Total Neoadjuvant Therapy for Rectal Cancer: An Emerging Option

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1 Total Neoadjuvant Therapy for Rectal Cancer: An Emerging Option Ethan B. Ludmir, MD 1 ; Manisha Palta, MD 2 ; Christopher G. Willett, MD 2 ; and Brian G. Czito, MD 2 The treatment of locally advanced rectal cancer (LARC) has benefited from improved surgical techniques and from the implementation of neoadjuvant chemoradiotherapy (CRT), which have markedly decreased the rates of local recurrence. However, distant metastatic disease remains the most significant cause of death for these patients. Although adjuvant chemotherapy (ChT) after neoadjuvant CRT and definitive surgery is commonly recommended, the value of adjuvant systemic therapy remains less clear. Trials evaluating adjuvant ChT for rectal cancer have been handicapped by poor compliance rates and inconsistent survival results. Shifting systemic therapy delivery to the neoadjuvant setting has the promise to improve compliance rates, reduce toxicity, and decrease distant relapse rates. Recently, multiple prospective trials have reported on the use of total neoadjuvant therapy (TNT) for patients with LARC, incorporating both ChT and CRT in the neoadjuvant setting. Here, the authors review the promising results from those trials. Because the studies have largely focused on pathologic outcomes (primarily pathologic complete response rates), ongoing phase 2 and 3 trials are now underway assessing the long-term disease-related outcomes with TNT. In addition to improving survival, TNT has the potential to increase the pool of patients with LARC who are eligible for organ preservation, which is also being evaluated. Cancer 2017;123: VC 2017 American Cancer Society. KEYWORDS: chemoradiation, chemotherapy, neoadjuvant therapy, nonoperative management, organ preservation, radiation therapy, rectal cancer, total neoadjuvant therapy. INTRODUCTION Nearly 40,000 rectal cancers will be diagnosed in the United States in Historically, high local recurrence rates were observed despite definitive surgery for rectal cancer. 2 With improved surgical techniques and the addition of neoadjuvant radiation therapy (RT), 5-year local recurrence rates have decreased from >25% to approximately 5% to 10%. 2-7 However, these advances have not appreciably decreased the approximately 30% risk of distant metastatic recurrence, which remains the leading cause of rectal cancer-related death. 4-8 This has shifted the focus onto the role of additional systemic treatments to decrease the risk of distant recurrence. Current guidelines support the role of adjuvant chemotherapy (ChT) after neoadjuvant chemoradiation (CRT) and definitive surgery in stage II/III rectal cancer, 9 reflecting the general paradigm of rectal cancer treatment in the United States: neoadjuvant CRT followed by definitive surgery and, finally, adjuvant ChT. However, the role of adjuvant ChT in rectal cancer remains less clear, and its inclusion in the treatment aforementioned paradigm is at least partially extrapolated from colon cancer trials. 10,11 Trials specifically assessing adjuvant ChT in patients with rectal cancer have not convincingly demonstrated benefits in disease-related outcomes. 5,12-14 Recently, multiple trials have reported promising outcomes using a total neoadjuvant therapy (TNT) approach, in which all planned RT and ChT are delivered in the preoperative setting. Here, we review the rationale for TNT in rectal cancer as well as the current TNT literature, including ongoing trials. BACKGROUND Over the last several decades, local control (LC) for rectal cancer has markedly improved because of advances in surgical technique and the adoption of neoadjuvant CRT. Total mesorectal excision (TME) during surgical resection of localized rectal cancer, which involves removal of the entire circumferential perirectal tissue envelope, decreases rates of both involved surgical margins and local recurrences. 3,6 Similarly, for patients with locally advanced rectal cancer (LARC), including T3 and T4 tumors and lymph node-positive disease, neoadjuvant CRT has exhibited the ability to both Corresponding author: Brian G. Czito, MD, Department of Radiation Oncology, Duke University Medical Center, Box 3085, Durham, NC 27710; Fax: (919) ; brian.czito@duke.edu 1 Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 2 Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina. DOI: /cncr.30600, Received: October 7, 2016; Revised: January 2, 2017; Accepted: January 10, 2017, Published online March 10, 2017 in Wiley Online Library (wileyonlinelibrary.com) Cancer May 1,

2 improve disease-free survival (DFS) and LC. 4,15 Multiple trials have assessed the role of adjuvant versus neoadjuvant therapy as well as RT versus CRT. 4,15-19 These data have supported the current practice in the United States of giving fluoropyrimidine-based neoadjuvant CRT, using long-course RT (typically 50.4 gray [Gy] over approximately 5.5 weeks). In other countries, neoadjuvant short-course RT alone (25 Gy over 1 week) is alternatively used. 20,21 However, preoperative RT and TME have both contributed to improvements in LC rates for patients with LARC. With these advances in local therapy, the leading cause of death in patients with LARC is now distant metastases, and increasing emphasis has been placed on the role of systemic treatment. 6-8 In patients with colon cancer, postoperative ChT improves DFS and overall survival (OS) for those who have lymph node-positive disease. 10,11 Similarly, trials of adjuvant rectal cancer therapy from the 1970s and 1980s demonstrated improved DFS when patients received concurrent and adjuvant ChT plus adjuvant RT. 22 Collectively, results from colon cancer trials as well as adjuvant rectal cancer studies appear to justify the current recommendation to give adjuvant ChT to patients with LARC. However, these experiences have not specifically assessed the role of adjuvant ChT in the contemporary era of neoadjuvant CRT for rectal cancer. Therefore several trials were undertaken to address this question of whether adjuvant ChT improves disease-related outcomes for patients with LARC after neoadjuvant CRT and definitive surgery. 5,12-14,23,24 The largest of these studies, European Organization for Research and Treatment of Cancer (EORTC) trial 22921, demonstrated that adjuvant ChT (with 5-fluorouracil [5-FU]/leucovorin) for patients with T3 and T4 rectal cancer did not improve disease control or survival after neoadjuvant RT or CRT, with an approximately 30% 10-year rate of distant metastasis in all study arms. 5,12,13 Notably, compliance with adjuvant ChT was poor: only 73% of patients assigned to adjuvant ChT actually initiated postoperative ChT, and only 43% received 95% of the planned 5-FU dose. 5 Similar results were observed in 3 other trials, which demonstrated no improvement in disease-related outcomes with the addition of adjuvant fluoropyrimidine-based ChT to neoadjuvant RT/CRT and surgery for LARC. 14,23-25 Whereas 2 of those trials were closed early because of slow accrual and were consequently underpowered, 23,24 the EORTC trial and an Italian study did not demonstrate benefit from adjuvant ChT despite adequate sample sizes. 5,14 Like the EORTC study, the Italian trial suffered from poor compliance with adjuvant therapy: only 58% of patients received 3 of 6 planned adjuvant ChT cycles (a ChT regimen of 5-FU/folinic acid). 14 For these trials, the most common reasons for poor adjuvant ChT compliance were treatment-related/postoperative toxicities, disease progression, and patient refusal. 5,14 Given these limitations, the role of adjuvant ChT in the modern treatment of rectal cancer remains in question, and alternate approaches are needed to improve distant control and survival. 25,26 MERITS OF A TOTAL NEOADJUVANT APPROACH Delivering ChT in the neoadjuvant setting has the promise to remedy many of the pitfalls associated with adjuvant ChT approaches that resulted in poor compliance. With the high incidence of postoperative complications and treatment-related toxicities limiting adjuvant ChT compliance across multiple trials, neoadjuvant ChT (NAC) may allow for greater treatment compliance. Avoiding ChT in the postoperative setting might also reduce overall toxicity rates. Earlier delivery of full-dose, systemic therapy to eliminate micrometastatic disease has the potential to decrease the risk of disease progression during treatment and improve disease-related outcomes. Others have noted that positioning surgery as the final step in the treatment algorithm for LARC could allow for earlier reversal of a diverting stoma postoperatively. 8 With NAC, TNT for rectal cancer can also facilitate the selection of patients who may benefit from organ preservation, or a watchand-wait approach, for their cancer. In this context, NAC added to neoadjuvant CRT might help further identify patients for whom surgical resection can be safely omitted. 27 This would include increasing rates of tumor regression through both increased time for CRT downstaging to occur and a ChT-related antitumor effect, thereby expanding the pool of patients who are eligible for organ preservation. For patients who do undergo definitive surgery, increased tumor regression with NAC could further promote complete (R0) resection rates. Conversely, there are potential disadvantages to NAC. Most notably, the delay in definitive surgery could allow for local disease progression, particularly in those patients who do not respond to NAC. NAC also may impact the performance status of patients who undergo planned surgical resection and/or potentially increase surgical complication rates. Therefore, clinical data are required to determine whether TNT improves treatment compliance with systemic therapy as well as disease-related outcomes Cancer May 1, 2017

3 TNT for Rectal Cancer/Ludmir et al CURRENT EVIDENCE FOR TNT Recently, multiple prospective clinical trials have been published assessing the role of TNT for LARC, dramatically expanding the available literature on the subject. Two neoadjuvant paradigms have emerged from these studies: 1) CRT followed by NAC, and 2) NAC followed by CRT. Here, we review the clinical evidence for each of these approaches, focusing first on treatment compliance and then on disease-related outcomes. Finally, we review the role of TNT in organ-preservation strategies as well as future directions and ongoing trials with TNT. COMPLIANCE CRT Followed by NAC The first TNT strategy relies on administering NAC between CRT and definitive surgery. This paradigm was tested in a recent, prospective, multi-institutional phase 2 trial by Garcia-Aguilar et al. 28 In that trial, patients were assigned to receive CRT (with concurrent 5-FU) followed by NAC and then surgical resection (Table 1) Four treatment arms were included, defined by the number of NAC cycles between CRT and surgery (TME); these arms assigned patients to 0, 2, 4, or 6 cycles of modified FOLFOX6 (5-FU/leucovorin/oxaliplatin) chemotherapy between CRT and surgery (Table 1). 28 Treatment compliance with NAC was good, with 77% to 82% of patients completing all prescribed NAC cycles, depending on treatment arm. This is in contrast to the adjuvant ChT trials mentioned above, which reported ChT compliance rates of 43% to 58%. 5,14 Furthermore, despite more extensive chemotherapy before surgery, the postoperative complication rates did not differ based on treatment arm (Table 1). The recently reported Polish II trial also assessed the role of NAC between RT and definitive surgery. 29 In that phase 3 trial, patients with fixed T3/T4 lesions were randomized to receive either short-course RT (SC-RT) (25Gy in 5 fractions) followed by 3 cycles of FOLFOX or long-course CRT (LC-CRT) (50.4 Gy over 5 weeks) with concurrent FOLFOX6 (Table 1). 29 Compliance with oxaliplatin delivery favored the SC-RT/NAC arm over the LC-CRT arm (72% vs 64%), as did the overall toxicity profile. 29 Whereas the study by Garcia-Aguilar et al and the Polish II trial represent the largest experiences with (C)RT followed by NAC, other smaller prospective studies have assessed this paradigm, as highlighted in Table Included among these are several prospective, studies that had >90% NAC completion rates. 30,31,33 NAC Followed by CRT Similarly impressive treatment compliance rates have been observed in studies using the second TNT paradigm induction NAC followed by CRT and then surgery. For instance, the Spanish Grupo Cancer de Recto 3 (GCR-3) trial recently published long-term results. 35 In that phase 2, two-arm study, patients with LARC were randomized to receive 4 cycles of capecitabine/oxaliplatin (CAPOX) either before neoadjuvant CRT or after surgery (Table 2) The neoadjuvant ChT arm had both markedly improved ChT compliance (94% ChT completion in the neoadjuvant arm vs 57% in the adjuvant arm; P ) and a superior toxicity profile (19% grade 3/4 ChT toxicities in the neoadjuvant arm vs 54% in the adjuvant arm; P 5.004) (Table 2). 35,36 These improved compliance rates are echoed in the phase 2 EXPERT and EXPERT-C trials (Table 2). EXPERT, a phase 2 trial assessing the role of NAC with 4 cycles of CAPOX, demonstrated an 89% NAC completion rate. 37 EXPERT-C, an sister trial to EXPERT, assessed the role of adding cetuximab to capecitabine-based NAC and concurrent ChT; EXPERT-C similarly reported NAC compliance rates >90% regardless of whether cetuximab was included in the ChT regimen. 38 A pooled analysis of the EXPERT trials (PAN-EX) reported a combined 91% rate of NAC compliance for all patients. 34 Table 2 highlights these studies (GCR-3, EXPERT, EXPERT-C, and PAN-EX), as well as several smaller prospective series that assessed the role of NAC received before CRT; these also revealed generally high compliance rates using the same treatment paradigm (Table 2) DISEASE-RELATED OUTCOMES CRT Followed by NAC Both treatment strategies demonstrate promising compliance rates, but the critical clinical question is whether improved treatment compliance translates into superior disease-related outcomes. Most of these prospective studies used short-term pathologic endpoints, such as pathologic complete response (pcr) or R0 resection rates. This includes the trial by Garcia-Aguilar et al, in which the primary study endpoint was the pcr rate. 28 Remarkably, pcr rates increased significantly with increasing cycles of FOLFOX between CRT and TME, with 38% of patients achieving pcr when 6 cycles of NAC were prescribed after CRT (compared with an 18% pcr rate for patients who did not receive NAC between CRT and TME) (Table 1). 28 In addition, no patients experienced disease progression during NAC, irrespective of treatment arm. 28 Cancer May 1,

4 TABLE 1. TNT Studies assessing CRT followed by NAC Study (Citation) Year of Publication Design No. CRT Regimen NAC Regimen Adjuvant Therapy Compliance Post-Operative Complication Rate, % pcr Rate, % a R0 Resection DFS Rate, % a (3-year), % OS (3-year), % Garcia-Aguilar Phase 2 nonrandomized four-arm Bujko (Polish II trial) Phase 3 randomized two-arm Gao Prospective Gao 31 (sandwich regimen) 2014 Phase 2 Zhu Phase 2 Zampino Prospective 259 CRT (w/5-fu) None mfolfox6 (8 cycles) recommended, but not mandatory. CRT (w/5-fu) mfolfox6 (2 cycles) CRT (w/5-fu) mfolfox6 CRT (w/5-fu) mfolfox6 (6 cycles) 515 RT (5x 5Gy) FOLFOX4 (3 cycles) CRT (w/5-fu/ leucovorin/ oxaliplatin) 36 CRT (w/capox) CAPOX (1 cycle) 51 CRT (w/capox) CAPOX (1 cycle prior to CRT, and 1 cycle after CRT) 42 CRT (w/ CAPOX) mfolfox6 (6 cycles) recommended, but not mandatory. mfolfox6 recommended, but not mandatory. mfolfox6 (2 cycles) recommended, but not mandatory. Not reported; left to treating physician discretion. None Not reported; left to treating physician discretion. Cape (1 cycle) 51 CRT (w/cape) Cape (2 cycles) Unspecified adjuvant ChT given. NR 15 (Grade 3) NR NR 82% completed NAC. 6 (Grade 3) NR NR 81% completed NAC. 4 (Grade 3) NR NR 77% completed NAC. 9 (Grade 3) NR NR 63% completed both RT and NAC; 72% oxaliplatin compliance. 66% completed CRT; 64% oxaliplatin compliance. 100% completed RT; 94% completed NAC. CAPOX 100% completed RT, 98% completed NAC. CAPOX (6-8 cycles) 100% completed RT and Cape (including NAC); 76% oxaliplatin compliance. Adjuvant ChT tailored to degree of pathologic response. 100% completed CRT; 94% completed NAC. 29 (all complications) (all complications) (all complications) NR NR 11 (all complications) NR NR 13 (surgical site infection) (all complications) (5-year) NR Abbreviations: 5-FU, 5-fluorouracil; Cape, capecitabine; CAPOX, capecitabine/oxaliplatin; ChT, chemotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; FOLFOX6, 5-fluorouracil, leucovorin, and oxaliplatin; Gy, gray; mfolfox6, modified FOLFOX6; NAC, neoadjuvant chemotherapy; NR, not reported; OS, overall survival; pcr, pathologic complete response; R0, microscopically clear resection; RT, radiotherapy. a The R0 resection rate for the Polish II study includes patients who did not undergo surgical resection; other R0 resection rates are reported as the proportion of patients who underwent surgical resection (Bujko K, Wyrwicz L, Rutkowski A, et al. Long-course oxaliplatin-based preoperative chemoradiation versus Gy and consolidation chemotherapy for ct4 or fixed ct3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016;27: ) Cancer May 1, 2017

5 TNT for Rectal Cancer/Ludmir et al TABLE 2. TNT Studies assessing NAC followed by CRT Study (Citation) Year(s) of Publication Design No. NAC Regimen CRT Regimen Adjuvant Therapy Compliance Post-Operative Complication Rate, % pcr Rate, % a R0 Resection DFS Rate, % a (5-year), % OS (5-year), % GCR-3 35, , 2015 Phase 2 randomized two-arm EXPERT Phase 2 EXPERT-C Phase 2 randomized two-arm PAN-EX Pooled analysis of EXPERT and EXPERT-C CONTRE Prospective Dueland Phase 2 Gao Prospective Marechal Phase 2 randomized two-arm Dipetrillo Phase 2 Schou Prospective AVACROSS Phase 2 Koeberle Phase CAPOX CRT (w/capox) None 94% completed NAC; 85% completed RT. None CRT (w/capox) CAPOX 57% completed adjuvant ChT; 80% completed RT. 105 CAPOX 165 CAPOX 1 Cetuximab CAPOX CRT (w/cape) Cape (12 weeks) 89% completed NAC; 91% completed CRT. CRT (w/cape1 Cetixumab) CAPOX 1 Cetixumab 95% completed NAC; 91% completed CRT. CRT (w/cape) CAPOX 93% completed NAC; 90% completed CRT % completed NAC; 88% completed CRT; 68% completed adjuvant ChT. 39 mfolfox6 CRT (w/5-fu None reported 92% completed NAC; 90% (8 cycles) or Cape) completed CRT. 97 FLOX (2 cycles) CRT (w/capox) None reported 98% completed NAC; 95% completed RT. 42 CAPOX (1 cycle) CRT (w/capox) Unspecified adjuvant ChT given. 57 mfolfox6 (2 cycles) CRT (w/5-fu) Not reported; left to treating physician discretion. None CRT (w/ 5-FU) Not reported; left to treating physician discretion. 26 mfolfox6 1 Bevacizumab (2 cycles) 84 CAPOX (2 cycles) 47 CAPOX 1 Bevacizumab 60 CAPOX (1 cycle) CRT (w/ 5-FU, Ox, and Bevacizumab) mfolfox6 1 Bevacizumab (6 cycles) 100% completed both NAC and CRT. 96% completed both NAC and CRT. 51 (all grades) (all grades) (post-operative complications preventing start of adjuvant ChT) 0 (peri-operative death) 11 (KRAS-wt only) 2 (peri-operative death) 7 (KRAS-wt NR NR 92 NR NR only) NR (ileus) NR NR NR (all complications) NR NR 25 (all complications) NR NR 97% completed CRT. 31 (all complications) NR NR 60% completed both NAC and CRT; 25% completed adjuvant ChT. CRT (w/cape) None reported 91% completed 21 NAC cycles; 93% completed CRT. CRT (w/cape1 Bevacizumab) CRT (w/capox) CAPOX recommended, but not mandatory. Not reported; left to treating physician discretion. 85% completed NAC; 83% completed CRT. 87% received all oxaliplatin doses, 93% completed RT. 36 (all complications) 20 NR NR NR 9 (surgical site infection) (all complications) (32-month mean follow-up) NR NR NR NR Abbreviations: 5-FU, 5-fluorouracil; AVACROSS, Spanish study of the addition of bevacizumab to capecitabine-oxaliplatin induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined, poor-prognosis, locally advanced rectal cancer; Cape, capecitabine; CAPOX, capecitabine/oxaliplatin; ChT, chemotherapy; CONTRE, Complete Neoadjuvant Treatment for Rectal Cancer; CRT, chemoradiotherapy; DFS, disease-free survival; EXPERT and EXPERT-C, trials of neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer; FLOX, 5-fluorouracil/folinic acid/oxaliplatin; FOLFOX6, 5-fluorouracil/leucovorin/oxaliplatin; mfolfox6, modified FOLFOX6; GCR-3, Spanish Rectal Cancer Group Study 3; KRAS, v-ki-ras2 Kirstin rat sarcoma oncogene homolog; NAC, neoadjuvant chemotherapy; NR, not reported; OS, overall survival; Ox, oxaliplatin; pcr, pathologic complete response; R0, microscopically clear resection; RT, radiotherapy; wt, wild type. a pcr rates for the EXPERT-C trial are provided only for patients with KRAS wt tumors. The R0 resection rate was based on the population of patients who underwent surgical resection (Dewdney A, Cunningham D, Tabernero J, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012;30: ). Cancer May 1,

6 Although the high pcr and treatment compliance rates from the Garcia-Aguilar et al study are encouraging, there are caveats to this trial (and many other TNT trials) using pcr as a primary endpoint. The pcr rate has been correlated with improved long-term disease-related outcomes, including OS; one series demonstrated that patients with LARC who achieved a pcr had 2-year DFS and OS rates of 93% and 91%, respectively. 47 However, it has never been demonstrated that a pcr following neoadjuvant therapy for rectal cancer meets formal criteria as a surrogate endpoint for LC or OS. 48,49 To that end, although pcr rates may be helpful in identifying promising/active neoadjuvant regimens, phase 3 trials evaluating long-term outcomes (ie, DFS, OS) are needed to validate novel neoadjuvant approaches. 8,50 A related point is that the interval between CRT alone and TME may be an independent variable affecting pcr rates. Multiple series have suggested increased pcr rates with intervals greater than 7 or 8 weeks between completion of CRT and definitive surgery However, in the study by Garcia-Aguilar et al, all treatment arms had a median interval between CRT and TME of >8 weeks. 28 Randomized prospective data have demonstrated no increased pcr rates with an 11-week (vs a 7-week) interval between CRT and surgery, and retrospective data examining even longer intervals have not demonstrated higher pcr rates with intervals >12 weeks. 54,55 Collectively, it remains unclear whether the administered chemotherapy, the progressively longer interval between CRT and TME, or a combination of the two contributed to the progressively higher pcr rates observed in the study by Garcia-Aguilar et al. Unlike the Garcia-Aguilar study, the Polish II trial provided long-term disease-related outcomes for the 2 treatment arms SC-RT/NAC and LC-CRT. 29 In that trial, both treatment arms had similar intervals between RT initiation and surgery (approximately 12 weeks). Moreover, there were no differences in the R0 resection, LC, or DFS rates between the treatment arms. 29 However, the SC-RT/NAC arm had improved 3-year OS compared with the LC-CRT arm (3-year OS, 73% vs 65%; P 5.046). Interpretation of these findings in the context of other studies is challenging; on one hand, the SC-RT/ NAC arm appeared to have better compliance with oxaliplatin delivery than the CRT arm as well as a better toxicity profile (Table 1). In contrast, it is difficult to explain improved OS in the SC-RT/NAC arm with similar disease control rates (LC, DC, DFS) in the LC-CRT arm. 29 One interpretation suggests that patients who receive SC- RT/NAC are more likely to survive longer following recurrence than those who receive LC-CRT; in that trial, the authors speculate that the higher radiation dose per fraction in the SC-RT/NAC arm results in the development of enhanced antitumor immune response, resulting in increased response rates to subsequent salvage therapies. 29 Long-term follow-up may clarify these trends further, although the improved toxicity profile and compliance rates in the SC-RT/NAC arm are noteworthy. Together, the encouraging results from both the trial by Garcia-Aguilar et al and the Polish II study have spurred efforts to implement these approaches in future trials, as discussed below. NAC Followed by CRT The promising disease-related outcomes observed with the first TNT approach (CRT followed by NAC) have not been as apparent in trials assessing the second treatment approach (NAC followed by CRT). In the GCR-3 trial, there were no differences in DFS or OS at 5 years between the neoadjuvant and adjuvant ChT arms. 35,36 Furthermore, in contrast to the study by Garcia-Aguilar et al, the encouraging NAC compliance rates in GCR-3 did not translate into higher pcr rates (13%-14% irrespective of treatment arm) (Table 2). Although GCR-3 was not powered to detect differences in long-term disease-related outcomes, the authors suggest that the similar pcr rates between the treatment arms might have been caused by elements of their study design (a multi-institutional trial with patients stratified only by institution); this resulted in differences in tumor characteristics between treatment arms, including higher rates of threatened circumferential margins in the NAC arm. 35,36 Alternatively, it is possible that NAC does not significantly impact pcr rates and that the interval from CRT to surgery is the primary factor driving pcr in this context. Of the studies highlighted in Table 2, the trial that most closely resembles that by Garcia-Aguilar et al may be the Brown University CONTRE study. 39 In this prospective trial, patients received 8 cycles of mfolfox6 before CRT, with 92% NAC completion in the trial. 39 The authors reported that all patients underwent R0 resection, with surgery between 6 and 10 weeks after CRT completion, and 33% of patients had a pcr (Table 2). 39 These results are similar to those from the trial by Garcia-Aguilar et al for the treatment arm assigned to 6 cycles of neoadjuvant FOLFOX (100% R0 resection rate and 38% pcr rate). 28 Although it is difficult to draw conclusions from disparate phase 2 trials, these parallels suggest that future efforts might consider using NAC regimens with 6 to 8 cycles of FOLFOX to assess TNT efficacy Cancer May 1, 2017

7 TNT for Rectal Cancer/Ludmir et al ORGAN PRESERVATION In addition to improvements in treatment compliance and disease-related outcomes, a total neoadjuvant approach for patients with LARC has the potential to improve patient selection for organ preservation. The strategy of organ preservation, also known in the literature as a watch-and-wait or nonoperative management approach, has been pioneered at the Angelita and Joaquim Gama Institute (University of S~ao Paulo School of Medicine). 56 This approach involves clinical assessment of treatment response after CRT; for those patients who achieve a complete clinical response (ccr), immediate surgery is deferred, and patients are closely followed with a strict surveillance regimen. 27,56 Although the current literature for organ preservation in rectal cancer was recently reviewed elsewhere, evidence from the Gama Institute supports the TNT paradigm. 27 Initially, investigators reported a 27% ccr rate for patients who received CRT alone (50.4 Gy RT with concurrent 5-FU/leucovorin). 56 Subsequently, these investigators attempted to increase the ccr rate by adding ChT after CRT during the 8-week to 10-week interval between CRT completion and evaluation of treatment response. 57,58 With the addition of 3 cycles of 5-FU/leucovorin after CRT, along with an increased radiation dose (54 Gy) and an additional cycle of ChT during CRT (3 concurrent ChT cycles instead of 2), the ccr rate improved to 57%. 56,58 This substantial improvement in the ccr rate with ChT after CRT parallels the findings in the trial by Garcia-Aguilar et al, in which the pcr rate similarly doubled with the addition of NAC after CRT. 28,58 Like the TNT data detailed above, the regimen of CRT followed by ChT was well tolerated, with a reported 97% treatment completion rate. 57 Furthermore, that group assessed tumor metabolic activity after treatment with CRT alone versus CRT followed by additional ChT. 59 Through molecular imaging with radiolabeled glucose and positron emission tomography, investigators demonstrated that the addition of ChT during the resting period after CRT markedly decreased the probability of tumor regaining metabolic activity. 59 This finding, coupled with the improved ccr rates with additional ChT, supports the notion that NAC after CRT likely contributes at least in part to the improved pathologic outcomes observed by Garcia-Aguilar et al rather than just the temporal interval between CRT and surgery alone. 28,58,59 Taken together, these efforts have validated the TNT approach of additional chemotherapy in the preoperative setting, resulting in a considerable increase in the proportion of patients who are eligible for organ preservation. FUTURE DIRECTIONS Although reports for TNT approaches in rectal cancer have significantly increased, these trials have generally focused on short-term pathologic endpoints, such as pcr and R0 resection rates. Future studies will likely need to focus on long-term disease-related outcomes before total neoadjuvant strategies can be validated as evidence-based alternatives to current treatment paradigms. To that end, multiple trials are underway testing whether TNT can improve disease control and survival. The RAPIDO study is a prospective trial randomizing patients to either a control arm using a standard paradigm (neoadjuvant CRT followed by surgery and adjuvant ChT) or an experimental arm similar to that of the Polish II trial (SC-RT followed by NAC and, finally, surgery). 60 The primary trial endpoint is 3-year DFS. UK investigators are also attempting to assess the role of NAC combined with neoadjuvant SC- RT in the COPERNICUS trial: preliminary results reported 95% NAC completion rates, and all patients underwent R0 resection. 61 These results are now being used to support the CREATE trial, a phase 3 trial with the objective of determining whether induction NAC before neoadjuvant SC-RT or LC-CRT can improve 3-year DFS. 62 It is also noteworthy that these trials have been designed with well defined parameters for the delivery of adjuvant ChT after surgery. Many of the prospective studies completed to date have included the option for adjuvant ChT in patients assigned to NAC, which is generally left to the discretion of treating providers (Tables 1 and 2). Because these trials have usually used pathologic primary endpoints (R0 resection rate, pcr rate), few provided details regarding adjuvant therapy. The sole exception to this is the GCR-3 study, in which neoadjuvant and adjuvant ChT were directly compared in a 2-arm trial. 35,36 With this in mind, ongoing phase 3 trials examining disease-related outcomes with TNT are including clear guidelines regarding the role and permissibility of adjuvant ChT; this should help elucidate the long-term survival and toxicity with a strictly total neoadjuvant approach. Other efforts are underway to intensify and improve the efficacy of neoadjuvant treatments. Particular emphasis has been placed on the role of improving the concurrent chemotherapy component of neoadjuvant CRT. 8,63,64 To that end, a recently presented phase 2 clinical trial platform is aiming to identify novel sensitizing agents administered with neoadjuvant CRT that might improve disease-related outcomes. 65 This platform will use a TNT approach, with neoadjuvant FOLFOX followed by CRT and then definitive surgery. On the basis Cancer May 1,

8 of promising phase 1 data, the platform will begin by evaluating the addition of the poly-adp-ribose polymerase (PARP) inhibitor veliparib to concurrent CRT. 65,66 With this platform, experimental arms can systematically test experimental radiosensitizers during CRT to improve TNT efficacy. Alternative approaches have investigated whether neoadjuvant RT is necessary in these patients and whether ChT alone could be sufficient as neoadjuvant treatment for select patients with LARC. A single-institution phase 2 trial demonstrated that selective omission of neoadjuvant RT might be feasible for patients who respond to neoadjuvant FOLFOX-based ChT. 67 These results spurred the ongoing phase 2/3 PROSPECT trial. 68 That study is currently randomizing patients with LARC to a standard arm (neoadjuvant CRT followed by surgery and adjuvant FOLFOX) or an experimental arm. Patients in the experimental arm will receive neoadjuvant FOLFOX (6 cycles), and responding patients will proceed to TME with further adjuvant ChT postoperatively; nonresponding patients will revert to neoadjuvant CRT followed by surgery. 68 The primary endpoint for the trial is DFS. Along the same lines, the phase 2 BACCHUS trial will evaluate whether patients who respond to FOLFOXbased neoadjuvant ChT regimens can forego RT before TME. 69 These efforts to tailor neoadjuvant therapy based on initial response might help allow an eligible subset of patients to defer RT without compromising outcomes. This selection is likely important, because a recently published phase 3 trial that did not select for treatment response demonstrated inferior pathologic outcomes with neoadjuvant FOLFOX-based ChT versus neoadjuvant CRT. 70 Finally, as performed in other oncologic sites, there is increasing interest in the possibility of organ preservation for patients with LARC. Organ preservation for rectal cancer provides a potential opportunity to spare patients the morbidity and mortality of surgery. 27 Validation and optimization of a TNT approach could increase the proportion of patients with LARC who are eligible for organ preservation, consistent with data emerging from the Gama Institute. After the publication of results from the trial by Garcia-Aguilar et al, the Rectal Cancer Consortium is now accruing patients to a phase 2 trial evaluating TNT and organ preservation. 71,72 In this trial, patients with LARC will be randomized to one of two neoadjuvant treatment arms: either induction ChT (8 cycles of FOLFOX [or equivalent CAPOX]) followed by CRT, or CRT followed by NAC (8 cycles of FOL- FOX). For both arms, patients who achieve a ccr will proceed with a watch-and-wait approach using close surveillance, and those with no ccr will proceed to TME. The primary endpoint for this study is 3-year DFS. 71 This trial, tying together multiple themes presented here, will compare long-term disease-related outcomes between the two major TNT strategies NAC followed by CRT versus CRT followed by NAC while attempting to expand the pool of patients who are eligible for organ preservation. SUMMARY The recent burgeoning of TNT literature for LARC highlights the promise of this approach. With improved treatment compliance and reduced toxicities, TNT has the potential to increase distant control and survival rates for patients with LARC. Trials reported to date have largely limited their focus to short-term pathologic endpoints, and ongoing phase 2 and 3 trials should provide longterm, disease-related outcomes with TNT compared with the current approach using adjuvant ChT. Finally, optimization of TNT may further facilitate and identify greater numbers of patients with rectal cancer who are potentially eligible for organ preservation. 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