a) surgery alone, (b) postoperative chemotherapy of bolus 5-FU (500 mg/m2 in weeks 1 and 5 and methyl-CCNU (semustine given day 1), (c) postoperative radiation treatment of 40 to 48 Gy split course, or (d) postoperative chemotherapy and radiation therapy of 40 to 44 Gy plus bolus 5-FU (138). The severe acute toxicity was 61% in the combined modality treatment arm as compared to 31% with chemotherapy only and 18% with radiation only. In a 9-year update, postoperative chemotherapy and radiation therapy improved the overall survival to 54% versus 27% with observation after surgery. There was a prolonged time to recurrence and a decreased recurrence rate of 33% versus 55% with combined adjuvant treatment. Local failure rate was decreased to 10% versus 25% with surgery alone. Therefore, this trial concluded a significant overall survival advantage of nearly double for patients who had combined modality treatment after surgical resection.
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The Mayo-NCCTG compared postoperative radiation therapy against postoperative radiation therapy and chemotherapy (94). Two hundred and four patients were included with T3 or T4 or node-positive tumors and all received one cycle of 5FU and semustine before randomization. The radiation dose was 45 to 50.4 Gy. The 5-year local regional failure was higher in the radiation only arm of 25% versus 15%, and the 5-year overall survival rate was 40% versus 55%. Combined postoperative chemotherapy and radiation therapy reduced recurrence by 34%, local recurrence by 46%, and distant metastases by 37%. Cancer deaths were reduced by 36%, and overall deaths were reduced by 29%.
Based on the results of these studies, the National Institute of Health Consensus Conference recommended that the combined use of radiation and chemotherapy is more effective than postoperative radiation alone, with a greater potential for improved survival, and is recommended. Several subsequent studies have attempted to delineate the kind of chemotherapy and delivery options in the combined modality treatment (129).
NCCTG 86–47-51 study compared chemotherapy regimens to be added to the postoperative radiation. Six hundred sixty stage II or III patients were randomized to systemic chemotherapy given (5-FU vs. 5-FU + semustine) and the method of delivery (bolus vs. continuous infusion 5-FU) (131). Nine weeks of chemotherapy were given followed by the experimental chemotherapy concurrently with 50.4 to 54 Gy radiation with additional chemotherapy thereafter. The bolus 5FU dose was 500 mg/m2 on day 1 to 5 during weeks 1 and 5, whereas the continuous infusion 5-FU was 225 mg/m2 per day. With a median follow-up of 46 months, there was a 27% improvement in relapse-free survival of 63% versus 53% in favor of continuous infusion 5-FU. The 4-year overall survival was 70% versus 60% in favor of continuous infusion. The time to relapse and the distant metastasis rate (31% vs. 40%) were also lower. There was no difference in local recurrence. Bolus 5-FU had a higher rate of leucopenia, while continuous infusion had more acute severe diarrhea. Semustine was of no additional benefit.
Intergroup 0114 study compared different chemotherapy regimens with radiation treatment for 1,695 patients (159). There were four arms of the study comparing (a) bolus 5-FU alone, (b) 5-FU and leucovorin, (c) 5FU plus levamisole, and (d) 5-FU and leucovorin plus levamisole. The levamisole was not given during the radiation treatment. The radiation treatment dose was 45 Gy with a 5.4- to 9-Gy boost to a total of 50.4 to 54 Gy. With a median follow-up of 7.4 years, there was no difference in overall survival or disease-free survival among the four groups. The three-drug regimen had a greater toxicity. Levamisole and leucovorin did not appear to add any benefit to the 5-FU.
Favorable T3N0
Several studies have shown that there may be a subset of tumors that might not need adjuvant therapy because of low risk of recurrence with surgery alone. Memorial Sloan-Kettering evaluated 95 patients with T3N0 rectal cancer treated by surgery alone (109). Seventy-nine patients underwent LAR and 16% underwent APR, both with sharp mesorectal excision. With 53.3-month follow-up, 6% had a local recurrence, 13% had distant metastases, and 3% had both local recurrence and distant metastases. Lymphovascular invasion was the only histological factor that was important for local recurrence. This study suggests that sharp mesorectal excision with LAR or APR for T3N0 rectal cancers results in low local recurrences of <10% without the use of adjuvant therapy.
In a retrospective review of 117 patients with T3N0 rectal cancer treated at MGH Willett et al. (170) reported that perirectal tumor invasion ≥2 mm, LVI, and poorly differentiated histology were independent factors for increased risk of distant metastasis and worse relapse-free survival. Only depth of invasion was significant for local control. Of the 25 patients with favorable histological features (well differentiated/moderately differentiated, invading <2 mm into the perirectal fat, no LVI), the 10-year actuarial local control and relapse-free survival were 95% and 87%, respectively, as compared to 71% and 55% in the unfavorable group. Thus, a limited subset of patients with T3N0 rectal cancer may have an excellent outcome with surgery alone, but there are no randomized data to support the omission of adjuvant therapy for this group of patients at the present time.
Side Effects of Combined Chemoradiation
Although combined chemoradiation is the recommended approach for postoperative adjuvant therapy, it has to be kept in mind that the acute side effects can be considerably greater than postoperative radiation alone. In the NCCTG 79–47-51 study the incidence of nausea, vomiting, and diarrhea were significantly higher than with radiation alone (114). Patients also developed more stomatitis with mucosal ulceration and a slightly greater hematological toxicity as well (9% vs. 2%). Hydration is therefore critical in these patients as some patients may exhibit hypersensitivity to 5-FU with grade 4 diarrhea and an occasional death due to dehydration. Patients need to be supported with intravenous fluids and treatment interruption until the diarrhea is stabilized. Severe late toxicity was similar in both arms (7%). The incidence of diarrhea is greater with continuous infusion of 5-FU as compared to bolus 5-FU, and hand/foot syndrome is also more common in infusional therapy (97,114). In the Intergroup trials, 24% of patients receiving concurrent pelvic radiation and continuous infusion 5-FU experienced severe or life-threatening diarrhea (113). Chronic bowel injury was seen in 25% of the patients treated with postoperative radiation.
A key late side effect with postoperative radiation in patients undergoing low anterior resection is rectal urgency with frequent bowel movements, known as clustering. Patients can have six to 10 bowel movements in a short period of time, which can be quite distressing. There is also the likelihood of frequent nighttime bowel movements and occasional incontinence. These symptoms are related to the development of anastomotic strictures and fibrosis with lack of elasticity of the neorectum (93,101).
Treatment Technique for Postop Adjuvant Treatment
External-beam treatment portals for rectal carcinoma should always encompass the sites at greatest risk: The presacral space, the primary tumor site, and (for post-APR cases) the perineum. Other areas at risk include the internal iliac and distal common iliac nodes. The risk in the para-aortic region is sufficiently low, and the morbidity from treatment is sufficiently high to exclude this region from adjuvant rectal cancer radiation portals. The external iliac nodes should be covered for lesions extending to the dentate line.
In general, patients with rectal carcinoma should be treated in the prone position because this reduces the volume of small bowel within the pelvis (54). For patients with prior pelvic surgery, maneuvers to reduce volume of small bowel include treatment with a full bladder and the use of bowel-displacement techniques such as a belly board (foam board table with a cutout to allow the upper-abdominal contents to fall forward) or a foam board mound designed to push the full bladder posteriorly and cephalad (54). The use of shaped lateral fields reduces the dose to small bowel located in the anterior superior aspects of the pelvis.
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If conventional (two-dimensional) treatment planning is used, a four-field (anteroposterior/posteroanterior [AP/PA]/right/left [R/L] lateral) or three-field (PA/R/L lateral) technique generally is used. The superior port edge is placed at the L4/L5 interspace—usually in the mid-L5 vertebral body. The distal port edge should be 5 cm below palpable tumor for patients receiving preoperative treatment. For postoperative cases the distal port edge is about 5 cm below the best estimate of the preoperative tumor bed and (if an APR has been performed) below the perineum. Anterior and posterior portals must have at least a 1.5-cm margin on the pelvic brim. There is an underappreciated incidence of lateral pelvic lymph node involvement that is not part of the routine resection of the rectum or the rectal mesentery.
Lateral treatment portals should encompass the entire sacrum posteriorly. A radiopaque marker should be placed at the posterior aspect of the anus to make certain that blocks in the posterior-inferior aspect of the portal do not impinge on targeted portions of anorectum. The anterior margin should be at least 4 cm anterior to the rectum, as determined by the rectal contrast placed at simulation. The use of intrarectal contrast during simulation ensures that the portals will be designed with the rectum at maximum distension. If the tumor has considerable extrarectal extension, then these guidelines should be modified to make certain that all macroscopic disease (determined by CT scan) is encompassed with about a 4-cm margin.
The usual dose given to pelvic portals is 4,500 cGy in 25 fractions of 180 cGy each. An additional boost is recommended for patients receiving postoperative radiation (164). Small bowel must be excluded from the boost volume after about 5,000 cGy. Typically, if small bowel cannot be excluded, the boost dose is 540 cGy. If it can be excluded, the usual boost dose is 900 cGy.
Recently, three-dimensional (3D) treatment planning has begun to be applied to rectal cancer (123). This is implemented best with careful attention to the concepts of clinical target volume (CTV) and planning target volumes (PTV). The initial CTV should include macroscopic disease with an approximately 2-cm margin in mesentery and within the course of the large bowel. In addition, the initial CTV should include rectal mesentery and nodal regions at risk.
Although there is no consensus on the optimum time for start of postoperative radiation, it is therefore recommended that treatment should begin 3 to 6 weeks after surgery.
Neoadjuvant Therapy
Considerable debate has evolved regarding the optimal approach to adjuvant therapy in rectal cancer. Although both pre- and postoperative adjuvant therapy can be effective, there has been a significant recent trend toward greater use of neoadjuvant treatment. Tumor down staging, improved resectability, and potential for expanded sphincter preservation options in the distal rectum also encourage the use of a neoadjuvant approach in the management of this disease. Historically several trials utilizing relatively moderate doses of preoperative radiation have been undertaken, with results consistently showing an improvement in local control but minimal or no improvement in overall survival (42,75,92). Recent studies from Europe have demonstrated that appropriate neoadjuvant preoperative radiation results in improvement of both local control and survival, and these results have had a significant impact on the current management of this disease (52,86).
The Swedish rectal preoperative radiation trial included 1,168 patients from 1987 to 1990 with resectable, Dukes A–C rectal cancer (133). Patients were randomized to 25 Gy in five fractions in 1 week followed by surgery 1 week later versus surgery alone. The surgery was rated as curative if margins were negative. With a median follow-up of 7 years there was a significant reduction in local control in all three Dukes stages with preoperative radiation therapy as compared to surgery alone. The 5-year local recurrence with preoperative radiation treatment was 12% versus 27% for surgery alone. The local recurrence with preoperative radiation and curative surgery was 9% versus 23% with curative surgery alone. This study showed a 10% absolute overall survival advantage for preoperative radiation therapy of 58% versus 48% at 9 years (p = 0.004) and an advantage in cancer-specific survival among all patients of 74% in the preoperative arm versus 65% in the surgery only arm (p = 0.002).
One caveat of this study is that the surgery alone arm did not utilize TME, which may have resulted in an unacceptably high local failure rate of 27%. Late effects suggested more bowel movement frequency, incontinence, urgency, and soiling in the preoperative radiation treatment arm, although overall quality of life was rated good (19). This trial set the standard of care in many European centers, but the dose of 5 Gy times five fractions may induce significant acute and late toxicity, and the short interval between radiation and surgery may not have allowed sufficient time for tumor regression (downstaging) for improved sphincter preservation. Justification for a longer interval after preoperative radiation treatment before surgery was given by a French trial, Lyon 90–01, which delivered 39 Gy in 3 Gy per fraction without any chemotherapy preoperatively (50). Two hundred one patients were randomized after 6 to 8 weeks. The local control and overall survival after a median follow-up of 33 months were the same in both arms of the study. However, the pathological complete response was 7% versus 14% (p = NSS) and the pathological down staging was 10% versus 26% (p = 0.007) in favor of the longer interval before surgery.
The TME experience by Heald et al. (74) suggested that TME alone is sufficient for achieving low local recurrence rates. A Dutch (CKVO 95–04) multicenter, phase III study of 1,861 patients was undertaken to evaluate the role of short course preoperative radiation with TME. Patients were randomized to TME alone versus 25 Gy in five fractions followed by TME surgery (86). No fixed tumors were included in the study, and half of the patients had T1 or T2 disease. The overall survival was the same in both arms of the study (82% at 2 years). However the local recurrence at 2 years was 8.2% in the TME-only arm as compared to 2.4% in the preoperative arm, highlighting the value of radiation treatment, even with TME. The sphincter preservation rate was the same in both arms, and there was no clear evidence of any downstaging effect. The perineal complication rate was slightly higher in the preoperative radiation arm of 26% versus 18% in the TME arm, while all other complications were equal. A more recent update indicates a higher incidence of sexual dysfunction and slower recovery of bowel function, more fecal incontinence, and generally poorer quality of life with short-course preoperative radiation.
Two meta-analyses of approximately 6,000 patients each were done to explore the benefit of preoperative radiation treatment. One analysis included 14 randomized controlled trials and reported that neoadjuvant radiation treatment was associated with significantly fewer local recurrences, improved specific survival, and an overall survival benefit (27). The second meta-analysis, provided by the Colorectal Cancer Collaborative Group, also reported on 14 randomized controlled trials (3). They noted a significant reduction in the risk of local recurrence and death from rectal cancer with preoperative radiotherapy.
Neoadjuvant Chemoradiation
The improvement in outcomes with combined chemoradiation and postoperative adjuvant therapy has led to similar recent approaches in the neoadjuvant therapy of this disease. In the
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United States this has become widely accepted, but in other parts of the world several groups have undertaken studies to examine the potential benefit from neoadjuvant chemoradiation as compared to radiation alone.
Preoperative radiation therapy was compared with combined preoperative chemotherapy and radiation therapy in a French study (Fédération Francophone de la Canérologie Digestive), FFCD 9203 (56). Patients with resectable T3 and T4 tumors were randomized to 45 Gy of radiation alone versus radiation with concurrent bolus 5-FU (350 mg/m2) plus leucovorin on days 1 to 5 during weeks 1 to 5. After surgery, four cycles of adjuvant chemotherapy were given. With a median follow-up of 69 months, there was an equivalent rate (51%) of sphincter-sparing surgery. Combined treatment led to improved pathological complete response rate of 11.4% versus 3.6% and an improved 5-year local failure rate of 8% versus 16.5%. There was, however, no difference in overall survival.
A similar study undertaken by the European Organization for Research and Treatment of Cancer (EORTC 22921) randomized patients to four arms, 45 Gy alone versus 45 Gy plus 5-FU leucovorin followed by surgery and patients further randomized to adjuvant therapy with 5-FU leucovorin (23). Results of the study indicate similar results to the French study with increased downstaging (14% versus 5.3%; p = 0.0001) with no difference in five-year survival (56% versus 54%). However, local control was significantly improved with the addition of chemotherapy. This information suggests that while there is less recurrence, there is no conclusive evidence that combined treatment offers a survival benefit compared to radiation alone. There was, however, a higher incidence of acute toxicity associated with combined chemoradiation.
In contrast to these studies, institutional experience from the United States does suggest significantly higher downstaging with the use of preoperative chemotherapy, and several institutional studies suggest an improvement in overall survival, and, therefore, notwithstanding the results from the randomized studies, most investigators currently utilize a combined modality approach to neoadjuvant therapy in this disease (149).
A study to determine whether a short course (5 Gy for five fractions) approach to neoadjuvant therapy is better than a protracted approach 50.4 Gy using 1.8 to 2 Gy fractions with concomitant bolus 5-FU and leucovorin given during weeks 1 and 5 was undertaken by the Polish rectal cancer group (26). Although a higher pathologic complete-response rate was seen with chemoradiation (16% vs. 1%), fewer positive radial margins (4% vs. 13%), and considerably reduced size of the tumor by approximately 1.9 cm no difference in the rate of sphincter preservation, local control or survival was seen.
There is considerable difference in the way chemotherapy has been administered in many of the trials undertaken and those that are ongoing. 5-FU has been used concurrent with radiation because of its well-established potentiating effect with radiation. However, several studies have used bolus 5-FU, while others have used leucovorin-modulated 5-FU during the first and last week of radiation. The results of the Intergroup study demonstrating a superiority of low-dose continuous infusion of 5-FU has been extrapolated to the neoadjuvant setting and appears to be the preferred approach to treatment (131). New drugs, including oxaliplatin, irinotecan, and oral fluoropyrimidines, have recently been shown to be effective in the treatment of metastatic colorectal cancer. These have now been incorporated into testing of new strategies with neoadjuvant therapy. Capecitabine is an oral fluoropyrimidine prodrug that is readily absorbed in the gastrointestinal tract and mimics the efficacy of continuous infusion 5-FU while avoiding the risk of side effects and complications due to a central line for CVI 5-FU (39). Capecitabine requires the presence of thymidine phosphorylase (TP) for conversion to the active form of 5-FU within the cells. TP is present in higher concentration in tumor cells, particularly colorectal cancer than in normal tissues, and this potentially creates a therapeutic advantage for capecitabine as compared to intravenous 5-FU (151). Studies of capecitabine in combination with radiation have shown similar response rates to 5FU, and, therefore, this drug appears promising for trials in the neoadjuvant therapy (43,44,89). Capecitabine is generally given in two divided doses, 825 mg twice a day during the course of radiation treatment. Acute toxicity of diarrhea, stomatitis, nausea, and neutropenia are also somewhat less with capecitabine than with 5-FU/leucovorin, however, the incidence of hand/foot syndrome is higher with capecitabine (30).
Several newer options for neoadjuvant therapy include the addition of irinotecan or oxaliplatin to 5-FU and radiation (11,100,143,144). Early data from phase 1 and 2 trials suggest that an oxaliplatin dose of 60 mg/m2 can be combined safely with continuous infusion 5-FU and standard radiation approaches with acceptable grade 3 toxicity and promising rates of pathological downstaging and with CR rates of 20% to 30%. Toxicity of irinotecan with a dose of 50 mg/m2 once a week with continuous infusion 5-FU and radiation in the combined modality approach is somewhat higher but appears to be tolerable and also has yielded high response rates with complete responses of 25% to 30% (117). Ongoing phase III trials in the United States and Europe are evaluating capecitabine and oxaliplatin delivered neoadjuvantly with radiation therapy.
RTOG 00–12 is a randomized phase II study of neoadjuvant combined modality combined-modality radiation for distal rectal cancer. One-hundred and three patients with T3 or T4 distal rectal cancer (<9 cm from the dentate line) were randomized to continuous venous infusion 5-FU plus hyperfractionated radiation treatment of 55.2 to 60 Gy (1.2 Gy twice a day) versus continuous venous infusion 5-FU and irinotecan with conventional fractionation radiation of 50 to 54 Gy (1.8 Gy per fraction). The response rate between the two arms was similar with a pathological complete response rate of 28%, higher than in other studies (121).
Radiation dose is of critical importance in downstaging of cancer. The dose response of rectal cancer is steep in the dose range of 40 to 60 Gy. Several studies have shown the impact of radiation dose escalation on the rate of pathological complete response to neoadjuvant therapy (6,122). In a review of patients at Princess Margaret Hospital who received 40 Gy, 46 Gy, or 50 Gy in 2 Gy/fraction with continuous infusion 5-FU, the pathological complete response was 18%, 23%, and 33% respectively for the three dose levels (121). The two-year local relapse-free survival was 72%, 90%, 89% and disease-free survival 62%, 84%, and 78% for the 40 Gy, 46 Gy, and 50 Gy levels respectively (178). The overall survival was 72%, 94%, and 92% respectively. Doses of 46 Gy or 50 Gy were more effective than 40 Gy, but there was no difference between 46 or 50 Gy. Similar results have been reported from other studies as well.
Preoperative Versus Postoperative
Three phase III trials were conducted to compare preoperative versus postoperative chemoradiation treatment. The first trial was an RTOG 94-01/Intergroup 0417 trial that accrued 53 patients but closed early due to poor accrual. NSABP R-03 was scheduled to accrue 900 patients but also closed after accruing 267 patients (81). Patients with operable adenocarcinoma of the rectum were randomized (and stratified based on age and sex) to surgery followed by one cycle of 5-FU/LV and then concurrent bolus (weeks 1 and 5) 5-FU/LV with radiation treatment versus 5-FU/LV for 1 cycle then concurrent chemoradiation treatment followed by surgery. All patients received adjuvant 5-FU and leucovorin for four cycles. The study was underpowered, but the 1-year results showed a 10% sphincter preservation advantage in the preoperative arm (44% vs. 34%) with slightly higher grade 4 and 5 toxicity (34% vs. 23%) and diarrhea (24% vs. 12%) in this
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arm as well. The clinical complete response rate was 23%, and the pathological complete response rate was 10%. The disease-free survival at 1 year was 83% preop versus 78% postop (p = NSS).
The definitive phase III study in favor of preoperative radiation therapy was the CAO/ARO/AIO-94 study performed by the German Rectal Cancer group (149). Eight hundred twenty-three clinically staged T3 and T4 or node-positive rectal cancers were randomized to arm 1: Preoperative chemotherapy and radiation therapy followed by TME 6 weeks later, or arm 2: TME followed by postoperative chemotherapy and radiation therapy. The radiation therapy used was 50.4 Gy in 28 fractions with a 5.4 Gy as a small volume boost in the postoperative arm. The chemotherapy used was 5-FU given as 1 g/m2 per day during the 1st and 5th weeks of radiotherapy as a 120-hour continuous infusion. Both arms received four additional cycles of 5-FU at 500 mg/m2 per day for 5 days every 4 weeks. All surgeons were trained in the use of TME and were asked prior to treatment to evaluate the possibility of sphincter preservation. The 5-year results revealed a pelvic recurrence ratio of 6% versus 13% (p = 0.02) in favor of the preoperative arm. The distant recurrence rate was 36% versus 38% (p = NSS), disease-free survival was 68% versus 65% (p = NSS), and overall survival was 76% versus 74% (p = NSS) for preoperative radiation versus postoperative, respectively. There was significant tumor downstaging after preoperative combined modality treatment with an 8% pathological complete response rate. Nodal positivity was 25% in the preoperative versus 40% in the postoperative arm. The sphincter preservation rate in 188 patients with low-lying tumors (declared by the surgeon prior to randomization to require an APR) revealed that 39% versus 19% had a sphincter-preserving low anterior resection (p = 0.004) in the preoperative versus the postoperative arm. There were fewer acute (27% vs. 40%) and late toxicities (14% vs. 24%) in preoperative-treatment group. Thus, preoperative combined preoperative chemotherapy and radiation therapy resulted in significantly less local failures in the pelvis by half and also provided twice the sphincter preservation. Importantly, there was no difference in overall survival or disease-free survival between the two arms.
An example of radiation fields employed preoperatively are shown in Figure 58.5A,B. This patient received 45 Gy with four fields (AP/PA, right and left lateral) followed by field reductions to a dose of 50.4 to 54 Gy, as used with a patient with a T4 rectal cancer.
Locally Advanced Rectal Cancer
Clinical T4 tumors may not be resected completely due to tumor fixation. Preoperative radiation treatment is recommended to facilitate curative resections.
M.D. Anderson investigators demonstrated that preoperative chemotherapy and radiation therapy increased overall survival (80% vs. 60%), local control (95% vs. 66%), and the number of sphincter preserving procedures (35% vs. 7%) as compared to radiation alone (167). Memorial Sloan-Kettering Cancer Center reported a gross total resection rate of 97%, pathological complete response rate of 25%, 4-year local control of 70%, and 4-year overall survival of 67% when giving preoperative chemotherapy of 5-FU and leucovorin with 50.4 Gy of radiation followed by surgery (115). Preoperative radiation and chemotherapy resulted in improved resectability rates and possible improved local control and survival.
The IORT experience at MGH was reviewed by Nakfoor et al. (125). Preoperative continuous infusion 5-FU plus 50.4 to 54 Gy of radiation was given followed by a 4- to 6-week break and surgery. No intraoperative radiation was given if metastases were present at surgical exploration, if there were adequate margins >1 cm, or if there was less than T4 disease. Ten to 12.5 Gy were given for complete resection, 12.5 to 15 Gy for microscopic residual, and 17.5 to 20 Gy for gross residual disease. The 5-year local control was 90%, 65%, 55%, and the disease specific survival at 5 years was 65%, 45%, and 15%, for these three dose levels, respectively. The 5-year actuarial risk of complications was 15%, however. The risk of peripheral neuropathy was 20% for doses >15 Gy. IORT improves local control, especially with a gross total resection, but not survival for locally advanced rectal cancer.
Reirradiation
Recurrent rectal cancer is often approached the same way as T4 disease with an aggressive treatment plan of combined chemotherapy and radiation therapy followed by surgery and
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then adjuvant chemotherapy. At the time of surgery, IORT is considered. Approximately 10% of patients with T1 and T2N0 disease will fail locally after surgery, usually due to an inadequate lymph node dissection. The recurrences are found along the pelvic sidewall or in nonpelvic sidewall areas such as the uterus, prostate, or vagina. Because the pelvic sidewall is a difficult surgical resection, these recurrences face worse. The 5-year overall survival is approximately 20% (165). The local control is about 40% in patients with no prior radiation to 10% to 20% in patients who had prior radiation.
Forty-seven patients in an Italian retrospective study were treated with preoperative combined chemotherapy and radiation therapy (162). Patients who did not have prior radiation treatment received 45 Gy with continuous infusion 5-FU and mitomycin C followed by surgery and intraoperative radiation therapy of 10 to 15 Gy. Leucovorin and 5-FU were given for six to nine cycles adjuvantly. If patients had prior radiation treatment, they were given 23.4 Gy instead. The 5-year overall survival was 20% for all patients, 60% for resected tumors, 0% for unresected tumors, and 40% for patients treated by external beam, surgery, and IORT. The 5-year local control rate was 30% for all patients, 70% for completely resected tumors, 0% for unresectable tumors, and 80% for external beam, surgery, and IORT. Eighty-five percent had palliation of pain with a duration of 12 months.
Long-term results of reirradiation for patients with recurrent rectal carcinoma were reported by Mohiuddin et al. (119). One-hundred and three patients who developed locoregional recurrence after surgery with preoperative or postoperative radiation treatment (median dose 50.4 Gy) were reirradiated with concurrent 5FU continuous infusion. Patients were treated with opposed laterals or a three-field technique with a posterior field and two laterals to the presacral area and gross tumor volume with 2- to 4-cm margin. Patients received 30 Gy (1.2 Gy twice a day) or 30.6 Gy (1.8 Gy every day) followed by a boost of 6 to 20 Gy to gross tumor volume (2 cm margin). Forty-one patients were surgically explored after treatment, and 34 underwent resection, with six patients having sphincter-sparing surgery. With immediate follow-up of 2 years, the 5-year overall survival rate was 19%. Patients who underwent resection had a higher survival rate with tolerable acute and late toxicity. Palliation of bleeding was achieved in 100% of patients.
Postoperative
The problem of unacceptably high local recurrence after surgery has led to many studies exploring the potential benefit of postoperative adjuvant therapy (12,40). One of the advantages of postoperative radiation is the ability to selectively treat patients at high risk of local failure on the basis of pathologic stage. Disadvantages include a potentially hypoxic postsurgical bed, making radiation less effective and potentially higher complications due to increased small bowel in the radiation field, and a larger treatment volume, especially if the patient undergoes an APR and the perineal scar needs to be covered.
There have been several large trials of postoperative radiation with or without chemotherapy (3,94,138). In general, surgery alone has resulted in a 25% local failure rate and 40% to 50% overall survival for T3 or T4 or node-positive patients, while radiation with the addition of chemotherapy has yielded a lower local failure rate of 10% to 15% and higher overall survival rate of 50% to 60%.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-01study randomized 555 patients into three arms after surgery: (a) observation, (b) postoperative chemotherapy of eight cycles of MOF (5FU, CCNU [semustine], and vincristine), and (c) postoperative radiation treatment alone of 46 to 47 Gy (49). Postoperative chemotherapy improved disease-free survival but not overall survival. The benefit of improved overall survival with MOF was restricted to men in subset analysis. Postoperative radiation treatment trended toward improved local control but not overall survival.
The NSABP R-02 study (182) enrolled 694 stage B and C patients and asked two questions in its study design: (a) Does the addition of radiation to chemotherapy improve outcome? and (b) Is MOF superior to 5-FU/LV in men? There were four treatment arms for males and two treatment arms for females. Five cycles of MOF were compared to six cycles of 5-FU/LV with or without radiation for the men. For women, 5-FU/LV was compared against additional radiation. The radiation dose was 50.4 Gy. At 5 years, the locoregional failure was 13% for the chemotherapy only arm as compared to 8% with the addition of radiation and chemotherapy. Additionally, 5-FU/LV showed better relapse-free survival and disease-free survival but not overall survival as compared to MOF. The conclusions of the two NSABP trials were that while postoperative radiation treatment did not appear to improve overall survival, there was an improvement in local control.
Two trials that did show an improvement in survival were the Gastrointestinal Tumor Study Group (GITSG) and North Central Cancer Treatment Group (NCCTG) studies. GITSG study was a four-arm trial of 227 patients with stage B2 and C rectal cancer who were randomized to either (a) surgery alone, (b) postoperative chemotherapy of bolus 5-FU (500 mg/m2 in weeks 1 and 5 and methyl-CCNU (semustine given day 1), (c) postoperative radiation treatment of 40 to 48 Gy split course, or (d) postoperative chemotherapy and radiation therapy of 40 to 44 Gy plus bolus 5-FU (138). The severe acute toxicity was 61% in the combined modality treatment arm as compared to 31% with chemotherapy only and 18% with radiation only. In a 9-year update, postoperative chemotherapy and radiation therapy improved the overall survival to 54% versus 27% with observation after surgery. There was a prolonged time to recurrence and a decreased recurrence rate of 33% versus 55% with combined adjuvant treatment. Local failure rate was decreased to 10% versus 25% with surgery alone. Therefore, this trial concluded a significant overall survival advantage of nearly double for patients who had combined modality treatment after surgical resection.
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The Mayo-NCCTG compared postoperative radiation therapy against postoperative radiation therapy and chemotherapy (94). Two hundred and four patients were included with T3 or T4 or node-positive tumors and all received one cycle of 5FU and semustine before randomization. The radiation dose was 45 to 50.4 Gy. The 5-year local regional failure was higher in the radiation only arm of 25% versus 15%, and the 5-year overall survival rate was 40% versus 55%. Combined postoperative chemotherapy and radiation therapy reduced recurrence by 34%, local recurrence by 46%, and distant metastases by 37%. Cancer deaths were reduced by 36%, and overall deaths were reduced by 29%.
Based on the results of these studies, the National Institute of Health Consensus Conference recommended that the combined use of radiation and chemotherapy is more effective than postoperative radiation alone, with a greater potential for improved survival, and is recommended. Several subsequent studies have attempted to delineate the kind of chemotherapy and delivery options in the combined modality treatment (129).
NCCTG 86–47-51 study compared chemotherapy regimens to be added to the postoperative radiation. Six hundred sixty stage II or III patients were randomized to systemic chemotherapy given (5-FU vs. 5-FU + semustine) and the method of delivery (bolus vs. continuous infusion 5-FU) (131). Nine weeks of chemotherapy were given followed by the experimental chemotherapy concurrently with 50.4 to 54 Gy radiation with additional chemotherapy thereafter. The bolus 5FU dose was 500 mg/m2 on day 1 to 5 during weeks 1 and 5, whereas the continuous infusion 5-FU was 225 mg/m2 per day. With a median follow-up of 46 months, there was a 27% improvement in relapse-free survival of 63% versus 53% in favor of continuous infusion 5-FU. The 4-year overall survival was 70% versus 60% in favor of continuous infusion. The time to relapse and the distant metastasis rate (31% vs. 40%) were also lower. There was no difference in local recurrence. Bolus 5-FU had a higher rate of leucopenia, while continuous infusion had more acute severe diarrhea. Semustine was of no additional benefit.
Intergroup 0114 study compared different chemotherapy regimens with radiation treatment for 1,695 patients (159). There were four arms of the study comparing (a) bolus 5-FU alone, (b) 5-FU and leucovorin, (c) 5FU plus levamisole, and (d) 5-FU and leucovorin plus levamisole. The levamisole was not given during the radiation treatment. The radiation treatment dose was 45 Gy with a 5.4- to 9-Gy boost to a total of 50.4 to 54 Gy. With a median follow-up of 7.4 years, there was no difference in overall survival or disease-free survival among the four groups. The three-drug regimen had a greater toxicity. Levamisole and leucovorin did not appear to add any benefit to the 5-FU.
Favorable T3N0
Several studies have shown that there may be a subset of tumors that might not need adjuvant therapy because of low risk of recurrence with surgery alone. Memorial Sloan-Kettering evaluated 95 patients with T3N0 rectal cancer treated by surgery alone (109). Seventy-nine patients underwent LAR and 16% underwent APR, both with sharp mesorectal excision. With 53.3-month follow-up, 6% had a local recurrence, 13% had distant metastases, and 3% had both local recurrence and distant metastases. Lymphovascular invasion was the only histological factor that was important for local recurrence. This study suggests that sharp mesorectal excision with LAR or APR for T3N0 rectal cancers results in low local recurrences of <10% without the use of adjuvant therapy.
In a retrospective review of 117 patients with T3N0 rectal cancer treated at MGH Willett et al. (170) reported that perirectal tumor invasion ≥2 mm, LVI, and poorly differentiated histology were independent factors for increased risk of distant metastasis and worse relapse-free survival. Only depth of invasion was significant for local control. Of the 25 patients with favorable histological features (well differentiated/moderately differentiated, invading <2 mm into the perirectal fat, no LVI), the 10-year actuarial local control and relapse-free survival were 95% and 87%, respectively, as compared to 71% and 55% in the unfavorable group. Thus, a limited subset of patients with T3N0 rectal cancer may have an excellent outcome with surgery alone, but there are no randomized data to support the omission of adjuvant therapy for this group of patients at the present time.
Side Effects of Combined Chemoradiation
Although combined chemoradiation is the recommended approach for postoperative adjuvant therapy, it has to be kept in mind that the acute side effects can be considerably greater than postoperative radiation alone. In the NCCTG 79–47-51 study the incidence of nausea, vomiting, and diarrhea were significantly higher than with radiation alone (114). Patients also developed more stomatitis with mucosal ulceration and a slightly greater hematological toxicity as well (9% vs. 2%). Hydration is therefore critical in these patients as some patients may exhibit hypersensitivity to 5-FU with grade 4 diarrhea and an occasional death due to dehydration. Patients need to be supported with intravenous fluids and treatment interruption until the diarrhea is stabilized. Severe late toxicity was similar in both arms (7%). The incidence of diarrhea is greater with continuous infusion of 5-FU as compared to bolus 5-FU, and hand/foot syndrome is also more common in infusional therapy (97,114). In the Intergroup trials, 24% of patients receiving concurrent pelvic radiation and continuous infusion 5-FU experienced severe or life-threatening diarrhea (113). Chronic bowel injury was seen in 25% of the patients treated with postoperative radiation.
A key late side effect with postoperative radiation in patients undergoing low anterior resection is rectal urgency with frequent bowel movements, known as clustering. Patients can have six to 10 bowel movements in a short period of time, which can be quite distressing. There is also the likelihood of frequent nighttime bowel movements and occasional incontinence. These symptoms are related to the development of anastomotic strictures and fibrosis with lack of elasticity of the neorectum (93,101).
Treatment Technique for Postop Adjuvant Treatment
External-beam treatment portals for rectal carcinoma should always encompass the sites at greatest risk: The presacral space, the primary tumor site, and (for post-APR cases) the perineum. Other areas at risk include the internal iliac and distal common iliac nodes. The risk in the para-aortic region is sufficiently low, and the morbidity from treatment is sufficiently high to exclude this region from adjuvant rectal cancer radiation portals. The external iliac nodes should be covered for lesions extending to the dentate line.
In general, patients with rectal carcinoma should be treated in the prone position because this reduces the volume of small bowel within the pelvis (54). For patients with prior pelvic surgery, maneuvers to reduce volume of small bowel include treatment with a full bladder and the use of bowel-displacement techniques such as a belly board (foam board table with a cutout to allow the upper-abdominal contents to fall forward) or a foam board mound designed to push the full bladder posteriorly and cephalad (54). The use of shaped lateral fields reduces the dose to small bowel located in the anterior superior aspects of the pelvis.
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If conventional (two-dimensional) treatment planning is used, a four-field (anteroposterior/posteroanterior [AP/PA]/right/left [R/L] lateral) or three-field (PA/R/L lateral) technique generally is used. The superior port edge is placed at the L4/L5 interspace—usually in the mid-L5 vertebral body. The distal port edge should be 5 cm below palpable tumor for patients receiving preoperative treatment. For postoperative cases the distal port edge is about 5 cm below the best estimate of the preoperative tumor bed and (if an APR has been performed) below the perineum. Anterior and posterior portals must have at least a 1.5-cm margin on the pelvic brim. There is an underappreciated incidence of lateral pelvic lymph node involvement that is not part of the routine resection of the rectum or the rectal mesentery.
Lateral treatment portals should encompass the entire sacrum posteriorly. A radiopaque marker should be placed at the posterior aspect of the anus to make certain that blocks in the posterior-inferior aspect of the portal do not impinge on targeted portions of anorectum. The anterior margin should be at least 4 cm anterior to the rectum, as determined by the rectal contrast placed at simulation. The use of intrarectal contrast during simulation ensures that the portals will be designed with the rectum at maximum distension. If the tumor has considerable extrarectal extension, then these guidelines should be modified to make certain that all macroscopic disease (determined by CT scan) is encompassed with about a 4-cm margin.
The usual dose given to pelvic portals is 4,500 cGy in 25 fractions of 180 cGy each. An additional boost is recommended for patients receiving postoperative radiation (164). Small bowel must be excluded from the boost volume after about 5,000 cGy. Typically, if small bowel cannot be excluded, the boost dose is 540 cGy. If it can be excluded, the usual boost dose is 900 cGy.
Recently, three-dimensional (3D) treatment planning has begun to be applied to rectal cancer (123). This is implemented best with careful attention to the concepts of clinical target volume (CTV) and planning target volumes (PTV). The initial CTV should include macroscopic disease with an approximately 2-cm margin in mesentery and within the course of the large bowel. In addition, the initial CTV should include rectal mesentery and nodal regions at risk.
Although there is no consensus on the optimum time for start of postoperative radiation, it is therefore recommended that treatment should begin 3 to 6 weeks after surgery.
Neoadjuvant Therapy
Considerable debate has evolved regarding the optimal approach to adjuvant therapy in rectal cancer. Although both pre- and postoperative adjuvant therapy can be effective, there has been a significant recent trend toward greater use of neoadjuvant treatment. Tumor down staging, improved resectability, and potential for expanded sphincter preservation options in the distal rectum also encourage the use of a neoadjuvant approach in the management of this disease. Historically several trials utilizing relatively moderate doses of preoperative radiation have been undertaken, with results consistently showing an improvement in local control but minimal or no improvement in overall survival (42,75,92). Recent studies from Europe have demonstrated that appropriate neoadjuvant preoperative radiation results in improvement of both local control and survival, and these results have had a significant impact on the current management of this disease (52,86).
The Swedish rectal preoperative radiation trial included 1,168 patients from 1987 to 1990 with resectable, Dukes A–C rectal cancer (133). Patients were randomized to 25 Gy in five fractions in 1 week followed by surgery 1 week later versus surgery alone. The surgery was rated as curative if margins were negative. With a median follow-up of 7 years there was a significant reduction in local control in all three Dukes stages with preoperative radiation therapy as compared to surgery alone. The 5-year local recurrence with preoperative radiation treatment was 12% versus 27% for surgery alone. The local recurrence with preoperative radiation and curative surgery was 9% versus 23% with curative surgery alone. This study showed a 10% absolute overall survival advantage for preoperative radiation therapy of 58% versus 48% at 9 years (p = 0.004) and an advantage in cancer-specific survival among all patients of 74% in the preoperative arm versus 65% in the surgery only arm (p = 0.002).
One caveat of this study is that the surgery alone arm did not utilize TME, which may have resulted in an unacceptably high local failure rate of 27%. Late effects suggested more bowel movement frequency, incontinence, urgency, and soiling in the preoperative radiation treatment arm, although overall quality of life was rated good (19). This trial set the standard of care in many European centers, but the dose of 5 Gy times five fractions may induce significant acute and late toxicity, and the short interval between radiation and surgery may not have allowed sufficient time for tumor regression (downstaging) for improved sphincter preservation. Justification for a longer interval after preoperative radiation treatment before surgery was given by a French trial, Lyon 90–01, which delivered 39 Gy in 3 Gy per fraction without any chemotherapy preoperatively (50). Two hundred one patients were randomized after 6 to 8 weeks. The local control and overall survival after a median follow-up of 33 months were the same in both arms of the study. However, the pathological complete response was 7% versus 14% (p = NSS) and the pathological down staging was 10% versus 26% (p = 0.007) in favor of the longer interval before surgery.
The TME experience by Heald et al. (74) suggested that TME alone is sufficient for achieving low local recurrence rates. A Dutch (CKVO 95–04) multicenter, phase III study of 1,861 patients was undertaken to evaluate the role of short course preoperative radiation with TME. Patients were randomized to TME alone versus 25 Gy in five fractions followed by TME surgery (86). No fixed tumors were included in the study, and half of the patients had T1 or T2 disease. The overall survival was the same in both arms of the study (82% at 2 years). However the local recurrence at 2 years was 8.2% in the TME-only arm as compared to 2.4% in the preoperative arm, highlighting the value of radiation treatment, even with TME. The sphincter preservation rate was the same in both arms, and there was no clear evidence of any downstaging effect. The perineal complication rate was slightly higher in the preoperative radiation arm of 26% versus 18% in the TME arm, while all other complications were equal. A more recent update indicates a higher incidence of sexual dysfunction and slower recovery of bowel function, more fecal incontinence, and generally poorer quality of life with short-course preoperative radiation.
Two meta-analyses of approximately 6,000 patients each were done to explore the benefit of preoperative radiation treatment. One analysis included 14 randomized controlled trials and reported that neoadjuvant radiation treatment was associated with significantly fewer local recurrences, improved specific survival, and an overall survival benefit (27). The second meta-analysis, provided by the Colorectal Cancer Collaborative Group, also reported on 14 randomized controlled trials (3). They noted a significant reduction in the risk of local recurrence and death from rectal cancer with preoperative radiotherapy.
Neoadjuvant Chemoradiation
The improvement in outcomes with combined chemoradiation and postoperative adjuvant therapy has led to similar recent approaches in the neoadjuvant therapy of this disease. In the
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United States this has become widely accepted, but in other parts of the world several groups have undertaken studies to examine the potential benefit from neoadjuvant chemoradiation as compared to radiation alone.
Preoperative radiation therapy was compared with combined preoperative chemotherapy and radiation therapy in a French study (Fédération Francophone de la Canérologie Digestive), FFCD 9203 (56). Patients with resectable T3 and T4 tumors were randomized to 45 Gy of radiation alone versus radiation with concurrent bolus 5-FU (350 mg/m2) plus leucovorin on days 1 to 5 during weeks 1 to 5. After surgery, four cycles of adjuvant chemotherapy were given. With a median follow-up of 69 months, there was an equivalent rate (51%) of sphincter-sparing surgery. Combined treatment led to improved pathological complete response rate of 11.4% versus 3.6% and an improved 5-year local failure rate of 8% versus 16.5%. There was, however, no difference in overall survival.
A similar study undertaken by the European Organization for Research and Treatment of Cancer (EORTC 22921) randomized patients to four arms, 45 Gy alone versus 45 Gy plus 5-FU leucovorin followed by surgery and patients further randomized to adjuvant therapy with 5-FU leucovorin (23). Results of the study indicate similar results to the French study with increased downstaging (14% versus 5.3%; p = 0.0001) with no difference in five-year survival (56% versus 54%). However, local control was significantly improved with the addition of chemotherapy. This information suggests that while there is less recurrence, there is no conclusive evidence that combined treatment offers a survival benefit compared to radiation alone. There was, however, a higher incidence of acute toxicity associated with combined chemoradiation.
In contrast to these studies, institutional experience from the United States does suggest significantly higher downstaging with the use of preoperative chemotherapy, and several institutional studies suggest an improvement in overall survival, and, therefore, notwithstanding the results from the randomized studies, most investigators currently utilize a combined modality approach to neoadjuvant therapy in this disease (149).
A study to determine whether a short course (5 Gy for five fractions) approach to neoadjuvant therapy is better than a protracted approach 50.4 Gy using 1.8 to 2 Gy fractions with concomitant bolus 5-FU and leucovorin given during weeks 1 and 5 was undertaken by the Polish rectal cancer group (26). Although a higher pathologic complete-response rate was seen with chemoradiation (16% vs. 1%), fewer positive radial margins (4% vs. 13%), and considerably reduced size of the tumor by approximately 1.9 cm no difference in the rate of sphincter preservation, local control or survival was seen.
There is considerable difference in the way chemotherapy has been administered in many of the trials undertaken and those that are ongoing. 5-FU has been used concurrent with radiation because of its well-established potentiating effect with radiation. However, several studies have used bolus 5-FU, while others have used leucovorin-modulated 5-FU during the first and last week of radiation. The results of the Intergroup study demonstrating a superiority of low-dose continuous infusion of 5-FU has been extrapolated to the neoadjuvant setting and appears to be the preferred approach to treatment (131). New drugs, including oxaliplatin, irinotecan, and oral fluoropyrimidines, have recently been shown to be effective in the treatment of metastatic colorectal cancer. These have now been incorporated into testing of new strategies with neoadjuvant therapy. Capecitabine is an oral fluoropyrimidine prodrug that is readily absorbed in the gastrointestinal tract and mimics the efficacy of continuous infusion 5-FU while avoiding the risk of side effects and complications due to a central line for CVI 5-FU (39). Capecitabine requires the presence of thymidine phosphorylase (TP) for conversion to the active form of 5-FU within the cells. TP is present in higher concentration in tumor cells, particularly colorectal cancer than in normal tissues, and this potentially creates a therapeutic advantage for capecitabine as compared to intravenous 5-FU (151). Studies of capecitabine in combination with radiation have shown similar response rates to 5FU, and, therefore, this drug appears promising for trials in the neoadjuvant therapy (43,44,89). Capecitabine is generally given in two divided doses, 825 mg twice a day during the course of radiation treatment. Acute toxicity of diarrhea, stomatitis, nausea, and neutropenia are also somewhat less with capecitabine than with 5-FU/leucovorin, however, the incidence of hand/foot syndrome is higher with capecitabine (30).
Several newer options for neoadjuvant therapy include the addition of irinotecan or oxaliplatin to 5-FU and radiation (11,100,143,144). Early data from phase 1 and 2 trials suggest that an oxaliplatin dose of 60 mg/m2 can be combined safely with continuous infusion 5-FU and standard radiation approaches with acceptable grade 3 toxicity and promising rates of pathological downstaging and with CR rates of 20% to 30%. Toxicity of irinotecan with a dose of 50 mg/m2 once a week with continuous infusion 5-FU and radiation in the combined modality approach is somewhat higher but appears to be tolerable and also has yielded high response rates with complete responses of 25% to 30% (117). Ongoing phase III trials in the United States and Europe are evaluating capecitabine and oxaliplatin delivered neoadjuvantly with radiation therapy.
RTOG 00–12 is a randomized phase II study of neoadjuvant combined modality combined-modality radiation for distal rectal cancer. One-hundred and three patients with T3 or T4 distal rectal cancer (<9 cm from the dentate line) were randomized to continuous venous infusion 5-FU plus hyperfractionated radiation treatment of 55.2 to 60 Gy (1.2 Gy twice a day) versus continuous venous infusion 5-FU and irinotecan with conventional fractionation radiation of 50 to 54 Gy (1.8 Gy per fraction). The response rate between the two arms was similar with a pathological complete response rate of 28%, higher than in other studies (121).
Radiation dose is of critical importance in downstaging of cancer. The dose response of rectal cancer is steep in the dose range of 40 to 60 Gy. Several studies have shown the impact of radiation dose escalation on the rate of pathological complete response to neoadjuvant therapy (6,122). In a review of patients at Princess Margaret Hospital who received 40 Gy, 46 Gy, or 50 Gy in 2 Gy/fraction with continuous infusion 5-FU, the pathological complete response was 18%, 23%, and 33% respectively for the three dose levels (121). The two-year local relapse-free survival was 72%, 90%, 89% and disease-free survival 62%, 84%, and 78% for the 40 Gy, 46 Gy, and 50 Gy levels respectively (178). The overall survival was 72%, 94%, and 92% respectively. Doses of 46 Gy or 50 Gy were more effective than 40 Gy, but there was no difference between 46 or 50 Gy. Similar results have been reported from other studies as well.
Preoperative Versus Postoperative
Three phase III trials were conducted to compare preoperative versus postoperative chemoradiation treatment. The first trial was an RTOG 94-01/Intergroup 0417 trial that accrued 53 patients but closed early due to poor accrual. NSABP R-03 was scheduled to accrue 900 patients but also closed after accruing 267 patients (81). Patients with operable adenocarcinoma of the rectum were randomized (and stratified based on age and sex) to surgery followed by one cycle of 5-FU/LV and then concurrent bolus (weeks 1 and 5) 5-FU/LV with radiation treatment versus 5-FU/LV for 1 cycle then concurrent chemoradiation treatment followed by surgery. All patients received adjuvant 5-FU and leucovorin for four cycles. The study was underpowered, but the 1-year results showed a 10% sphincter preservation advantage in the preoperative arm (44% vs. 34%) with slightly higher grade 4 and 5 toxicity (34% vs. 23%) and diarrhea (24% vs. 12%) in this
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arm as well. The clinical complete response rate was 23%, and the pathological complete response rate was 10%. The disease-free survival at 1 year was 83% preop versus 78% postop (p = NSS).
The definitive phase III study in favor of preoperative radiation therapy was the CAO/ARO/AIO-94 study performed by the German Rectal Cancer group (149). Eight hundred twenty-three clinically staged T3 and T4 or node-positive rectal cancers were randomized to arm 1: Preoperative chemotherapy and radiation therapy followed by TME 6 weeks later, or arm 2: TME followed by postoperative chemotherapy and radiation therapy. The radiation therapy used was 50.4 Gy in 28 fractions with a 5.4 Gy as a small volume boost in the postoperative arm. The chemotherapy used was 5-FU given as 1 g/m2 per day during the 1st and 5th weeks of radiotherapy as a 120-hour continuous infusion. Both arms received four additional cycles of 5-FU at 500 mg/m2 per day for 5 days every 4 weeks. All surgeons were trained in the use of TME and were asked prior to treatment to evaluate the possibility of sphincter preservation. The 5-year results revealed a pelvic recurrence ratio of 6% versus 13% (p = 0.02) in favor of the preoperative arm. The distant recurrence rate was 36% versus 38% (p = NSS), disease-free survival was 68% versus 65% (p = NSS), and overall survival was 76% versus 74% (p = NSS) for preoperative radiation versus postoperative, respectively. There was significant tumor downstaging after preoperative combined modality treatment with an 8% pathological complete response rate. Nodal positivity was 25% in the preoperative versus 40% in the postoperative arm. The sphincter preservation rate in 188 patients with low-lying tumors (declared by the surgeon prior to randomization to require an APR) revealed that 39% versus 19% had a sphincter-preserving low anterior resection (p = 0.004) in the preoperative versus the postoperative arm. There were fewer acute (27% vs. 40%) and late toxicities (14% vs. 24%) in preoperative-treatment group. Thus, preoperative combined preoperative chemotherapy and radiation therapy resulted in significantly less local failures in the pelvis by half and also provided twice the sphincter preservation. Importantly, there was no difference in overall survival or disease-free survival between the two arms.
An example of radiation fields employed preoperatively are shown in Figure 58.5A,B. This patient received 45 Gy with four fields (AP/PA, right and left lateral) followed by field reductions to a dose of 50.4 to 54 Gy, as used with a patient with a T4 rectal cancer.
Locally Advanced Rectal Cancer
Clinical T4 tumors may not be resected completely due to tumor fixation. Preoperative radiation treatment is recommended to facilitate curative resections.
M.D. Anderson investigators demonstrated that preoperative chemotherapy and radiation therapy increased overall survival (80% vs. 60%), local control (95% vs. 66%), and the number of sphincter preserving procedures (35% vs. 7%) as compared to radiation alone (167). Memorial Sloan-Kettering Cancer Center reported a gross total resection rate of 97%, pathological complete response rate of 25%, 4-year local control of 70%, and 4-year overall survival of 67% when giving preoperative chemotherapy of 5-FU and leucovorin with 50.4 Gy of radiation followed by surgery (115). Preoperative radiation and chemotherapy resulted in improved resectability rates and possible improved local control and survival.
The IORT experience at MGH was reviewed by Nakfoor et al. (125). Preoperative continuous infusion 5-FU plus 50.4 to 54 Gy of radiation was given followed by a 4- to 6-week break and surgery. No intraoperative radiation was given if metastases were present at surgical exploration, if there were adequate margins >1 cm, or if there was less than T4 disease. Ten to 12.5 Gy were given for complete resection, 12.5 to 15 Gy for microscopic residual, and 17.5 to 20 Gy for gross residual disease. The 5-year local control was 90%, 65%, 55%, and the disease specific survival at 5 years was 65%, 45%, and 15%, for these three dose levels, respectively. The 5-year actuarial risk of complications was 15%, however. The risk of peripheral neuropathy was 20% for doses >15 Gy. IORT improves local control, especially with a gross total resection, but not survival for locally advanced rectal cancer.
Reirradiation
Recurrent rectal cancer is often approached the same way as T4 disease with an aggressive treatment plan of combined chemotherapy and radiation therapy followed by surgery and
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then adjuvant chemotherapy. At the time of surgery, IORT is considered. Approximately 10% of patients with T1 and T2N0 disease will fail locally after surgery, usually due to an inadequate lymph node dissection. The recurrences are found along the pelvic sidewall or in nonpelvic sidewall areas such as the uterus, prostate, or vagina. Because the pelvic sidewall is a difficult surgical resection, these recurrences face worse. The 5-year overall survival is approximately 20% (165). The local control is about 40% in patients with no prior radiation to 10% to 20% in patients who had prior radiation.
Forty-seven patients in an Italian retrospective study were treated with preoperative combined chemotherapy and radiation therapy (162). Patients who did not have prior radiation treatment received 45 Gy with continuous infusion 5-FU and mitomycin C followed by surgery and intraoperative radiation therapy of 10 to 15 Gy. Leucovorin and 5-FU were given for six to nine cycles adjuvantly. If patients had prior radiation treatment, they were given 23.4 Gy instead. The 5-year overall survival was 20% for all patients, 60% for resected tumors, 0% for unresected tumors, and 40% for patients treated by external beam, surgery, and IORT. The 5-year local control rate was 30% for all patients, 70% for completely resected tumors, 0% for unresectable tumors, and 80% for external beam, surgery, and IORT. Eighty-five percent had palliation of pain with a duration of 12 months.
Long-term results of reirradiation for patients with recurrent rectal carcinoma were reported by Mohiuddin et al. (119). One-hundred and three patients who developed locoregional recurrence after surgery with preoperative or postoperative radiation treatment (median dose 50.4 Gy) were reirradiated with concurrent 5FU continuous infusion. Patients were treated with opposed laterals or a three-field technique with a posterior field and two laterals to the presacral area and gross tumor volume with 2- to 4-cm margin. Patients received 30 Gy (1.2 Gy twice a day) or 30.6 Gy (1.8 Gy every day) followed by a boost of 6 to 20 Gy to gross tumor volume (2 cm margin). Forty-one patients were surgically explored after treatment, and 34 underwent resection, with six patients having sphincter-sparing surgery. With immediate follow-up of 2 years, the 5-year overall survival rate was 19%. Patients who underwent resection had a higher survival rate with tolerable acute and late toxicity. Palliation of bleeding was achieved in 100% of patients.
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