Neoadjuvant Combined-Modality Therapy for Locally Advanced Rectal Cancer and Its Future Direction

Rectal cancer treatment presents a challenge, and its optimal management requires a multidisciplinary approach involving surgical, medical, and radiation oncologists. Advances in surgical techniques, radiotherapy, and medical imaging technology have transformed the therapeutic landscape and have led to substantial improvements in both local disease control and patient survival. The currently established standard of care for patients with locally advanced rectal cancer involves preoperative (neoadjuvant) concurrent radiotherapy and infusional fluorouracil–based or oral capecitabine–based chemotherapy, also known as chemoradiotherapy (CRT), followed by surgery. Surgery is often followed by adjuvant chemotherapy. Here we discuss the evolution of standard therapy for rectal cancer patients and the use of preoperative CRT for the treatment of locally advanced disease. Treatment schemes that have attempted to broaden the horizons of standard therapy include the use of induction chemotherapy and “watch-and-wait” approaches. We examine several novel trials using these and other treatment approaches, which may eventually lead to better patient selection and the avoidance of overtreatment and unnecessary adverse effects.

Introduction

Colorectal cancer is the second leading cause of cancer-related death in the United States and the fourth leading cause worldwide.[1] Globally, it is estimated that approximately 1.57 million patients are diagnosed with, and more than 771,000 are expected to die from, colorectal cancer each year. Thirty percent of these cancers have been reported to arise in the rectum.[1,2]

Given the challenging nature of rectal cancer, ideally treatment should occur in a multidisciplinary setting and involve collaborative input from surgical, radiation, and medical oncologists. The choice of therapeutic approach for rectal cancer is based on several factors; whether trimodality therapy (surgery, radiotherapy [RT], and chemotherapy) is used depends greatly on tumor stage and the location of the tumor in the rectum. For patients with locally advanced rectal cancer, preoperative chemoradiotherapy (CRT) has been established as the standard of care. Thus, accurate preoperative staging of rectal cancer is, perhaps, the most critical step in the management of this disease.

Staging of rectal cancer is generally carried out using either endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI). EUS has high sensitivity and specificity in the staging of early (T1 and T2) rectal tumors. However, MRI (thin-section, high-resolution, phased-array coil MRI of the pelvis) is preferred for T3 or T4 tumors, since it provides excellent soft-tissue spatial and contrast resolution, is better at predicting mesorectal nodal involvement, and more accurately assesses the status of the circumferential resection margin.[3]

The Current Standard of Care for Locally Advanced Rectal Cancer

Currently, the only definitive indication for the use of preoperative CRT is the presence of a T3, T4, or node-positive tumor. This treatment paradigm consists of around 6 weeks of neoadjuvant CRT (infusional fluorouracil [5-FU] or oral capecitabine concurrent with RT), followed by 6 or more weeks of recovery prior to surgery (usually with total mesorectal excision [TME]), which in turn is frequently followed by adjuvant chemotherapy.[4,5]

Preoperative CRT is most often used if a patient has a distal rectal tumor for which an abdominoperineal resection (APR) is believed to be necessary. The use of CRT prior to surgery could convert an APR to a sphincter-preserving operation, such as a low anterior resection with coloanal anastomosis, which has the potential to profoundly improve a patient’s quality of life.

Evolution of the current standard of care

Surgery. Surgical resection, particularly the use of TME, remains the cornerstone of standard therapy for rectal cancer. TME involves complete removal of the primary tumor and the associated perirectal lymph nodes, without disruption of the mesorectum.

Surgery plus RT. Advances in surgical resection techniques afford curative potential for rectal cancer; however, local and distant tumor recurrence following surgical resection continues to be a problem, and this necessitates further efforts to improve initial local control.[6-8] Additionally, a permanent colostomy has a major negative impact on patient quality of life. Treatment options that improve outcome while avoiding the use of colostomy, especially in patients with low-lying tumors, are highly desirable.

The combination of surgery with other anticancer therapeutic modalities has been explored in the hope of improving outcomes. For example, RT was introduced and then quickly integrated into the treatment paradigm for rectal cancer. This approach was evaluated in several randomized trials, first in the postoperative and then in the preoperative setting,[9-17] resulting in reduced local recurrence rates, but with little impact on disease-free survival (DFS) or overall survival (OS). The Swedish Rectal Cancer Trial randomly assigned 1,168 patients with resectable rectal cancer either to surgery alone or to short-course preoperative RT (25 Gy delivered in 5 fractions in 1 week) followed by surgery.[18] The addition of short-course RT resulted in improved survival, although there was a higher incidence of late gastrointestinal toxicities. The Swedish Rectal Cancer Trial was the only study to demonstrate a significant improvement in survival following the use of short-course preoperative RT, even though local recurrence rates were high in this study.[18,19] The Dutch Colorectal Cancer Group study repeated the trial design used in the Swedish trial, except that TME was the only surgical technique allowed, and only patients eligible for this procedure were enrolled.[20,21] As with all other studies,[9-17] improvement in local control was observed but there was no difference in OS.

Surgery plus CRT. It became evident that the combination of RT and surgery led to an improvement in the rate of local control; however, no study findings to date have confirmed the RT-induced improvement in patient survival seen in the Swedish Trial.[18,19] Thus, in continued efforts to improve outcome, the next rational step was to attempt augmentation of RT with chemotherapy. Several phase III trials were conducted to examine whether the addition of 5-FU–based chemotherapy to RT resulted in a better pathologic response and better outcome.

In 1993, the European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy Group initiated the EORTC 22921 trial, which randomized more than 1,000 patients with T3/4 resectable rectal cancer, using a 2 × 2 factorial design, to one of the following four treatment regimens (along with surgery): 1) preoperative RT (the control arm), 2) preoperative CRT, 3) preoperative RT and postoperative chemotherapy, or 4) preoperative CRT and postoperative chemotherapy. RT consisted of 45 Gy delivered to the posterior pelvis in 25 fractions of 1.8 Gy over a period of 5 weeks. Preoperative and postoperative chemotherapy regimens involved 5-FU plus leucovorin. Preoperative chemotherapy was delivered in two 5-day courses during the first and fifth weeks of RT. 5-FU was given at a dose of 350 mg/m² per day, and leucovorin at a dose of 20 mg/m² per day. Surgery was scheduled to take place 3 to 10 weeks after treatment. In addition to effects on local tumor control, the ability of the four treatment approaches to improve OS and progression-free survival (PFS) was analyzed.[22]

CRT resulted in downsizing and downstaging of tumors and increased local control rates. Local failure rates were significantly lower in all three groups that received chemotherapy, compared with the control arm (preoperative RT alone), regardless of whether chemotherapy was given prior to or following surgery.

Patients undergoing preoperative CRT had a significantly higher rate of pathologic complete response (pCR; 14% vs 5%). However, the addition of chemotherapy, either concurrently with preoperative RT (neoadjuvant chemotherapy), or postoperatively (adjuvant chemotherapy) was not associated with any improvement in PFS or OS.

Updated long-term results of this study were published in Lancet Oncology in 2014.[23] The reported cumulative incidence of local relapse at 10 years was 22.4% in patients who received RT alone, compared with 11% to 15% in the three groups that received chemotherapy.[23] Ten-year DFS was similar in patients who received preoperative CRT vs RT alone (46% vs 44%), as was OS (51% vs 49%). Moreover, adjuvant 5-FU–based chemotherapy after preoperative RT (with or without chemotherapy) still did not affect DFS or OS.

Other studies, such as the Fédération Francophone de Cancérologie Digestive (FFCD) trial 9203,[24] yielded similar results and showed that the addition of 5-FU to RT significantly increased the pCR and local disease control rate. In a meta-analysis that included EORTC 22921,[23] FFCD 9203,[24] and four other trials,[25-28] the addition of chemotherapy to preoperative RT for the treatment of locally advanced (T3/4 or node-positive) rectal cancer was associated with less local recurrence (odds ratio [OR] for local recurrence, 0.56 [95% CI, 0.42–0.75]).[29]

Thus, the addition of chemotherapy to conventional fractionation RT became a standard approach in the treatment of locally advanced rectal cancer, likely because of the reduction in local recurrence and improvement in pCR rates observed with CRT.

Neoadjuvant vs adjuvant CRT

Adjuvant CRT following resection was considered the standard treatment for stage II/III operable rectal cancer, primarily on the basis of evidence from colon cancer trials. However, with growing evidence for the benefits of CRT in the neoadjuvant setting in terms of pCR and local disease control (in comparison with RT alone), questions were raised regarding: 1) the best sequence of CRT to use in relation to surgery; 2) the optimal chemotherapy regimen to use; 3) whether the delivery of more efficient systemic therapy earlier in the course of treatment results in better outcomes, perhaps with the potential to eradicate subclinical metastatic disease; and 4) whether the lack of compliance observed for postoperative chemotherapy can be improved.

Several studies investigated pre- and postoperative CRT in patients with locally advanced rectal cancer, with the aim of determining the best sequence of CRT administration with surgery.[30-33] Despite researchers’ best earlier efforts, the optimal sequence did not become clear until results from the German Rectal Cancer Study Group trial became available in 2004.[30] This seminal trial firmly established the role of neoadjuvant CRT by directly comparing preoperative with postoperative CRT for locally advanced rectal cancer.[30]

The German Rectal Cancer Study Group trial was initiated in February 1995, and enrollment was extended through September 2002. The study enrolled 823 patients with clinical stage T3 or T4 or node-positive disease. Patients were then randomly assigned to receive either preoperative (n = 421) or postoperative (n = 402) CRT. The preoperative treatment consisted of 5,040 cGy delivered in fractions of 180 cGy per day, 5 days per week, concurrently with infusional 5-FU (1,000 mg/m² daily for 5 days during the first and fifth weeks of RT). All patients underwent TME 6 weeks after the completion of CRT. One month after this surgery, 4 additional cycles of adjuvant 5-FU (500 mg/m² bolus daily for 5 days, every 4 weeks) were administered. CRT was identical in the postoperative treatment group, except for the delivery of a boost of 540 cGy in the latter group. The primary endpoint was OS.

Results from a 46-month median follow-up analysis showed that preoperative CRT was associated with a significantly lower cumulative incidence of local relapse than postoperative CRT (6% vs 13%; P = .006). After 11 years of follow-up, the difference was smaller but persisted (7% vs 10% for pre- vs postsurgical CRT, respectively).[31] The 5-year DFS rates were 68% and 65%, respectively, and the 5-year OS rates were 76% and 74%, respectively (P = .80). Ten-year survival rates were also similar for pre- and postsurgical CRT (DFS was approximately 68% and OS was approximately 60% [taking the average of both pre- and postsurgical groups]). The rate of long-term toxic effects in the preoperative vs postoperative patients was 14% vs 24%, respectively (P = .01).

Following preoperative CRT, there was a significant shift toward earlier TNM staging, suggestive of significant preoperative CRT downstaging effects (P < .001). Furthermore, 8% of the patients in the preoperative CRT group had a complete response, and only 25% had positive lymph nodes (compared with 40% in the postoperative group).

In patients with tumors that had been predicted preoperatively by a surgeon to require an APR, the rate of sphincter-preserving surgery was more than twice as high after preoperative CRT compared with postoperative CRT (39% vs 19%, respectively; P = .004).

Importantly, 18% of patients in the postoperative treatment group (no CRT prior to surgery) who were determined preoperatively to have T3 or T4 disease or lymph node metastasis were found to actually have T1 or T2 or node-negative tumors on pathologic examination of the resected specimen. This important observation clearly highlights the limitations of preoperative staging at the time the study was performed, and perhaps the potential for overtreatment of some patients. The finding underscores the need for accurate staging so as to avoid unnecessary treatment of patients with early-stage tumors.

It is noteworthy that the German study clearly highlighted the postoperative compliance issue: 92% of patients in the preoperative arm received a full dose of RT, compared with only 54% in the postoperative arm (P < .001), and 89% compared with 50% received a full dose of chemotherapy (P < .001). Thus, the administration of CRT prior to major surgery (as opposed to postoperatively) may enhance the rate of curative surgery and permit sphincter preservation in patients with low-lying tumors-due to increased compliance, if for no other reason.[30,31]

By 2004, following dissemination of the German study results,[30,31] preoperative CRT was established as the new standard of care (Figure 1), and the use of postoperative CRT rapidly declined.

In addition to the German study, two other prospective randomized trials aimed to compare the efficacy of preoperative CRT with postoperative CRT for rectal cancer; these studies were initiated in the United States by the Radiation Therapy Oncology Group (RTOG; trial 94-01) and the National Surgical Adjuvant Breast and Bowel Project (NSABP; protocol R-03). Unfortunately, both studies were closed prematurely due to poor accrual.

Although preoperative CRT is widely accepted as the standard of care, an alternative approach using short-course neoadjuvant RT has been adopted as another standard approach for the treatment of patients with operable rectal cancer, particularly in Europe. This practice is largely based on the previously mentioned Swedish and Dutch studies,[18-21] which demonstrated that short-course neoadjuvant RT is associated with long-term outcomes that are comparable to those achieved using long-course CRT.

A Polish study compared short-course preoperative RT (25 Gy in 5 fractions of 5 Gy and surgery within 7 days) vs long-course RT (50.4 Gy) plus chemotherapy (5-FU) followed by surgery 4 to 6 weeks later.[26] There were no differences in sphincter preservation rates (primary endpoint), local recurrences, OS, or late toxicity between the two arms. However, long-course RT plus chemotherapy did result in higher pCR and negative circumferential margin rates. A similarly designed Australian study that compared short-course with long-course RT demonstrated no statistically significant difference in 3-year local control rates.[28] However, the authors concluded that long-course RT may be more effective for distal tumors because of the higher recurrence rates seen with short-course RT. The Polish and Australian studies have been criticized for their sample sizes, imbalances between the arms, and overall trial designs.[29]

Although short-course neoadjuvant RT has been adopted by some, particularly in Europe, as a standard approach for the treatment of patients with operable rectal cancer, the majority of US oncologists follow the standard of care for rectal cancer established by the German trial, as described previously and following.

Risk stratification of rectal cancer

The German trial not only established a new standard treatment paradigm for rectal cancer, it also shed light on some very important aspects of rectal cancer management-specifically, the risk stratification of rectal cancer patients undergoing neoadjuvant CRT, and the best way to predict DFS after preoperative therapy.

In a subsequent exploratory analysis of the German rectal cancer study,[34] the pathologic T stage and the nodal status after CRT were found to be the most important independent prognostic factors for DFS. The 5-year DFS was 85% for ypN0, 65% for ypN1, and 18% for ypN2 (the “y” added to a pathologic stage indicates a TNM stage that is determined following CRT). The poor outcomes seen in patients with ypN2 disease in this report suggest that positive lymph nodes after neoadjuvant CRT may indicate a more aggressive disease. It is thus reasonable to argue that such patients should undergo prolonged postoperative chemotherapy.

In addition to the nodal status after CRT, prognosis following neoadjuvant CRT was also associated with tumor regression grading (TRG). TRG incorporates the degree of fibrosis as well as the percentage of viable tumor cells.[34] In an updated report of long-term results after a median follow-up of 132 months, the 10-year DFS rates for patients with TRG 4 were 90%, for those with TRG 2 to 3 they were 74%, and for those with TRG 0 to 1 they were 63%.[35]

Whether the pathologic T stage, nodal status, and TRG can or should be used to modify postoperative treatment strategies remains unclear, as do questions of whether to use adjuvant chemotherapy in patients with a favorable or poor prognosis. Determination of the most effective postoperative treatment strategy is an active area of research and has the potential to offer a unique opportunity to improve the current treatment paradigm and provide guidance for selection of the optimal therapy.

Further risk stratification has been proposed in order to more effectively individualize therapy for stage II/III rectal cancer. In a pooled analysis of survival and relapse rates in five North American phase III trials, patients were separated into four risk groups by TN stage: low-risk (T1/2N0), intermediate-risk (T1/2N1, T3N0), moderately high-risk (T1/2N2, T3N1, T4N0), and high-risk (T3N2, T4N1/2).[36] Appropriateness criteria were recently developed that incorporated this risk stratification along with the distance from the distal tumor edge to the anal verge and the distance from the radial tumor edge to the edge of the mesorectal fascia, based on MRI.[37] An expert panel rated conventionally fractionated CRT as appropriate for neoadjuvant therapy for all stage II/III rectal cancers. Neoadjuvant short-course RT was rated appropriate for intermediate-risk disease ≤ 10 cm from the anal verge and ≥ 2 mm from the edge of the mesorectal fascia, and for moderate-risk disease < 5 cm from the anal verge or ≥ 5 cm from the anal verge and ≥ 2 mm from mesorectal fascia. The expert panel rated short-course RT as possibly being appropriate for other stage II/III rectal cancers.

Following the development of orally active fluoropyrimidines (ie, capecitabine), the natural question was whether capecitabine could replace infusional 5-FU in the CRT setting. Several studies in colon cancer demonstrated noninferiority and perhaps superiority of capecitabine compared with 5-FU. Whether such findings hold true for rectal cancer, and whether capecitabine can replace infusional 5-FU during RT in the neoadjuvant treatment of stage II and III rectal cancer were examined. Two clinical trials studied the effect of using capecitabine in place of infusional 5-FU, combined with RT, on pCR, sphincter-sparing surgery, and surgical downstaging.

The first such trial, carried out by German investigators,[38] was a neoadjuvant, open-label, multicenter, noninferiority, randomized phase III study that began in March 2002. The study explored the substitution of capecitabine for infusional 5-FU.[38] Specifically, the trial directly compared CRT (50.4 Gy) using capecitabine (825 mg/m² twice daily, on days 1 to 38) with CRT (50.4 Gy) using 5-FU (1,000 mg/m² by continuous infusion on days 1 to 5 and 29 to 33). A total of 401 patients with locally advanced rectal cancer were enrolled and randomly assigned to either the oral or IV fluoropyrimidine group. Five-year OS in the capecitabine group was noninferior to that in the 5-FU group (76% vs 67%; P = .0004), and 3-year DFS was higher in the capecitabine group than in the 5-FU group (75% [95% CI, 68%–81%] vs 67% [95% CI, 59%–73%]; P = .07; Table 3). Better 3-year DFS with capecitabine than with 5-FU was noted in both the adjuvant (78% [95% CI, 69%–85%] vs 69% [95% CI, 59%–77%]) and neoadjuvant cohorts (71% [95% CI, 60%–80%] vs 63% [95% CI, 51%–73%]). The local recurrence rate was similar for capecitabine and IV 5-FU (6% vs 7%; P = .67), but fewer patients developed distant metastases in the capecitabine group (19% vs 28% for capecitabine and IV 5-FU, respectively; P = .04). Patients who received capecitabine had significantly more hand-foot syndrome, fatigue, and proctitis, but less neutropenia.

The second phase III trial, which was conducted by the NSABP,[39] employed a 2 × 2 factorial noninferiority design to compare four regimens administered concomitantly with RT (45 Gy in 25 fractions over 5 weeks, followed by a boost). The aim of this study was to determine the optimal neoadjuvant chemotherapy regimen for stage II/III rectal cancer, including the best sequence of administration of preoperative CRT. The trial evaluated the substitution of capecitabine for IV 5-FU, as well as the intensification of chemotherapy via the addition of oxaliplatin.

Between September 2004 and August 2010, a total of 1,608 patients with clinical stage II or III rectal cancer were enrolled in the trial and randomized to undergo preoperative CRT consisting of one of the following four regimens: 1) RT plus 5-FU as a continuous infusion (225 mg/m² daily, 5 days per week) with oxaliplatin (50 mg/m² weekly); 2) RT plus 5-FU without oxaliplatin; 3) RT plus capecitabine (825 mg/m² twice daily, 5 days per week) with oxaliplatin (50 mg/m² weekly); or 4) RT plus capecitabine without oxaliplatin. There were no significant differences between the capecitabine and infusional 5-FU regimens (regardless of oxaliplatin treatment) for the rates of pCR (21% vs 18% for the capecitabine and infusional 5-FU regimens, respectively), sphincter-sparing surgery, or surgical downstaging. Patients who received capecitabine had rates of locoregional control (the primary endpoint) comparable to those in patients who received IV 5-FU (regardless of oxaliplatin treatment), with a 3-year incidence of any locoregional events of 12% vs 11%, respectively. OS rates were also comparable (81% vs 80%). Thus, data support the equivalence of daily oral capecitabine and IV 5-FU during RT for neoadjuvant therapy; however, different toxicity profiles are evident (patients who received capecitabine had significantly more hand-foot syndrome, fatigue, and proctitis, but less neutropenia).

Chemotherapy intensification

Although preoperative CRT combined-modality treatment has been established as the standard of care for patients with locally advanced rectal cancer, it remains unknown whether the intensification of chemotherapy will enhance rectal cancer outcomes. This concept is still under investigation, as is the optimal chemotherapy regimen to be administered concurrently with preoperative RT and postoperatively.

Preclinical study results show that oxaliplatin is a potent radiosensitizing agent.[40] Additionally, it has been shown that the addition of oxaliplatin to a 5-FU regimen in both the adjuvant and palliative treatment of colon cancer improves DFS and OS.[41] Thus, the addition of oxaliplatin to a standard CRT regimen using 5-FU for the preoperative treatment of patients with rectal cancer appears to be a logical step in the pursuit of improved local disease control and patient survival. In fact, several studies have examined the effect of adding oxaliplatin to neoadjuvant 5-FU–based CRT, as well as to postoperative chemotherapy, in patients with locally advanced rectal cancer (Table 1)[42-47]; most of these demonstrated greater toxicity from an oxaliplatin-containing regimen, but efficacy data have been conflicting. Overall, a role for neoadjuvant oxaliplatin in the treatment of locally advanced rectal cancer remains highly controversial (see Table 1).

In the recently published German CAO/ARO/AIO-04 trial, investigators evaluated two separate combinations of preoperative CRT, surgery, and adjuvant chemotherapy.[47] This multicenter, open-label, randomized phase III study included 1,265 patients who had cT3/4 or cN1/2 rectal tumors that were within 12 cm of the anal verge. Patients were randomly assigned to receive preoperative CRT (50.4 Gy with infusional 5-FU [1,000 mg/m² per day on days 1 to 5 and 29 to 33]), followed by surgery, then adjuvant chemotherapy (IV bolus 5-FU of 500 mg/m² daily for 5 days, every 29 days for 4 courses) or preoperative CRT with infusional 5-FU plus oxaliplatin, followed by surgery and 4 months of adjuvant therapy with modified FOLFOX6 (leucovorin [400 mg/m² IV over 2 hrs on day 1] before 5-FU [400 mg/m² IV bolus on day 1, followed by 2,400 mg/m² IV infusion over 46 hrs] plus oxaliplatin [85 mg/m² IV on day 1] on a 2-week schedule). The primary endpoint was DFS.

DFS at 3 years in the oxaliplatin-treated patients was 75.9%, compared with 71.2% in the non–oxaliplatin-treated group (hazard ratio [HR], 0.79 [95% CI, 0.64–0.98]; P = .03). There was no difference in the rate of complete (R0) resection, but the addition of preoperative oxaliplatin did appear to increase pCR rates (17% with oxaliplatin vs 13% without oxaliplatin; OR, 1.40 [95% CI, 1.02–1.92]; P = .038).

In corroboration of other trials, preoperative grade 3/4 adverse events occurred in a greater number of patients who received oxaliplatin with their preoperative 5-FU–based CRT (24% with oxaliplatin vs 20% without oxaliplatin). However, of the patients who received adjuvant FOLFOX6, 36% had grade 3/4 toxicity, which was identical to the rate in those whose adjuvant regimen did not include oxaliplatin.

The authors concluded that adding oxaliplatin to 5-FU–based neoadjuvant CRT and adjuvant chemotherapy significantly improved DFS in patients with cT3/4 or cN1/2 rectal cancer, compared with oxaliplatin-free regimens. They also concluded that the oxaliplatin-containing regimen could be deemed a new treatment option for patients with locally advanced rectal cancer. However, in an editorial that accompanied the publication of the study (entitled “Is the Benefit of Oxaliplatin in Rectal Cancer Clinically Relevant?”), Bengt Glimelius argued that adding oxaliplatin to both pre- and postoperative treatment of locally advanced rectal cancer could result in pronounced overtreatment, thereby risking the development of long-lasting neuropathy in many patients. Glimelius also questioned whether the observed improvement in 3-year DFS was meaningful. Certainly in patients with colon cancer, 3-year DFS was shown to be a good surrogate for OS; however, whether the same will prove to be the case for patients with rectal cancer remains to be seen.

Overall, the role of neoadjuvant oxaliplatin in the treatment of locally advanced rectal cancer remains controversial.

Future Directions

Neoadjuvant chemotherapy alone

As outlined previously, the present treatment model uses neoadjuvant CRT followed by surgery, frequently followed by adjuvant chemotherapy, for all patients with stage II or III rectal cancer. Although preoperative CRT results in less toxicity than postoperative treatment,[30] there is no doubt that CRT is associated with significant side effects. Since current surgical techniques achieve very good results and yield excellent local control rates-and given that the majority of disease recurrence seen in patients consists of distant metastatic disease-why is trimodality therapy necessary for all patients if the purpose of RT is only to decrease local recurrence rates? This question has led to significant debate as to whether all patients with stage II or III rectal cancer require such an intensive treatment approach, especially if they are confirmed TME candidates (a procedure associated with low rates of local recurrence). Some experts have argued that RT could be eliminated in certain patient populations, particularly those diagnosed as T3N0/T3N1 or those who do not require an APR.

Several studies[48-51] have explored the possibility of omitting RT from rectal cancer therapy. Although data from some of these trials support the use of neoadjuvant chemotherapy alone followed by tumor resection, the ability to reach any definitive conclusions has been hindered by the small number of patients in these trials (Table 2).

The potentially practice-changing PROSPECT trial (ClinicalTrials.gov identifier: NCT01515787) is currently ongoing and aims to yield a new treatment strategy that will enable us to better select patients and deliver more precise therapy (Figure 2). This prospective, randomized, phase II/III trial was conceived to challenge the existing treatment paradigm for patients with proximal rectal cancer not requiring an APR. The goal of the trial is to avoid overtreatment by administering the most appropriate therapy to all patients, and by tailoring treatment based on tolerance and response to induction chemotherapy. Patients with stage II/III (T3N0, T3N1, or T2N1) rectal cancer are initially randomly assigned either to preoperative FOLFOX or to standard preoperative CRT. In the preoperative FOLFOX arm, initial chemotherapy is followed by comprehensive restaging using MRI. Only those patients experiencing a less than 20% reduction in their rectal tumor size following initial FOLFOX will receive preoperative CRT. Following their respective preoperative treatment(s), all patients undergo TME followed by postoperative chemotherapy (see Figure 2). The primary endpoint of the study is DFS.

Two other phase II trials (ClinicalTrials.gov identifiers: NCT01211210 and NCT01650428 [BACCHUS trial]) challenge the standard of care by investigating the use of neoadjuvant chemotherapy alone. Primary endpoints are 3-year DFS and pCR rate, respectively.

Once complete, all these trials will play a key role in defining the ideal rectal cancer treatment regimen and sequence. However, until study endpoints are reached and results are available, neoadjuvant chemotherapy alone remains only an investigational approach.

Induction chemotherapy followed by chemoradiation

For patients with stage II/III rectal cancer, the current standard treatment sequence is as follows: 5 to 6 weeks of CRT, followed by 4 to 6 weeks of recovery time, followed by surgery (TME), followed by 4 to 6 weeks of postoperative recovery time, followed by initiation of adjuvant chemotherapy (see Figure 1). This timeline means that full systemic chemotherapy is not delivered until about 4 months after neoadjuvant CRT is initiated, and such a delay could theoretically allow for the development and dissemination of metastatic disease.

Thus, one could hypothesize that administering chemotherapy at an earlier point might treat micrometastases, thereby reducing the incidence of distant recurrence. This is the rationale for moving full systemic chemotherapy treatment forward to an earlier point in the rectal cancer treatment algorithm. Such a rationale makes the strategy of induction chemotherapy followed by CRT-sometimes called the “total neoadjuvant approach”-appear very attractive. Several trials with various designs and sample sizes have been conducted to examine the strategy of induction chemotherapy followed by CRT; Table 3 provides a summary of these. Four of the studies were single-arm trials: the CONTRE study[52]; the EXPERT trial[53]; the Danish study, by Schou et al[54]; and the Swiss study, by Koeberle et al.[55] All four trials treated patients with rectal cancer (T2–4) with induction chemotherapy (consisting of CAPOX [capecitabine plus oxaliplatin][53-55] or FOLFOX[52]), followed by neoadjuvant CRT (consisting of concomitant RT and capecitabine[52-54] or CAPOX[55]), followed by surgery. The EXPERT trial[53] in addition treated patients with postoperative adjuvant capecitabine. The pCR rates ranged from 20%[53-55] to 33%.[52] Also, the Danish study[54] reported a 5-year DFS and OS of 63% and 67%, respectively, while the EXPERT trial[53] reported a 3-year PFS, OS, and relapse-free survival (for patients who had complete resection) of 68%, 83%, and 74%, respectively. The Swiss Group,[55] who used oxaliplatin both in their induction therapy and their neoadjuvant CRT regimens, reported R0 resection and sphincter preservation rates of 98% and 84%, respectively.

The Spanish GCR-3 randomized study[56] aimed to compare the current conventional treatment paradigm (preoperative CRT, followed by surgery, followed by postoperative adjuvant therapy) with a similarly planned regimen of induction chemotherapy followed by CRT, then surgery. Of 108 rectal cancer patients (T3/4 and/or node-positive disease), 52 received preoperative CRT followed by surgery and then 4 cycles of postoperative adjuvant CAPOX (standard arm), while 56 received 4 cycles of CAPOX followed by CRT and then surgery (experimental arm). There were no significant differences between the two arms in pCR and DFS rates, 5-year cumulative incidence of local relapse, incidence of distant metastases, or OS. Thus, the implementation of induction chemotherapy prior to CRT did not improve outcomes in this study.[56]

Maréchal et al[57] also compared standard therapy (preoperative 5-FU–based CRT followed by surgery) with induction FOLFOX, followed by CRT, followed by surgery. The primary endpoint was the rate of achievement of local tumor excision (stage ypT0/1N0). On interim analysis, the ypT0/1N0 rates were 34.5% and 32.1%, respectively, and the study was deemed futile and prematurely closed.

Despite the studies conducted, induction chemotherapy followed by neoadjuvant treatment remains investigational and the benefits are still unclear. This is largely due to the use of single-arm studies and small sample sizes. The only randomized studies comparing induction chemotherapy strategies with CRT alone show no difference in long-term outcomes.

There is clearly a need for well-designed randomized controlled studies in rectal cancer. Currently there is an ongoing randomized phase III trial (the French PRODIGE 23 trial) that is randomly assigning 460 patients with locally advanced rectal cancer to either receive induction chemotherapy with FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin), followed by preoperative CRT (arm 1), or to receive preoperative CRT alone (arm 2). All patients will then undergo TME. The results from this trial should help us better understand the role of induction therapy in rectal cancer and help shape the treatment paradigm accordingly. The use of induction chemotherapy prior to neoadjuvant CRT in patients with rectal cancer should remain confined to the research setting until definitive data on the use of induction strategies become available.

The ‘watch-and-wait’ approach

Another controversial and potentially paradigm-changing approach is that of “watch-and-wait.” This approach takes as its premise that patients who achieve complete clinical response with CRT do not necessarily need to undergo surgical resection. Very recently, a group of oncologists in the United Kingdom questioned the currently accepted standard approach of tumor resection for all patients with localized rectal tumors.[58] The OnCoRe project, conducted by Renehan et al, attempted to provide evidence for the safety of a completely new watch-and-wait approach. In this approach, patients with rectal cancer and no evidence of metastases were treated with potentially preoperative CRT, and those who had a clinical complete response were given the option of “watching-and-waiting” and not going straight to surgery (those patients who did not have a clinical complete response were offered surgical resection following their CRT). In an analysis involving 218 patients matched for T stage, age, and performance status (among other criteria), 109 patients underwent the watch-and-wait approach post-CRT, while the other 109 patients underwent CRT followed by surgery. No difference in 3-year no-regrowth DFS was observed between groups (88% in the watch-and-wait group vs 78% in the group who underwent surgical resection; P = .02). However, patients in the watch-and-wait arm had significantly better 3-year colostomy-free survival than those who underwent surgical resection (74% vs 47%; P < .0001). These findings, which support the renouncing of surgical resection as the automatic standard treatment, exemplify an approach to decision making post-CRT that may potentially greatly benefit a large number of patients.

This approach is now being evaluated in a study led by Memorial Sloan Kettering Cancer Center (ClinicalTrials.gov identifier: NCT02008656), which is examining whether patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by nonoperative management will have an improved 3-year DFS compared with patients with similar tumors treated with the same neoadjuvant therapy, but followed by TME and adjuvant chemotherapy.

Conclusion

Rectal cancer is a complex disease to treat, and its optimal management requires a multidisciplinary approach, with involvement of surgical, medical, and radiation oncologists. Whereas in decades past we assumed that rectal cancer was different from colon cancer only in that it had a different anatomic location, we are beginning to increasingly recognize that it is also quite a different disease biologically. We cannot simply extend the results of colon cancer trials to rectal cancer patients. We also cannot treat all rectal cancer patients as if they were cut from the same cloth. We must develop a personalized treatment plan for each individual patient based on stage, location, gene expression, and the patient’s priorities-including his or her quality-of-life priorities. We anticipate that molecular profiling will allow for more precise treatments and predictions of outcomes. Interestingly, we find ourselves at a treatment turning point: we are beginning to look for ways to minimize treatment and are asking ourselves whether all that chemotherapy and surgery is really necessary, and whether we can shorten or even remove RT from the mix.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Fitzmaurice C, Dicker D, Pain A, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1:505-27.

2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90.

3. Mercury Study Group. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007;243:132-9.

4. Weiser MR, Zhang Z, Schrag D. Locally advanced rectal cancer: time for precision therapeutics. Am Soc Clin Oncol Educ Book. 2015:e192-e196.

5. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444-50.

6. Galandiuk S, Wieand HS, Moertel CG, et al. Patterns of recurrence after curative resection of carcinoma of the colon and rectum. Surg Gynecol Obstet. 1992;174:27-32.

7. Minsky BD, Mies C, Recht A, et al. Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival. Cancer. 1988;61:1408-16.

8. Phillips RK, Hittinger R, Blesovsky L, et al. Local recurrence following ‘curative’ surgery for large bowel cancer: I. The overall picture. Br J Surg. 1984;71:12-6.

9. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically rectal carcinoma. N Engl J Med. 1985;312:1465-72.

10. Balslev I, Pedersen M, Teglbjaerg PS, et al. Postoperative radiotherapy in Dukes’ B and C carcinoma of the rectum and rectosigmoid. A randomized multicenter study. Cancer. 1986;58:22-8.

11. Douglass HO Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med. 1986;315:1294-5.

12. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst. 1988;80:21-9.

13. Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg. 1988;208:606-14.

14. Higgins GA, Humphrey EW, Dwight RW, et al. Preoperative radiation and surgery for cancer of the rectum. Veterans Administration Surgical Oncology Group Trial II. Cancer. 1986;58:352-9.

15. Rider WD, Palmer JA, Mahoney LJ, Robertson CT. Preoperative irradiation in operable cancer of the rectum: report of the Toronto trial. Can J Surg. 1977;20:335-8.

16. Roswit B, Higgins GA, Keehn RJ. Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: report of a National Veterans Administration randomized study. Cancer. 1975;35:1597-602.

17. Wassif SB, Langenhorst BL, Hop WCJ. The contribution of preoperative radiotherapy in the management of borderline operability rectal cancer. In: Jones SE, Salmon SE (editors). Adjuvant therapy of cancer II. New York: Grune & Stratton; 1979. pp. 613-20.

18. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med. 1997;336:980-7.

19. Birgisson H, Pahlman L, Gunnarsson U, et al. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol. 2005;23:8697-705.

20. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638-46.

21. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575-82.

22. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results-EORTC 22921. J Clin Oncol. 2005;23:5620-7.

23. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15:184-90.

24. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620-5.

25. Boulis-Wassif S, Gerard A, Loygue J, et al. Final results of a randomized trial on the treatment of rectal cancer with preoperative radiotherapy alone or in combination with 5-fluorouracil, followed by radical surgery. Trial of the European Organization on Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. Cancer. 1984;53:1811-8.

26. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93:1215-23.

27. Latkauskas T, Pauzas H, Gineikiene I, et al. Initial results of a randomized controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or long-term chemoradiotherapy, both with delayed surgery. Colorectal Dis. 2012;14:294-8.

28. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012;30:3827-33.

29. McCarthy K, Pearson K, Fulton R, Hewitt J. Pre-operative chemoradiation for non-metastatic locally advanced rectal cancer. Cochrane Database Syst Rev. 2012;12:CD008368.

30. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731-40.

31. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926-33.

32. Mohiuddin M, Regine WF, John WJ, et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys. 2000;46:883-8.

33. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med. 1994;331:502-7.

34. Rodel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688-96.

35. Fokas E, Liersch T, Fietkau R, et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol. 2014;32:1554-62.

36. Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol. 2004;22:1785-96.

37. Goodman KA, Patton CE, Fisher GA, et al. Appropriate customization of radiation therapy for stage II and III rectal cancer: executive summary of an ASTRO clinical practice statement using the RAND/UCLA appropriateness method. Pract Radiat Oncol. 2016;6:166-75.

38. Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012;13:579-88.

39. O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. J Clin Oncol. 2014;32:1927-34.

40. Blackstock AW, Hess S, Chaney S. Oxaliplatin: in vitro evidence of its radiation sensitizing activity-pre-clinical observations relevant to clinical trials. Int J Radiat Oncol Biol Phys. 1999;45:253-4.

41. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51.

42. Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29:2773-80.

43. Gerard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol. 2010;28:1638-44.

44. Schmoll HJ, Haustermans K, Price TJ. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: first results of the PETACC-6 randomized phase III trial. J Clin Oncol. 2013;31(suppl):abstr 3531.

45. Schmoll HJ, Haustermans K, Price TJ. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: disease-free survival results at interim analysis. J Clin Oncol. 2014;32(suppl):abstr 3501.

46. Allegra CJ, Yothers G, O'Connell MJ. Neoadjuvant therapy for rectal cancer: mature results from NSABP protocol R-04. J Clin Oncol. 2014;32(suppl 3):abstr 390.

47. Rodel C, Graeven U, Fietkau R, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16:979-89.

48. Hasegawa J, Nishimura J, Mizushima T, et al. Neoadjuvant capecitabine and oxaliplatin (XELOX) combined with bevacizumab for high-risk localized rectal cancer. Cancer Chemother Pharmacol. 2014;73:1079-87.

49. Ishii Y, Hasegawa H, Endo T, et al. Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil, and leucovorin in patients with locally advanced rectal cancer. Eur J Surg Oncol. 2010;36:1061-5.

50. Schrag D, Weiser MR, Goodman KA, et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014;32:513-8.

51. Uehara K, Hiramatsu K, Maeda A, et al. Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 phase II trial. Jpn J Clin Oncol. 2013;43:964-71.

52. Perez K, Safran H, Sikov W, et al. Complete neoadjuvant treatment for rectal cancer: the Brown University Oncology Group CONTRE Study. Am J Clin Oncol. 2014 Nov 4. [Epub ahead of print]

53. Chua YJ, Barbachano Y, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010;11:241-8.

54. Schou JV, Larsen FO, Rasch L, et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Ann Oncol. 2012;23:2627-33.

55. Koeberle D, Burkhard R, von Moos R, et al. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer. Br J Cancer. 2008;98:1204-9.

56. Fernandez-Martos C, Garcia-Albeniz X, Pericay C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial. Ann Oncol. 2015;26:1722-8.

57. Maréchal R, Vos B, Polus M, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2012;23:1525-30.

58. Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol. 2015;17:174-83.