Update on Multidisciplinary Therapy for Locally Advanced Rectal Cancer

George J. Chang, M.D., M.S., F.A.C.S., F.A.S.C.R.S.

Assistant Professor of Surgical Oncology

Co-Associate Medical Director, Colorectal Center

The University of Texas, M. D. Anderson Cancer Center

Houston, Texas

Background

Rectal cancer is one of the most common cancers that affect men and women and is estimated to affect 40,870 new individuals in 2009.¹   Rectal cancer accounts for approximately 1/3 of the deaths due to colorectal cancer.  For patients who present with localized disease, the primary treatment is surgical resection.  Surgical resection provides control of local and regional disease as well as staging and prognostic information.  In patients with locally advanced rectal cancer, improved local control can be achieved with the addition of radiotherapy containing neoadjuvant or adjuvant regimens.  Locally advanced rectal cancer is comprised of tumors with extension beyond the muscularis propria (≥T3) or those with clinical or pathologic evidence for lymph node metastasis (N+).

Development of chemotherapy and radiation therapy strategies prior to total mesorectal excision (TME)

Rectal resection for cancer is a complex procedure which has historically been associated with a high rate of local failure of 15-50% with surgery alone.^2-4  There were a number of factors attributable for this including the narrow pelvic anatomy, the dual system of lymphatic drainage (mesorectal, iliac), and poor understanding of the oncologic requirements for resection.  In an effort to improve the rates of local disease control, a number of pivotal adjuvant therapy trials were performed in the United States.  Similarly neoadjuvant radiotherapy strategies were developed in Europe.  These trials demonstrated that the incorporation of radiotherapy in the neoadjuvant setting or chemoradiotherapy in the adjuvant setting could result in an approximately 50% relative reduction in the risk for local failure.

A number of pivotal studies in the U.S. examined the effects of the addition of radiation, chemotherapy, or both following surgical resection of locally advanced rectal cancer. The Gastrointestinal Tumor Study Group (GTSG) 7175 was a trial in which 227 patients with resected Dukes B or C rectal cancer were randomized to one of four treatment groups:  1) no adjuvant therapy, 2) postoperative radiotherapy (40-48 Gy), 3) postoperative chemotherapy (5-fluorouracil [5-FU]) and semustine), or 4) radiotherapy with concurrent 5-FU chemotherapy followed by additional 5-FU and semustine chemotherapy. ⁵  The rate of local recurrence after 5-years follow-up was the lowest in the combined modality arm (10.9%) as compared with 24% with no treatment, 20% with radiotherapy alone, and 26% with chemotherapy alone.  The combined therapy group also had improved disease-free and overall survival when compared to the other treatment arms, although with a significantly increased rate of treatment-related toxicity.

To evaluate the need for concurrent chemotherapy, the Mayo Clinic/North Central Cancer Treatment Group (NCCTG) 79-47-51 trial then randomized 209 patients after resection of Dukes B/C rectal cancer to postoperative radiation (45-50.4 Gy) or radiation with concurrent chemotherapy (5-FU and semustine). ⁶ The chemoradiation arm received 1 cycle of 5-FU with semustine before and after radiation and bolus 5-FU during radiation. After a median follow-up of more than 7 years, DFS and OS were improved and the cumulative risk for local failure was improved from 25% in the radiation only arm compared to 13.5% (P=0.04) with radiation and concurrent 5-FU chemotherapy.

The contribution of postoperative radiotherapy was evaluated in the National Adjuvant Surgical Breast and Bowel Program R-02 study, which randomized patients to post-operative 5-FU chemotherapy (males randomized to 5-FU +/- semustine and vincristine) or post-operative concurrent chemoradiotherapy (5-FU). ⁷  Chemoradiotherapy was preceded by 1 cycle and followed by 4-5 cycles of the assigned chemotherapy regimen.  After a mean 93 months of follow-up, the study showed no beneficial effect of post-operative radiotherapy on DFS or OS although it reduced the 5-year cumulative incidence of local failure from 13% to 8% (P =0.02).

While U.S. studies considered postoperative chemoradiotherapy strategies, preoperative radiotherapy utilizing a short-course regimen of 5 daily fractions of 5 Gy each followed by surgical resection the following week was investigated in Europe.  The Swedish Rectal Cancer Study built on the developing evidence and randomized 1168 patients to under conventional rectal resection or preoperative radiotherapy (5x5 Gy) followed by immediate surgical resection ⁸  Preoperative radiotherapy was associated with a reduction in local failure from 23% to 9% (P<0.001) in the radiotherapy treatment arm.  This trial also demonstrated improvements in DFS and OS although there were significantly more patients with Dukes A and B tumors in the preoperative treatment arm than in the surgery alone control.

Neoadjuvant radiotherapy in the post-TME era

Much of the interest in the adjuvant radiotherapy trials for resectable rectal cancer arose from the poor results achieved with conventional surgery alone.  The broad-scale popularization of the technique of sharp mesorectal dissection or total mesorectal excision (TME) led to dramatic improvements in oncologic and functional outcomes following surgery for rectal cancer.  The Dutch Rectal Cancer Study Group was the first multi-institutional randomized phase III study with surgical quality control to compare the routine performance of TME surgery to preoperative radiotherapy (5x5 Gy) followed by TME.⁹  After a median follow-up of 6 years, preoperative radiotherapy was associated with an improvement in the rate of local failure from 10.9% to 5.6% (P<0.001).  In this TME-based study, preoperative radiotherapy had no beneficial effect on DFS or OS.¹⁰  Among the lessons reinforced from this study, however, were that tumor location within the rectum and stage were important determinants of baseline risk for local failure and radiotherapy benefit with TME.  Patients with tumors within the proximal rectum (>10 cm from anal verge) or those without lymph node involvement (stage I-II) did not benefit from preoperative radiotherapy.  (Table)

These studies demonstrated that with conventional (non-TME) surgery, adjuvant long-course chemoradiotherapy and chemotherapy improve local control and DFS and may provide a benefit for OS.  Furthermore, preoperative short-course radiotherapy results in incremental improvements in local control with either conventional or TME surgery, although TME surgery alone may still be sufficient in some patients.  Furthermore, radiotherapy alone preceding TME does not improve distant disease control or overall survival.  These encouraging data, however, led to additional questions regarding the optimal timing of radiotherapy or chemoradiotherapy, the dosage and duration of radiotherapy, and the routine or selective utilization of radiotherapy.

What is the optimum timing of chemoradiotherapy (preoperative or post-operative)?

With the benefit of post-operative chemoradiotherapy having been established, even while the treatment regimens were being optimized, there was growing interest in considering preoperative therapy as a potentially more beneficial approach.  There are a number of reasons why the preoperative approach could be more effective:  1) the improved perfusion and oxygenation of the target tissue prior to surgical intervention may improve radiosensitivity; 2) the irradiated rectum would be removed and reconstruction using the healthy non-irradiated neorectum may improve bowel function; 3) the small bowel will be more mobile and more easily displaced from the field of radiation, prior to adhesion formation from abdominal surgery, reducing the potential for acute or late toxicity; 4) preoperative treatment may result in tumor shrinkage improving resectability and potential for sphincter preservation.

Two multi-institutional cooperative group trials were initiated in the U.S. in order to compare preoperative to post-operative chemoradiation therapy.  The NSABP R-03 trial randomized patients with rectal cancer to either preoperative radiotherapy with concurrent 5-FU on weeks 1 and 5 of radiation followed by a total of 6 cycles of 5-FU postoperative chemotherapy or to surgical resection followed by 1 cycle of post-operative 5-FU chemotherapy followed by chemoradiation and 5 additional cycles of chemotherapy.¹¹   This study registered 267 of a planned 900 patients over a 6 year period from 1993 through 1999 and was prematurely closed due to poor accrual but demonstrated no difference in the cumulative incidence of local failure (10.7% in each arm).  Preoperative therapy was associated with improved DFS (64.7% vs 53.4%, P=0.011) and a trend towards improved OS (74.% vs 65.6%, P=0.065) when compared to postoperative therapy.  Intergroup 0147 (RTOG 94-01) similarly closed early due to poor accrual after enrolling even fewer patients than NSABP R-03.

The first completed trial was conducted by the German Rectal Cancer Study Group, CAO/ARO/AIO-94.  In this study, 823 patients were randomized to receive 50.4 Gy pelvic radiation therapy with concurrent 5-FU during weeks 1 and 5 of radiation either preoperatively or post-operatively (5.4 Gy boost to the tumor be for post-operative group).¹²  Both groups were assigned to then receive 4 cycles of bolus 5-FU adjuvant chemotherapy (500 mg/m², 5 weekly doses, every four weeks).  There were no differences in DFS (68% preoperative arm vs 65% postoperative arm, P=0.32) or OS (76% preoperative arm vs 74% postoperative arm, P=0.80) between the arms; however preoperative treatment was associated with improvement in the rate of local failure (6% preoperative arm vs. 13% postoperative arm, P=0.006).  This study also incorporated TME surgery as well as a preoperative assessment of the potential for sphincter preservation and noted an improvement in sphincter preservation among the preoperatively treated group.  Moreover, the preoperative treatment strategy was associated with a significant reduction in the rates of both acute (27% preoperative arm vs 40% postoperative arm, P=0.001) and chronic (14% preoperative arm vs 24% postoperative arm, P=0.01) severe toxicity.  Another important finding of this trial was the fact that 18% of the patients assigned to postoperative therapy actually had stage I cancers and were overstaged as having stage II or III disease.

Thus in combination with TME surgery, preoperative 5-FU based chemoradiation therapy was associated with improved local control, reduced acute and chronic toxicity, and improved rates of sphincter preservation when compared to postoperative chemoradiotherapy.  However, the timing of chemoradiation therapy did not affect DFS or OS.

Which is better--preoperative radiotherapy or chemoradiotherapy?

The benefit of preoperative concurrent chemotherapy was demonstrated by the Fédération Francophone de Cancérologie Digestive (FFCD) 9203 trial which randomized 742 patients with palpable rectal cancers to undergo 45 Gy preoperative pelvic radiotherapy alone or 45 Gy radiotherapy with concurrent 5-FU during weeks 1 and 5 of radiation.¹³  The addition of concurrent chemotherapy reduced the 5-year rate of local failure from 16.5% to 8.1% (P=0.004) without affecting OS or DFS.  However, grade 3-4 acute toxicity was higher in the chemoradiotherapy arm (14.9% vs. 2.9%, P<0.001).  These findings were also supported by the EORTC 22921 trial which randomized over 1,000 patients to receive preoperative 45 Gy pelvic radiotherapy with or without concurrent 5-FU during weeks 1 and 5 of radiation¹⁴.  Patients within each preoperative treatment group were further randomized to receive 4 post-operative cycles of bolus 5-FU chemotherapy.  The cumulative incidence of local failure was similar for each of the three groups for which chemotherapy was administered (7.6-9.6%) but significantly higher in the group that received preoperative radiotherapy and no chemotherapy (17.1%, P=0.002).

In contrast the Polish Colorectal Study Group compared preoperative short course (5x5 Gy) radiotherapy to conventionally fractionated chemoradiation (50.4 Gy) in 312 patients with clinical stage T3 or T4 rectal cancer.¹⁵ After a median follow-up of 48 months, the actuarial 4-year cumulative incidence of local failure was 10.6% in the short course group and 15.6% in the chemoradiation group (P=0.21). The specified surgical technique included TME for low-lying tumors and tumor-specific mesorectal excision for more mid-rectal lesions, however there was no monitoring for surgical quality control which may account for the relatively highly local failure rates in this study.  No differences in DFS, OS, or rates of sphincter preservation were observed based on treatment strategy.  However, short course radiotherapy was associated with a significantly lower risk for severe acute toxicity (3.2%) vs conventional long-course chemoradiotherapy (18.2%, P<0.001) and better compliance with the treatment schedule, but the rate of severe late toxicity was similar (7.1% for short-course radiotherapy vs. 10.1% for CXRT, P=0.36). 

These studies highlight the ongoing controversy regarding the most effective preoperative treatment strategy.  The addition of radiosensitizing doses of concurrent chemotherapy appears to improve the oncologic benefit of preoperative long-course radiotherapy.  However, TME and short-course preoperative radiotherapy may be as effective as conventional long-course chemoradiation for local control.

Should preoperative radiotherapy be routine or given selectively for positive radial margins at resection?

Given the encouraging results with surgery alone, a number of investigators were interested in determining if there was an added benefit of routine preoperative radiotherapy and if patients could be selected for adjuvant radiotherapy based on margin status at resection.  The MRC CR07 and NCIC-CTG C016 study randomized patients to routine preoperative short course (5x5 Gy) radiotherapy versus selective long-course chemoradiotherapy for patients with involved circumferential resection margins (£1 mm). Surgeons were encouraged to performed TME surgery but no monitoring of the surgical technique was performed.  The rate of circumferential resection margin positivity was similar between the 2 arms (10% routine treatment vs 12% selective treatment). Sixty-nine percent of the CRM+ve patients assigned to receive post-operative chemoradiation in the selective treatment arm actually received the assigned treatment. After enrolling 1,350 patients, routine preoperative short-course radiotherapy was associated with a reduced 3-year risk for local recurrence (4.7%) when compared to the selective strategy (11.5%, HR 2.47, 95% CI: 1.6-3.79).  DFS was also improved (73.5% vs 66.7%, HR 0.76, 95% CI: 0.62-0.94) but no difference in OS was observed (70.3% vs 67.9%, 95% CI: 0.73-1.13).   As in the Dutch study, surgery alone resulted in low 3-year rates of local recurrence for early stage disease (2.8% stage I, 6.4% stage II) and a high risk for local failure (15.4%) among stage III patients.  However, in contrast to the Dutch study, both stage II and III patients experienced an incremental benefit in terms of local failure with preoperative radiotherapy with 3-year local recurrence rates of 1.9% and 7.4% for stage II and III, respectively, although the absolute benefit was much higher for the node positive patients.

An important lesson from this study was the observation that irrespective of the use of radiotherapy, the risk for local failure was high among patients with CRM+ve resections (16% vs 23%, HR1.56, 95% CI: 0.6-4.04, for routine and selective arms, respectively) and that the use of radiotherapy could not rescue a positive margin.  In fact when the CRM was positive, a statically significant difference in local control between the two study arms could not be demonstrated.  These results confirm the long-term findings from the Dutch Rectal Cancer Study where the rate of CRM+ve resection was 19% and among those patients, the cumulative incidence of local failure was not mitigated by the use of preoperative radiotherapy (23.5% vs. 19.7%, P=0.34 for TME vs. XRT + TME, respectively).

Thus these studies again demonstrated the importance of surgical quality for local control after surgical therapy for rectal cancer with the potential for good outcomes without radiotherapy.  However improved preoperative selection strategies are necessary as a selective post-operative strategy was not successful in rescuing a CRM positive resection and preventing local failure.  Moreover, it is generally recognized that the most important determinant of local recurrence is the status of the CRM at resection. One way to identify patients at risk for local failure is with high-resolution phased-array magnetic resonance imaging (MRI) of the rectum.  The Mercury Study Group observational study of high resolution MRI demonstrated a 98% specificity and 93% negative predictive value for CRM involvement at the time of TME.¹⁶  Furthermore the presence of mesorectal lymph node metastases can be determined based on MRI characteristics and the patients for whom preoperative radiotherapy should be recommended can therefore be identified.

The Prognostic Impact of Tumor Regression

Neoadjuvant concurrent chemoradiotherapy treatment strategies have the added effect of resulting in tumor regression.  In fact modern regimens have consistently demonstrated pathologic complete response (pCR) rates of up to 20% with 5-FU or capecitabine-based concurrent chemoradiotherapy.  Moreover, most patients will experience some degree of tumor regression and potential tumor down-staging.  The prognostic value of tumor regression has been explored and the degree of regression has been correlated to long-term survival outcomes.  In a subgroup of patients from the German Rectal Cancer Trial, 5-year DFS ranged from 86% for patients with complete tumor regression, to 75% for patients with 25-75% tumor regression, and 63% for patients with <25% tumor regression (P=0.006).¹⁷   Furthermore OS was improved with downstaging (P=0.003) and the persistence of positive lymph node involvement post-treatment was strongly associated with a higher risk of recurrence (P<0.001).¹⁸  These findings have been confirmed in a population-based evaluation of 12,513 patients with ypN+ or pN+ rectal cancer treated with either preoperative or post-operative radiotherapy between 1991 and 2004 and identified from the SEER registry.  After adjustment for relevant covariates, the presence of persistent lymph node metastasis (ypN+) following preoperative radiotherapy was associated with a 23% increase in the relative risk for cancer related mortality when compared to patients with pN+ stage who subsequently received post-operative radiotherapy.¹⁹

Recognizing the prognostic importance of tumor regression, the College of American Pathology has now included the tumor regression grade classification as an essential component of the protocol for pathologic reporting of rectal cancer resection specimens.  The CAP guidelines have incorporated a 4 category classification for tumor (primary tumor within bowel wall) response to treatment:   1) TRG 0, complete response; 2) TRG 1, moderate response; TRG 2, minimal response; and TRG 3, poor response.²⁰

Integrating Novel Concurrent Chemotherapy Regimens

Based on the observed improvements in prognosis associated with better tumor response to neoadjuvant treatment, a number of studies have been performed in an effort to identify more active combined modality regimens. Two phase III randomized studies have compared the addition of oxaliplatin to either 5-FU (STAR-01) or capecitabine (ACCORD 12/0405).^{21, 22}  Neither study could demonstrate an appreciable increase in the pCR rate when compared to the no-oxaliplatin arm (16% with 5-FU alone vs. 16% with 5-FU + oxaliplatin, P=0.94, STAR-01; 13.8% with capecitabine alone vs. 18.8% with capecitabine + oxaliplatin, P=0.12, ACCORD 12/0405), however the addition of oxaliplatin was associated with an increase in grade 3-4 toxicity (8% vs. 24%, P<0.0001, STAR-01; 10.9% vs. 25.4%, P<0.001, ACCORD 12/0405) and a reduction in the treatment completion rate (97% vs. 90%, STAR-01; 100% vs. 87%, ACCORD 12/0405).  Still a number of other ongoing phase III studies have incorporated these expanded regimens in an effort to improve treatment efficacy.  (TABLE)

Virtually every agent that has shown activity against colorectal cancer has been studied in combination with radiotherapy including capecitabine, irinotecan, oxaliplatin, and the biologic agents.  None of these phase I/II trials have been able to achieve pCR rates in combination with radiotherapy that were sufficient to warrant further investigation.  Furthermore, the expanded chemotherapy regimens have been associated with significant increases in treatment related toxicity, therefore there is currently no role for concurrent chemotherapy regimens utilizing more active chemotherapeutic agents in routine practice.

Is There a Role for Induction Chemotherapy?

The role of induction chemotherapy prior to preoperative chemoradiation therapy has been explored both in patients with poor-risk and conventional risk patients with locally advanced rectal cancer.  The theoretical advantages of induction chemotherapy include the potential for improved tumor regression as well as improved treatment compliance allowing for full systemic doses of chemotherapy to be delivered.  Using MRI to identify poor risk patients, 4 cycles of induction CapeOx followed by capecitabine CXRT (54 Gy) was associated with a high rate of R0 resection (96%) and a ypCR rate of 20%.²³  The Spanish Gruppo Cancer de Recto 3 Study was a randomized phase II study that built upon the lessons learned from the Royal Marsden experience. A total of 108 patients with locally advanced rectal cancer were randomly assigned to receive induction CapeOx chemotherapy followed by capecitabine CXRT or capecitabine CXRT followed by adjuvant CapeOx chemotherapy.²⁴  The rate of pCR was not different between the arms (13.5% for CXRT followed by adjuvant chemotherapy arm vs 14.3% for the induction chemotherapy arm).  However the induction strategy was associated with a significantly lower rate of treatment related severe grade 3-4 toxicity during chemotherapy administration (19% vs. 54%, P=0.0004).  Furthermore, the chemotherapy completion rates were much higher at 92% for the induction arm and 52% for the standard treatment arm (P=0.001).

Although the role of induction chemotherapy is still being defined, these studies demonstrate the safety of induction treatment and provide reassurance regarding concerns for disease progression during the delay to surgical resection.  Furthermore, the more favorable toxicity profile and potentially improved treatment completion rates when compared to conventional treatment strategies make the induction strategy an attractive alternative for further investigation.

Studies of Adjuvant Chemotherapy for Rectal Cancer

As limited modern data exists to guide adjuvant chemotherapy for patients with stage II and III rectal cancer, current treatment strategies have primarily been based on lessons learned from studies of adjuvant therapy for colon cancer.  However, selection for post-operative chemotherapy has been based on data from rectal cancer post-operative chemoradiation trials, which included patients with stage II and III cancers.  Therefore all stage II and stage III rectal cancer patients are currently recommended to undergo adjuvant chemotherapy.  In the U.S. first line treatment includes combination FOLFOX or CapeOx chemotherapy.  The importance of post-operative chemotherapy is based on the need to treat extra-pelvic micrometastatic disease, which is not addressed by pelvic radiotherapy.  However, exactly how much chemotherapy is necessary, or in which subgroups of patients, is still unknown.

The post-operative chemoradiation treatment trials in the U.S. prior to TME demonstrated the added benefit to chemotherapy among stage II and stage III rectal cancer patients.  However, limited data exists in the setting of preoperative radiotherapy or chemoradiotherapy and TME.  The EORTC 22921 trial randomized patients to receive preoperative long-course radiotherapy vs. chemoradiotherapy and to receive post-operative 4 cycles of bolus 5-FU or no further therapy in a 2x2 factorial design.¹⁴  For the 785 evaluable patients who had undergone R0 resection, 5-year OS was 67.2% and 63.2% in the adjuvant-treatment and the no-adjuvant treatment groups, respectively (P=0.12).  In fact the survival curves virtually overlapped during the first 4 years of follow-up but then began to diverge in favor of post-operative chemotherapy.  Similarly 5-year DFS was 58.2% and 52.2% in the adjuvant-treatment and the no-adjuvant treatment groups, respectively (P=0.13).   Again the survival curves virtually overlapped during the first 2-3 years of follow-up before beginning to diverge in favor of post-operative chemotherapy.  A subsequent exploratory post-hoc analysis evaluated the interaction between neoadjuvant chemoradiotherapy treatment response and adjuvant chemotherapy benefit and had the intriguing finding that only the good prognosis patients with tumor regression to ypT0-2 appeared to benefit from adjuvant 5-FU chemotherapy (P=0.011).²⁵  Based on this data, patients without regression should be considered for alternative adjuvant chemotherapies such as oxaliplatin or novel agents.

A number of ongoing studies have incorporated an adjuvant chemotherapy question within a study of a neoadjuvant concurrent chemotherapy strategy as previously outlined.  The Eastern Cooperative Group (ECOG) 5204 phase III randomized study was designed as a companion study for NSABP R-04.  In ECOG 5204, a planned 2100 patients will receive 6 months of adjuvant chemotherapy with FOLFOX +/- bevacizumab with the bevacizumab being given for an additional 6 months.  This study incorporates survival and quality of life endpoints as well as a number of planned correlative science studies.  These and future studies will need to address not only the optimal agents to use, but the duration of therapy and the selection of patients for treatment.

Conclusions

In summary, despite cross-Atlantic parallel development, neoadjuvant radiotherapy or concurrent chemoradiotherapy treatment strategies are clearly associated with improved pelvic disease control for patients with locally advanced, particularly node positive, rectal cancer.  The preoperative strategy is superior to postoperative and results in less toxicity.  Unfortunately, advances in chemotherapy for advanced colorectal cancer have not been translated to improved benefit when utilized in combination concurrent chemoradiotherapy.  Although significant tumor regression occurs following long-course chemoradiotherapy, pre- or post-operative radiotherapy cannot reverse the consequences of an incomplete (CRM +ve) resection.  Optimal surgery remains the cornerstone for the multidisciplinary management of rectal cancer.

Future investigations will help to refine the treatment and selection of patients for combined modality therapy and address questions regarding the optimum dosage, intensity, and duration of radiation as well as of the concurrent and adjuvant chemotherapy.

Table 1.  Effect of tumor location and stage on pre-operative radiotherapy benefit with TME.

Table 2.  Ongoing Phase III Rectal Cancer Neoadjuvant/Adjuvant Therapy Trials

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