Minimizing the Therapy-Related Morbidity in the Rectal Cancer Patient

Minimizing the Therapy-Related Morbidity in the Rectal Cancer Patient Tina Ashley Khair, DO,* and Peter Kozuch, MD† A decades long challenge for clinicians caring for patients with adenocarcinoma of the rectum has been to optimize oncologic outcomes while minimizing both disease- and treatment-associated morbidities. This review summarizes the landmark trials that have defined the current standard of adjuvant care for rectal cancer and ongoing/planned trials that may help shape future standards. The 1980s and 1990s witnessed validation of total mesorectal excision (TME) and 5-fluorouracil (%-FU)-based adjuvant chemoradiation therapy (CRT) as feasible and effective pillars of care for adenocarcinoma of the rectum. The parallel advancements in preoperative staging, colorectal surgery, radiation, and medical oncology during this time culminated in a trial reported by Sauer and colleagues in 2004. Not only did this trial effectively compare preoperative and postoperative adjuvant CRT but it also advocated the use of total mesorectal excision as the standardized resection in all patients. While this trial addressed important issues surrounding preoperative adjuvant CRT and TME, further evolution of rectal cancer treatment will address additional issues, such as the incorporation of the oral 5-fluorouracil prodrug capecitabine (Xeloda) and oxaliplatin in adjuvant programs and development of strategies to individualize treatment based on the location (upper, mid, or distal) and molecular features of rectal cancer. The evolution of these modalities will hopefully enable physicians to individualize care plans so that optimal outcomes may be achieved. Semin Colon Rectal Surg 21:120-125 © 2010 Elsevier Inc. All rights reserved.

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n estimated 40,740 cases of rectal cancer were diagnosed in 2008.1 The incidence of colorectal cancer has been decreasing an estimated 2.3% per year from 1998 to 2004 in part due to screening efforts.1 Coincident with the development of TME, a stable surgical platform with predictably low rates of local recurrence and improved survival, clinical trials in the 1980s and 1990s evaluated the role of adjuvant (postoperative) chemotherapy, radiation, and chemoradiation therapy programs in achieving optimal disease-free and overall survival outcomes. It is important to keep in mind that until the report by Sauer et al, the landmark randomized control trials that have informed the adjuvant care of rectal cancer did not require standardized TME. In contrast to TME, blunt pelvic dissection has been associated with inferior local recurrence rates ranging from 15% to 65% and survival rates of 35% to 56% for stage II and III disease.2-5 *Hematology and Oncology, Beth Israel Medical Center, New York, NY. †GI Medical Oncology, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY. Address reprint requests to Peter Kozuch, MD, GI Medical Oncology, Beth Israel Medical Center, Albert Einstein College of Medicine, 10 Union Square East, Suite 4C09, New York, NY 10003. E-mail: pkozuch@ chpnet.org

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1043-1489/10/$-see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.scrs.2010.01.010

Treatment with 5-FU, methyl-CCNU (1-(2-chloroethyl)3-(4-methylcyclohexyl)-1-nitrosurea; semustine), and vincristine (methyl-CCNU, 5-fluorouracil, and vincristine; MOF) was among the first adjuvant treatments to show improvement in 5-year overall survival (OS) as adjuvant treatment of Dukes B and C colon cancer compared with observation alone. Five years disease-free (disease-free survival (DFS)) and OS were statistically significantly different between the 2 arms with relative risks of 1.29 for both endpoints.6 Although these benefits were later demonstrated to be of limited duration, as disease-free and overall survival benefits were no longer apparent after 10 years, adjuvant MOF was tested in comparison with adjuvant radiotherapy alone or surgery alone by the National Surgical Breast and Bowel Project (NSABP) Protocol R-01.7 Following resection, patients with Dukes stage B (stage II) and C (stage III) rectal cancers were randomized to either observation, radiation, or adjuvant MOF. Radiation was administered by supervoltage equipment to 4600-4700 rad in 26-27 fractions given daily, 5 days per week by anterior-posterior fields. While quality assurance was independently verified, the protocol did permit perineal boosts to 5100-5300 rad, and the percentage of subjects who received boost therapy is not detailed. MOF was associated with an

Minimizing the therapy-related morbidity in the rectal cancer patient improvement in DFS (42% vs 30%; P ⫽ 0.006) and OS (53% vs 43%; P ⫽ 0.05). Local-regional recurrence as a first site of treatment failure was observed in 24.5% of patients treated with surgery only, 21.4% of patients treated with adjuvant chemotherapy, and 16% of patients treated with adjuvant radiation therapy. Distant recurrence as a first site of failure occurred in 26% of surgery patients, 24% of chemotherapy patients, and 31% of radiation patients. Adherence to chemotherapy, as planned, proved difficult as only 58% of patients received all planned 8 cycles of therapy. Reasons for early discontinuation included treatment failure, death, or development of second primary cancer. By contrast, no severe complications were associated with adjuvant radiation. Significant radiation enteritis did not occur and no treatment-related deaths were recorded. Eighty-four percent of eligible patients completed all planned radiation with patient refusal being the chief reason for not beginning therapy.8 The Gastrointestinal Tumor Study Group assessed whether adjuvant chemotherapy added clinical benefit to adjuvant radiation therapy. Compared with adjuvant radiation alone, adjuvant 5-FU CRT followed by 1 cycle of methyl-CCNU was associated with a decrease in local relapse rate (13.5% vs 25%, P ⫽ 0.036), a decrease in distant metastasis (28.8% vs 46%, P ⫽ 0.011), and an improved 5-year survival approximately 48% vs 58%. While patients receiving CRT had an increase in adverse events, such as nausea, vomiting, leukopenia, and thrombocytopenia, the frequency of severe acute reactions was similar in both groups. Late toxicity occurred in 13 patients (6.7% of all patients receiving radiation either alone or in combination). Nine patients developed small bowel obstruction, 1 developed small bowel hemorrhage, and 2 patients developed fibrotic pelvic masses causing bilateral ureteral obstruction.9 These studies led to adjuvant CRT becoming the standard of care for patients with stage II and III rectal cancer. Subsequent studies performed in the 1990s sought to identify less toxic CRT regimens. A 4-arm trial by the North Central Cancer Treatment Group compared bolus with prolonged infusion of 5-FU with or without methyl-CCNU as part of adjuvant CRT for patients with stage II and III rectal cancer.10 This was a 2 ⫻ 2 factorial designed trial comparing 2 cycles of unmodified bolus 5-FU given before and 2 cycles given after CRT with or without methyl-CCNU. The second randomization compared bolus 5-fluorouracil with uninterrupted continuous infusion 5-FU during radiation. Protocolspecified radiation was standardized and centrally reviewed for quality. Radiation was delivered by linear accelerator using multiple field techniques (anterior-posterior posterioranterior plus lateral fields) to 4500 cGy over 5 weeks followed by a boost of 540 cGy to the entire tumor bed and immediately adjacent lymph nodes were initiated by postoperative day 64 in all patients. Adherence to a specific surgical method, such as TME, was not required. Protracted infusion 5-FU was associated with a significant decrease in the overall rate of tumor relapse from 47% to 37% (P ⫽ 0.01), and a significant decrease in the rate of distant metastases from 40% to 31% (P ⫽ 0.03). Similarly, protracted 5-FU infusion was associated with a better 4-year overall survival rate of

121 70% vs 60% (P ⫽ 0.005), by log rank analysis. The use of methyl-CCNU did not demonstrate any clinical benefit. Small bowel obstruction requiring surgery following pelvic radiation occurred in 3% of subjects receiving protracted venous infusion 5-FU vs 2% of patients receiving 5-FU by bolus. The incidence of local recurrence was a statistically insignificant, 9% vs 11%, for patients receiving 5-FU and semustine vs patients receiving 5-FU alone, respectively. Local recurrence rate was not affected by bolus vs protracted 5-fluorouracil infusion. NSABP Protocol R-02 assessed the contribution of radiation therapy (RT) to chemotherapy. Patients with either Dukes’ B or C rectal carcinoma were randomized to receive postoperative chemotherapy, either alone or in combination with RT.11 All the women enrolled in the study were treated with 5-FU and leucovorin (LV), while the men were additionally randomized to receive either 5-FU/LV or MOF. Consistent with other studies, this trial concluded that the addition of RT to postoperative chemotherapy reduced the incidence of loco-regional relapse at 5 years (8% vs 13%, P ⫽ 0.02) but not the rate of distant metastatic disease as a first site of relapse, 31% vs 29%. Additionally, the 5-year relapse-free survival rate with 5-FU/LV (61%) was superior to MOF (55%), although 5-year overall survival was not statistically different, 65% vs 62%. In this trial, 5-FU 500 mg/M2 was administered as a bolus along with leucovorin 500 mg/M2 over 2 hours given weekly for 6 consecutive weeks, followed by 2 weeks off for 6 such cycles. In part due to gastrointestinal toxicity, in this trial 31% of subjects experienced more than 6 loose stools daily, the administration of leucovorin modified 5-FU on a weekly or daily ⫻ 5 schedule has been abandoned.

Adjuvant vs Neoadjuvant Treatment As adjuvant CRT gained standard of care stature, the development of preoperative or neoadjuvant RT and CRT began. The Swedish Rectal Cancer Trial specifically examined whether treatment with neoadjuvant RT (25 Gy given in 5 fractions of 5 Gy each, in 1 week) would improve overall survival and decrease rates of local recurrence. Surgical technique was not standardized, as the protocol did not require resection by TME. Patients were randomized to receive preoperative RT followed within 1 week by surgical resection or surgery alone. At 5-year follow-up, the rate of local recurrence was 11% in the RT group compared with 27% in the surgery alone group (P ⬍ 0.001). Moreover, the 5-year survival rate of 58% vs 48% favored the neoadjuvant RT arm (P ⫽ 0.004).12 In the Dutch trial, a similarly designed trial evaluated TME with or without preoperative radiation therapy, 25 Gy over 5 days.13 Among 1805 eligible patients, preoperative radiation was associated with a 2.4% local recurrence rate at 2-year follow-up vs 8.2% in the surgery-only group (P ⬍ 0.001). Subgroup analysis showed that radiation significantly reduced the risk of local recurrence in patients with distal and midrectal tumors (inferior margin less than or equal to 5 cm or 5.1-10 cm from the anal verge). The 2 year local recur-

122 rence rate for tumors within 5 cm of the anal verge was 10% vs 5.8%; for tumors 5-10 cm from the anal verge local recurrence rate was 10% vs 1%, both favoring radiation plus surgery. However, the local recurrence rate for tumors 10-15 cm from the anal verge was 3.8% for surgery alone and 1.3% for radiation plus surgery (P ⫽ 0.17). Despite the improvement in local recurrence rate the 2-year overall survival was the same, 82% vs 81.8% (P ⫽ 0.84).13 One of the most significant aspects of this trial is that it demonstrated the feasibility and efficacy of TME in a large multicenter trial. As these evaluations of neoadjuvant RT confirmed improved local recurrence-free survival but failed to demonstrate an OS benefit, it became increasingly important to investigate the use of chemotherapy plus RT in the preoperative setting. The German Rectal Cancer Study Group performed a landmark randomized control trial specifically comparing preoperative chemoradiotherapy with postoperative chemoradiotherapy in patients with preoperative stage II or III rectal cancer.14 Standardized TME was advocated for all patients and performed in 68% of subjects. To rule out potential bias with respect to the quality of surgery and commitment to sphincter preservation, patients were stratified according to surgeon. Patients were randomly assigned to receive 5-FU with RT either before or after surgical resection. After a median follow-up of 45.8 months, patients treated with neoadjuvant CRT were found to have an estimated overall 5-year survival rate of 76% compared with 74% in the adjuvant treatment group (P ⫽ 0.80). The incidence of local relapse favored the neoadjuvant group, 6% vs 13%. Moreover, grade 3 or 4 acute adverse events occurred in 27% of the patients in the neoadjuvant group compared with 40% in the adjuvant group. As well, long-term grade 3 or 4 adverse events were 14% in the neoadjuvant group compared with 24% in the adjuvant group (P ⫽ 0.01). Late toxicities included chronic diarrhea and small bowel obstruction (9% vs 15%, P ⫽ 0.07), anastomotic strictures (4% vs 12%, P ⫽ 0.003), and bladder problems (2% vs 4%, P not significant). Additional important findings from this trial include the fact that the preoperative arm was associated with a significantly higher proportion of patients with tumors situated within 5 cm of the anal verge and that a significantly higher percentage of patients in the postoperative arm refused to complete recommended adjuvant care. Also, while the rate of complete resection and sphincter preservation among all 799 evaluable patients was not influenced by treatment sequence, surgical outcomes among the 194 patients deemed, before randomization, to need abdominoperineal resection certainly were. In this subset of patients sphincter-sparing surgery was achievable in 39% of subjects receiving neoadjuvant CRT vs 19% of subjects in the adjuvant group. Notably, despite endorectal ultrasonography and computed tomographic scanning of the abdomen and pelvis to rule out TNM stage I tumors and distant metastatic disease, 4.6% and 1.5% of subjects in the postoperative treatment group were found to have stage I or stage IV, respectively, highlighting the need for improved preoperative clinical staging. By virtue of acute and chronic toxicities, percentage of patients able to tolerate all planned treatment, and DFS, this

T.A. Khair and P. Kozuch study demonstrated the superiority of neoadjuvant chemoradiation over adjuvant treatment. Improvement in OS was not achieved.

Assessing Value of Neoadjuvant 5-Fluorouracil The Federation Francophone de Cancerologie Digestive 9203 trial evaluated the relative contribution of 5-FU by randomizing patients to preoperative RT with or without concurrent 5-FU/leucovorin (bolus days 1-5 during weeks 1 and 5 of radiation therapy).15 All patients received adjuvant 5-FU/ LV. Neoadjuvant CRT was associated with a lower 5-year local recurrence rate of 8.1% vs 16.5%, (P value less than 0.5). However, overall survival was not statistically significantly different 67.9% vs 67.4%.

Developing Predictors of Survival As neoadjuvant chemotherapy was developed, investigators began to assess whether the pathologic and/or downstaging effects of preoperative CRT predicted survival outcomes. The relationship between a pathologic complete response (pCR) and recurrence-free survival/OS in preoperatively treated rectal cancer patients was in part established by Rodel et al, extending work done by Mandard et al in esophageal cancer patients.16,17 Tumor regression grading (TRG) ranged from TRG 4, no viable tumor cells detected, to TRG 0, fibrosis completely absent. TRG 4 was observed in 10.4% of 385 specimens and 5-year DFS in this group was 86%. By contrast, 15.3% and 8.3% of specimens were observed to have TRG 1 or 0 with associated 5-year DFS of 63%. Investigators at Memorial Sloan-Kettering Cancer Center observed a similar predictive value of pathologic response.18 In their experience patients who achieved a pCR had a 5-year recurrence-free survival of 96%, while those with no pathologic response had a 54% 5-year recurrence-free survival (P ⬍ 0.00001). Five-year OS also favored the pCR group, 90% vs 68% (P ⫽ 0.01). Of additional appeal, 91% of patients who achieved a pCR had sphincter preservation compared with 76% sphincter preservation in the group without pathologic response. Tumor regression was also evaluated and categorized in the aforementioned Federation Francophone de Cancerologie Digestive 9203 trial. Compared with patients receiving neoadjuvant RT only, the neoadjuvant CRT subjects were noted to have a higher incidence of complete tumor sterilization: 11.4% vs 3.6% (P ⬍ 0.05). The increased incidence of pathologic downstaging prompted researchers to recommend preoperative chemoradiotherapy for T3-T4 adenocarcinoma of the middle and distal rectum.15 Similarly, the German Rectal Cancer Study Group found that 8% of patients treated with neoadjuvant CRT achieved a pCR. Furthermore, there was evidence of downstaging in association with neoadjuvant CRT as 25% of preoperatively treated subjects had

Minimizing the therapy-related morbidity in the rectal cancer patient pathologically involved lymph nodes compared with 40% of postoperatively treated subjects.14

123 with assessment of clinical and pathologic complete response rates as well as sphincter-preservation rates among secondary endpoints.24

Incorporating Oxaliplatin Given the data demonstrating the superiority of neoadjuvant CRT over postoperative CRT and the emerging correlation between pCR and survival outcomes, investigators began to develop protocols designed to evaluate the feasibility and clinical benefit of incorporating additional systemic antineoplastic drugs into established 5-FU-based neoadjuvant CRT “backbones.” Based on its adjuvant benefits in stage II and III colon cancer, oxaliplatin became the lead candidate for development in neoadjuvant CRT treatment of stage II and III rectal cancer.19 The Lyon R0-04 Phase II Trial evaluated 5-FU, folinic acid, and oxaliplatin (FOLFOX) combined with RT. Overall, the treatment was well tolerated; 39 of 40 subjects completed all planned treatment and only 7 subjects experienced grade 3 toxicity. The pCR rate was 15% and an additional 30% of specimens were noted to have “a few residual cancer cells.”20 A dose finding phase I/II trial of neoadjuvant continuous infusion of 5-FU, RT, and escalating doses of oxaliplatin before TME demonstrated good tolerability with weekly oxaliplatin doses up to 60 mg/m2. Twenty-one of 25 patients experienced tumor downstaging following neoadjuvant treatment. Twenty-eight percent of patients were noted to have a pCR and 48% had downstaging with residual T1-T2 N0 disease.21 A phase III randomized controlled trial compared neoadjuvant radiation 45 Gy plus capecitabine (RT 45-Cap) vs RT50-Capox (radiation 5000 cGy, capecitabine, and weekly oxaliplatin).22 Capecitabine is an orally administered prodrug that is converted to 5-FU in the tumor where it inhibits DNA synthesis. Toxicity favored RT 45-Cap with 11% vs 25% experiencing grade 3 or 4 toxicity. Notably however there was no statistical difference in pCR rate (13.8% vs 18.8% (RT50 CapOx) P ⫽ 0.11), sphincter preservation (75% vs 78%), or involved circumferential margin (11% vs 6%; P ⫽ 0.12). Of hopeful interest, metastatic disease found at the time of resection favored the oxaliplatin arm, 2.8% vs 4%. Another phase III trial of neoadjuvant 5-FU CRT, with or without oxaliplatin, also showed more grade 3-4 toxicities, 24% vs 8%, in association with oxaliplatin.23 Again, the addition of oxaliplatin did not improve pathologic CR rates, which were 16% vs 15%. There was significantly less distant metastases seen in the oxaliplatin-treated group 3% vs 0.5% (P ⫽ 0.014).

Ongoing Trials The NSABP R-04 Phase III Study is an ongoing 4-arm 2 ⫻ 2 factorial trial in which all patients receive 4500 cGy over 25 fractions plus either a 540- or a 1080-cGy boost for resectable, ie, nonfixed and for fixed tumors, respectively. Patients are randomized to concurrent chemotherapy with either 5-FU or capecitabine with or without additional weekly oxaliplatin. The primary endpoint is the rate of local recurrence,

Minimizing Toxicity and Optimizing Outcomes: Chemotherapy Only as Perioperative Treatment of Mid- and Upper Rectal Cancer Given the excellent local control rates associated with TME25 and the increased activity of 5-FU ⫹ oxaliplatin, the so-called FOLFOX regimen, in both metastatic colorectal cancer and as adjuvant treatment for high risk stage II and stage III colon cancer, investigators at our institution decided to pilot a study of neoadjuvant FOLFOX for 6 cycles followed by TME followed by an additional 6 cycles of FOLFOX, so-called Chemotherapy Only for Mid-Upper Rectal Cancer (COMURC). In the absence of significant improvements in survival associated using CRT, together with the excellent local control achieved by a baseline of TME, our goals have been to examine the role of neoadjuvant and adjuvant chemotherapy in the hope of improving survival, reducing the long-term toxicity of CRT, and maintaining or improving local control. In that light, we believe that this trial is most defensibly conducted in carefully selected patients deemed to have lower risk disease characteristics on preoperative evaluation. Eligibility criteria specify for selection of patients with mid-upper rectal cancers between 6 and 12 cm from the anal verge that are T3N0M0 or T1-3N1M0 based on a combination of pretreatment clinical examination, transrectal ultrasound (TRUS), high-definition magnetic resonance imaging, and computed tomographic scanning. If patients are found to have pretreatment or preoperative evidence of T4, N2, or distal lesions (0-5 cm from anal verge), they are not eligible for COMURC and receive preoperative FOLFOX-based CRT. So that oncological outcome is not compromised, any pT4, pN2, or circumferential margin positive patients are offered postoperative radiation. The primary endpoint is the pCR rate with early stopping rules if the pCR rate is determined to be achieved in less than 10% of subjects. Secondary endpoints include overall TRG or the pathologic response rate, correlation of pathologic staging with preoperative ultrasound and pelvic magnetic resonance imaging staging, toxic side effects, DFS, and OS.

Observation vs Capecitabine-Oxaliplatin Following Neoadjuvant CRT and Resection Another approach that may result in sparing patient’s acute and subacute side effects from adjuvant chemotherapy is being addressed by the Capecitabine-Oxaliplatin Following Neoadjuvant CRT and Resection trial.26 Following fluoropyrimidine-based neoadjuvant chemoradiation therapy to at least 45 Gy and margin negative resection, 800 patients will be randomized to observation or 6 cycles of adjuvant oxaliplatin and capecitabine. Disease-free and overall survival are the primary objectives of this Cancer Research UK trial.

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Lifestyle Modifications The observed association of physical activity with reduced risk of various types of cancers has generated much interest. Epidemiologic and clinical work suggest a causal association between physical activity and colon cancer. A sedentary lifestyle is attributed to changes in hormone and growth factor levels, increased body fat content, and impaired immune function all possibly promoting the development of cancer.27 Physically active people have a reduced risk of developing colorectal cancer (CRC).28 Over 50 epidemiologic studies have examined the relationship between physical activity and the incidence of CRC, with the vast majority showing physical activity to be protective.29 A meta-analysis of 19 cohort studies showed a statistically significant 22% reduction in the risk of colon cancer in active males and 29% reduction in active females.27 Evaluating the impact of physical activity on recurrence following curative treatment of stage 2 and 3 colorectal cancer, the 41,528 subject Melbourne Collaborative Cohort Study found that exercise had virtually no association with disease-specific survival in stage I or IV cases but quite strong associations in patients with cancers that were stage II or III at diagnosis. In these patients, the hazard ratio for disease-specific survival, comparing exercisers with nonexercisers, was 0.49 (95% CI 0.30-0.79). The corresponding hazard ratio for overall survival was 0.61 (95% CI 0.41-0.92).30 Forty-four percent of patients identified themselves as exercisers in this trial. Meyerhardt et al reported a significant protective association with increasing levels of physical activity in patients following adjuvant chemotherapy for treatment of resected lymph node positive colon cancer.31 Three years DFS from the time of activity questionnaire completion was 75.1% for patients who engaged in less than 18 (metabolic equivalent task) MET-h/wk and 84.5% for patients who engaged in 18 or more MET-h/wk. One MET is the energy expenditure for sitting quietly for 1 hour. Given the apparent effect of 18 MET hours of activity/week in improving disease-free survival in patients with treated stage III colon cancer and the survival benefit of exercise demonstrated in patients with stage II and III CRC, our group and others are prospectively evaluating whether minimal educational reminders will improve the rate of compliance with exercise/activity recommendations in our patients with treated stage II and stage III CRC.

Moving Beyond Morphology In addition to establishing TRG as a predictor of outcome, emerging data on the use of molecular and genetic predictors for stage II colon cancer may eventually be incorporated into treatment planning for stage II rectal cancer. Chromosome 18q allelic loss (18q LOH) has been associated with disease progression and has been used as a prognostic marker for colorectal cancer. Jen and colleagues reported that the 5-year survival rate in patients with stage II disease and without the 18q deletion was 93% compared with 54% in patients with

the deletion and of the same stage. Using these findings, investigators proposed that patients with stage II disease and no allelic loss may not require adjuvant therapy to improve their OS.32 The Quick and Simple and Reliable validation study aimed at creating a recurrence score (RS) that could successfully predict recurrence risk, DFS, and OS in patients with stage II colon cancer much like the oncotype recurrence score used in early stage breast cancer. Forty-eight genes associated with recurrence risk and 66 genes predictive of 5-FU/LV benefit were identified by investigators. Gene expression was quantitated by RT-PCR tumor samples. Kerr et al reported that the risk for recurrence increased consistently with increasing RS:RS was also noted as a predictor of DFS (P ⫽ 0.01) and OS (P ⫽ 0.04). Investigators concluded that the colon cancer RS is a way to individualize recurrence risk in patients with stage II disease.33 High levels of microsatellite instability have been associated with a favorable prognosis in colon cancer but correlate with a poorer prognosis and a higher mortality rate in patients with rectal cancer.34 Eastern Cooperative Oncology Group 5202 is currently enrolling subjects with resected stage II colon cancer. If patients have high microsatellite instability or 18q LOH, they are deemed low risk for recurrence and assigned to observation. However, any combination that includes microsatellite stability or low microsatellite instability or 18q LOH is considered high risk and patients are assigned 12 cycles of adjuvant FOLFOX. This study will validate whether microsatellite instability and 18q LOH may be appropriately used to stratify stage II colon cancer patients into low and risk groups.35 The level of spontaneous or intrinsic apoptosis in rectal cancer patient has been shown to be predictive of local recurrence. In patients with nonirradiated, circumferential margin negative rectal cancer, lower than median intrinsic apoptosis was associated with more local recurrences (10.5% vs 6.1%, P ⫽ 0.06). The authors of this paper suggested that intrinsic apoptosis index could be used to identify patients who may not need radiation therapy.36 However, when chemotherapy is combined with preoperative radiation therapy pre- and post therapy apoptosis, p53, Bcl-2, Bax and Cox-2 were not associated with local recurrence rates, OS, or tumor regression. Combined preoperative chemoradiation was found to be affected in even highly apoptotic tumors.37

Conclusions Over the past 20 years, the standard application of total mesorectal excision plus neoadjuvant chemoradiation has significantly benefited patients with stage II and stage III rectal cancer. Undoubtedly, the clinical development of broadly applicable new technologies will allow us to further improve the tolerability and effectiveness of multidisciplinary rectal cancer treatment. The advent of molecular and genetic profiles will allow us to subcategorize patients’ disease and will serve as a basis for individual treatment plans. Advances in RT techniques, including the development of endorectal brachytherapy are detailed elsewhere in this symposium (see

Minimizing the therapy-related morbidity in the rectal cancer patient Vuong et al, this issue). Despite the advances, surgical resection will remain the foundation of the treatment of locally advanced rectal cancer. As systemic anti-neoplastics develop and mature, it will be important that researchers continue to examine the use of newer chemotherapeutic and other systemic agents in the neoadjuvant setting, with the overall goal of improving survival, reducing metastatic disease and local failures, and reducing the morbidity of treatment.

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