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Rectal Cancer The German CAO/ARO/AIO-04 trial sought to integrate oxaliplatin into both the preoperative and adjuvant fluoropyrimidine-based platform. pCR rates were modestly improved with oxaliplatin (17 versus 13 %), with high rates of compliance and acceptable toxicity. 22 By contrast, results from the Italian STAR-01 and French ACCORD 12/0405-PRODIGE2 trials adding oxaliplatin to fluoropyrimidine-based CRT regimens did not demonstrate improved pCR rates, with a significant increase in grade 3/4 toxicity rates seen. 23,24 The NSABP R-04 Intergroup trial initially sought to test the value of capecitabine compared with continuous infusion 5FU, but was later amended to a 2x2 design to also evaluate oxaliplatin as a component of preoperative CRT. Secondary endpoints of pCR, sphincter-sparing surgery, surgical downstaging, and acute toxicity were recently reported. No statistical differences were seen in surgical outcomes between arms, but the addition of oxaliplatin to either fluoropyrimidine regimen significantly increased toxicity rates. 21 Whether combination therapy with oxaliplatin will improve long- term clinical outcomes remains unclear. Updated results of ACCORD 12/0405-PRODIGE2 found no improvements in DFS or OS, while CAO/ARO/AIO-04 presented at 2014 ASCO suggested a DFS benefit at 3 years. 25,26 Randomized Comparisons of Short- and Long-course Radiotherapy Two published randomized trials have compared short-course RT and long-course CRT (see Table 4). Polish investigators randomized 312 patients with resectable T3/T4 rectal cancers to 50.4 Gy in 28 fractions with concurrent bolus 5FU and leucovorin followed by TME 4–6 weeks later versus short-course RT (25 Gy/5 fractions) followed by TME in 1  week. Compared with long-course CRT, short-course RT resulted in lower rates of early grade 3/4 toxicities (3.2 versus 18.2 %; p<0.001) and improved compliance (97.9 versus 69.2 %). 27 No significant difference was seen in sphincter preservation (the primary study endpoint), although it was not specified prior to treatment which patients would likely require an APR. Downstaging effects including a higher pCR rate (0.7 versus 16.1 %) and lower rates of positive circumferential margins (12.9 versus 4.4 %; p=0.017) in the long-course CRT arm. Adjuvant chemotherapy was left to the discretion of the treating physicians and was more commonly given in the short-course arm (46 versus 30  %). At a median follow-up of 48 months, there was no significant difference in LR (10.6 versus 15.6 %; p=0.21), 4-year DFS (58.4 versus 55.6 %), 4-year OS (67.2 versus 66.2 %), or severe late toxicity (10 versus 7 %) between the short and long courses, respectively. The second trial was conducted by the Trans-Tasman Radiation Oncology Group (TROG) in which 326 patients with T3N0-2 rectal cancers were randomly assigned to 50.4 Gy in 28 fractions with daily continuous infusional 5FU followed by TME 4–6 weeks later versus short-course RT (25 Gy/5 fractions). Unlike the Polish trial, all patients were staged using modern techniques and adjuvant chemotherapy was administered with short and long courses receiving 6 and 4 cycles, respectively. Pathologic downstaging (45 versus 28  %; p=0.002) and pCR (15 versus 1  %) rates were more common in patients assigned to long-course CRT. 28 No significant difference in APR rates were seen in distal (<5 cm) tumors (79 versus 77  %). At a median follow-up time of 6 years, no significant difference was seen in 3-year LR (7.5 versus 5.7 %), 5-year DM (27 versus 30 %), 5-year OS (74 versus 70 %), or late toxicity rates when comparing 142 short-course with long course, respectively. German investigators have conducted a third trial of similar design to the TROG study and results are eagerly anticipated. Future Directions A potential limitation of the short-course regimen is limited opportunity for tumor downstaging. By allowing a 4–8 week period following radiotherapy (as in the long-course regimen), improved pCR and downstaging may be seen with short-course RT. The Stockholm III trial was designed to further study these endpoints. Patients with resectable rectal cancer are randomized to one of three arms: short-course RT followed by surgery in 1 week, the same short-course RT followed by delayed surgery 4–8 weeks following treatment completion, or long-course RT followed by surgery in 4–8 weeks. 29 Another potential treatment approach using the short-course regimen is the integration of neoadjuvant chemotherapy. The RAPIDO trial, also from Sweden, is randomizing patients with locally advanced rectal cancer to preoperative long-course CRT and selective postoperative adjuvant chemotherapy versus short-course RT followed by 6 cycles of capecitabine and oxaliplatin before surgery. 30 Not all patients are expected to derive clinically meaningful benefit from neoadjuvant treatment. In the Dutch TME trial, short-course RT in stage I and II patients reduced LR, but also put patients at risk for late toxicities including long-term bowel dysfunction. 8,9 As a result, neoadjuvant therapy is typically reserved for cT3-4 and/or node positive rectal cancer or select cases of earlier stage distal tumors that may be downstaged to a potential sphincter-sparing surgery candidate. Select pT3N0 patients have a low risk of LR and may avoid adjuvant CRT. 31 Staging studies are sometimes inaccurate resulting in possible overtreatment for patients who may have reasonable outcomes with surgery alone. In the German Rectal trial, 18 % of patients in the postoperative arm were found to have early stage disease despite preoperative imaging classification of cT3- 4 or node positive disease. 11 By contrast, in a series of cT3N0 patients treated with neoadjuvant CRT and resection, 22  % had pathologically positive mesorectal nodes. 32 This number would have been presumably higher without preoperative treatment. Further improvements in imaging techniques may better select patients for neoadjuvant treatment. Recently, several alternative treatment paradigms have emerged. In an effort to administer systemic chemotherapeutic doses earlier, investigators at Memorial Sloan Kettering Cancer Center conducted a pilot trial of neoadjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with bevacizumab for clinical stage II–III rectal cancer patients. Chemotherapy was given for six cycles with selective rather than consistent use of chemoradiotherapy for stable/progressive disease. Out of 32 study participants, two did not complete the prescribed six cycles due to toxicity and were treated with neoadjuvant chemoradiation; all patients had an R0 resection with a pCR of 25 %. 33 No local failures have occurred after 4 years of follow-up. Other trials, however, have not demonstrated as promising results with a chemotherapy-alone neoadjuvant approach. 34 The use of preoperative chemotherapy alone in selected patients is now being evaluated in the Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT) trial. Another approach includes the omission of surgery in clinical complete responders to neoadjuvant CRT. One single institution’s experience has been On c ol og y & H ematolog y Re vie w