31 Adjuvant Therapy for Colorectal Cancer

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31

Adjuvant Therapy for Colorectal Cancer

Judith L. Trudel and Lars A. Påhlman

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Colon Cancer

The stage of disease at presentation remains the most important prognostic factor for colon cancer patients.¹Stage I disease carries an excellent prognosis of more than 95% 5-year survival rate, and surgical treatment alone is considered sufficient; adjuvant treatment is not indicated. In contrast, adjuvant treatment has repeatedly been shown to improve survival for Stage III disease. The role of adjuvant treatment for Stage II (node-negative) disease remains controversial.

Adjuvant Chemotherapy for Node-positive Disease (Stage III)

Overall 5-year survival from curative surgery for Stage III colon cancer is 30%–60%.¹Recurrences are often systemic, hence the need for systemic adjuvant treatment in these high- risk patients. Adjuvant chemotherapy improves survival by approximately 10%–15%.

5-Fluorouracil (5-FU)/leucovorin (LV)-based adjuvant chemotherapy for Stage III disease is the standard of care in the United States today.² Historically, single-agent chemotherapeutic agents such as thiotepa or fluoropyrim- idines did not prove helpful as adjuvant treatment of colon cancer. Progressively, several combination trials of chemotherapy and immune modulators helped refine the recommendations made for adjuvant treatment. In 1988, the NSABP (National Surgical Adjuvant Breast and Bowel Project) CO-1 trial documented a significant 8% improvement in overall 5-year survival for Stage II and Stage III disease when adjuvant chemotherapy with MOF (semustine, vincristine, and 5-FU) was used.³In 1989, the NCCTG (North Central Cancer Treatment Group) published a three-arm randomized study of 401 Dukes’ Stage B and C patients comparing surgical resection alone to levamisole and to 5-FU plus levamisole. 5-FU plus levamisole significantly decreased the recurrence rates and improved overall survival, particularly in Dukes’ C patients.⁴The large Intergroup 0035 study

confirmed the efficacy of 5-FU plus levamisole in 971 patients with Dukes’ Stage C cancer in 1990⁵; death rates were reduced by 33% (P = .0007), and recurrence rates by 40% (P < .0001). In 1990, the NIH (National Institutes of Health) published a consensus statement establishing 5-FU plus levamisole as the standard adjuvant therapy for Stage III colon cancer.⁶A recent European study has confirmed a significant reduction of 25% in the odds of cancer death in Stage III patients receiving adjuvant 5-FU and levamisole.⁷

While the usefulness of 5-FU/levamisole in Stage III disease was being confirmed, LV emerged as a beneficial agent for the treatment of metastatic disease. Its applicability to Stage II and Stage III disease was confirmed by the IMPACT (International Multicenter Pooled Analyses of Colon Cancer Trials) study of 1526 patients, published in 1995. In this study, 3-year disease-free survival increased from 62% to 71% (P = .0001) whereas overall survival increased from 78%

to 83% (P = .029) in the 5-FU/LV group compared with sur- gical controls.⁸The NSAPB C-03 randomized trial of 1081 Stage II and Stage III patients comparing MOF to 5-FU/LV had documented a similar advantage of 5-FU/LV, with a 3-year disease-free survival increase from 64% to 73%

(P = .0004) and an overall survival increase from 77% to 84% (P = .003) in the 5-FU/LV group compared with MOF.⁹

The relative merits of levamisole and LV as modulators of 5-FU-based adjuvant chemotherapy, and the optimal duration of treatment were investigated in several studies published between 1998 and 2000. The NCCTG/NCIC (National Cancer Institute of Canada)¹⁰study of 915 patients compared 6 months 5-FU/levamisole; 6 months 5-FU/LV/levamisole;

1 year 5-FU/levamisole; and 1 year 5-FU/LV/levamisole.

Triple therapy for 6 months was as effective as 12 months;

and 6-month triple therapy provided superior 5-year overall survival and disease-free survival compared with 5-FU/levamisole. The Intergroup trial 0089 of 3759 patients compared 1 year 5-FU/levamisole; 5-FU/high-dose LV for 32 weeks; and 5-FU/low-dose LV with or without levamisole for six cycles.¹¹ There were no differences between the four treatment arms

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with regard to 5-year disease-free and overall survival. The NSABP CO-4 study¹²and the QUASAR Collaborative Group study¹³have later confirmed the survival advantage provided by LV modulation over levamisole. Based on the results of these studies, the new standard for treatment was changed to 6 months of adjuvant chemotherapy with 5-FU/LV for Stage III, node-positive disease.

The newer chemotherapeutic agents currently under study or in use for treatment of metastatic disease (e.g., irinotecan, capecitabine, oxaliplatin) are undergoing evaluation for their usefulness in the adjuvant treatment of patients with Stage II and Stage III disease. Recent data from the multicenter international randomized MOSAIC trial have confirmed that the addition of oxaliplatin to 5-FU/LV (FOLFOX) further decreases the risk of recurrence in Stage II and Stage III disease by 23%, resulting in a significant improvement in 3-year disease-free survival.¹⁴Another important trial, the PETACC 3 trial, will soon report the results. In that trial 5-FU/leucov- ourin is compared with irinotecan to 5-FU/LV (FOLFIRI) in both Stage II and Stage III colon cancer.

Several tumor characteristics such as microsatellite instability and the expression of DNA synthesis-associated enzymes have recently been found to predict chemoresistance to 5-FU and irinotecan.^15,16This is an area of research that is evolving rapidly, and will certainly change the recommendations for adjuvant treatment in both node-positive and node- negative disease.

Adjuvant Chemotherapy for Node-negative Disease (Stage II)

Whereas the efficacy and benefits of adjuvant chemotherapy for Stage III node-positive disease is unequivocally documented through numerous randomized trials, the role of adjuvant chemotherapy for Stage II node-negative disease is still controversial. The data from the early studies that prompted the NIH recommendation for adjuvant treatment in Stage III disease did not support a similar recommendation for Stage II disease.^4,5Recent metaanalyses have yielded conflicting results.

The IMPACT-B₂(International Multicenter Pooled Analysis of B₂Colon Cancer Trials) Group published a pooled analysis of five trials conducted from 1982 to 1989 and regrouping 1016 patients with Stage B₂colon cancer.¹⁷Relapse rates, all-cause death rates, 5-year event-free survival and overall survival were similar in patients treated with adjuvant 5-FU/LV compared with controls. Increasing age and poor tumor differentiation were indicators of poor prognosis.¹⁷A SEER-Medicare cohort analysis of 3700 patients with resected Stage II colon cancer did not reveal any improvement in 5-year survival in patients having received adjuvant chemotherapy compared with controls (74% versus 72%).¹⁸In contrast, a pooled analysis of four NSABP trials (CO1, CO2, CO3, and CO4) with widely different treatment and control arms regrouping 1565 patients with Dukes’ B disease (Stage II) and 2255 patients with Dukes’ C disease (Stage III) concluded that patients with Dukes’ B

disease (Stage II) should be offered adjuvant chemotherapy.¹⁹ The authors calculated a 30% relative reduction in mortality for Stage II patients having received adjuvant chemotherapy. That metaanalysis has since been widely criticized for its method- ologic flaws, and the controversy rages on. The likelihood of reaching a resolution on this subject is remote: to detect a significant survival benefit among Stage II colon cancer patients (who have an estimated 5-year survival of 80%), an adjuvant trial with a no-treatment control arm would require a sample size of 5000–8000 patients.²⁰ The recent data from the MOSAIC trial showing a significant improvement of 3-year disease-free survival and a 23% reduction of recurrence risk using a combination of 5-FU/LV/oxaliplatin (FOLFOX) in Stage II disease will undoubtedly spur renewed interest in this debate.¹⁴At this time, the use of adjuvant chemotherapy for Stage II node-negative disease remains an unanswered question, mainly because the prognosis for Stage II node-negative disease is good overall, and many patients would face unneces- sary treatment. For the time being, patients with Stage II colon cancer at high risk for tumor recurrence might be considered for adjuvant treatment on an individual basis, or might be entered in a clinical trial.

Radiotherapy

Local recurrence of rectal cancer after surgery with curative intent has always been recognized as a significant clinical problem. Combined chemoradiotherapy has been shown to increase both local control and survival for patients with locally advanced and node-positive rectal cancer.²¹ In contrast, although local failure and recurrence after surgery for colon cancer had been described, there long existed an unwritten consensus that treatment failures in colon cancer surgery were primarily systemic rather than local. Thus, no prospective, randomized study was devised to provide data on the role of external beam radiotherapy in preventing local recurrence or improving survival after colon surgery. The recognition that selected individuals with colon cancer were at a high risk for local recurrence eventually came from retrospective reviews of patterns of failure after surgery with curative intent. Two large retrospective reviews^22,23helped define the risk factors for local recurrence after surgery for colon cancer. Locoregional failure was identified in 19%²²to 46%²³ of patients overall; at least half of local recurrences were in the original tumor bed. Only 13% of the local recurrences were salvageable surgically.²²The most important risk factors for local recurrence were: 1) pathologic staging, with local recurrence rates of 35% in modified Astler-Coller Stages B3, C2, or C3 versus 7% in Stages A, B1, and C1²; 2) primary tumor localization in a fixed, nonperitonealized segment of the colon, with the highest failure rates in the cecum, descending colon, hepatic or splenic flexures, and sigmoid colon^22,23; 3) colon carcinoma complicated by perforation or obstruction, with a two- to three-fold increase in local recurrence for any given pathologic stage.²²

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Identification of individuals at high risk for local recurrence after curative surgery for colon cancer triggered a number of studies on the role of external beam radiotherapy in preventing local recurrence or improving survival after colon surgery. Several disparate single-institutional retrospective studies suggested an improvement in local failure and recurrence rates with adjuvant radiotherapy compared with historical controls.^25–26Wide variations in radiation techniques and doses, concurrent use and choice of chemotherapy, and patient selection criteria make comparison among studies difficult. Overall, local control rates ranged from 60% to 88%, a significant improvement over controls treated by surgery alone. A single randomized prospective study initiated jointly by the NCCTG and RTOG, comparing chemotherapy alone with F-FU/levamisole versus combined chemotherapy/radiotherapy closed prematurely because of poor accrual; although no differences were observed in overall survival between treatment arms, the study lacked sufficient statistical power to draw valid conclusions.²⁷

At this time, the precise role of adjuvant radiotherapy in the treatment of colon cancer remains undefined. There are no data to support a systematic recommendation for therapy or a well-recognized adjuvant regimen. The potential risks of adjuvant radiotherapy for colon cancer, particularly radiation damage to surrounding organs (e.g., small bowel) are significant. Treatment for individuals deemed at high risk for local recurrence after curative surgery for colon cancer should be individualized.

Immunotherapy, Tumor Vaccines, and Gene Therapy

The goal of cancer immunotherapy treatments is to stimulate the body’s immune system in order to improve host defense mechanisms against growing tumors. Colorectal cancer immunotherapy strategies have evolved dramatically over the past 30 years. Nonspecific immune stimulation with bacterial cell products (e.g., BCG) and cytokines (e.g., interleukin-2) has recently been superseded by more specific immune stimulation targeted against colorectal tumor-expressed antigens.

Whereas some tumor antigens are present in normal tissues but overexpressed in cancer, other tumor antigens are restricted to cancer tissues. Vaccines stimulate the immune system to recognize and act specifically against these tumor- expressed antigens, through either the humoral or cellular pathway.

More than 25 Phase I and Phase II studies have explored a variety of vaccines based on whole colorectal tumor cells, virus-modified tumor cells, gene-modified tumor cells, tumor antigen-derived peptides, tumor cell lysates, proteins or carbohydrates, monoclonal antibodies, plasmid or viral vectors encoding tumor antigens, and dendritic cell-based vaccines. Promising results were observed in some animal models and Phase I and II studies, prompting ongoing research efforts.

A few Phase III studies have also yielded promising results.²⁸ Three large studies have looked at the effect of immune stimulation with autologous irradiated tumor vaccine plus BCG in patients with colorectal cancer. Hoover et al.²⁹ randomized 98 patients with colon or rectal cancer to surgical resection alone or surgical resection followed by vaccination with autologous irradiated tumor plus BCG. There was no difference in disease-free or overall survival in the 80 eligible patients, but subset analysis showed a significant improvement in disease-free survival for colon cancer patients. The Eastern Cooperative Oncology Group (ECOG) randomized Stage II and Stage III colon cancer patients to either observa- tion or vaccination with autologous irradiated tumor plus BCG. There was no survival difference between groups, but patients with a marked delayed cutaneous hypersensitivity showed a trend toward better disease-free and overall survival, suggesting that survival correlated with the patient’s immune response to vaccination.³⁰Vermoken et al.³¹randomized 254 patients operated for colon cancer to either observa- tion or vaccination with autologous irradiated tumor plus BCG immediately after operation, followed by a vaccine booster 6 months after operation. The overall risk for recurrence was decreased by 44% in all vaccinated patients, with a 61% reduction in Stage II patients. Vaccination significantly increased recurrence-free survival, and there was a trend toward improved overall survival.³¹ Because of its marginal efficacy, the complexity in the preparation of the vaccine, and the introduction of more effective chemotherapeutic agents, tumor cell-based immunotherapy is not frequently used in colon cancer patients.

Gene therapy is based on the concept of transferring genetic material into target cells, which would allow for correction of genetic defects in tumor suppressor genes, inacti- vation of oncogenes, or insertion of treatment-sensitizing genes (such as drug-converting enzymes) or “suicide genes”

into the colorectal cells. Correction of p53 mutations, inacti- vation of k-ras gene product p21, and the delivery of prodrug converting enzymes are currently being studied. The long- term potential for clinical usefulness of these techniques remains to be defined.

Rectal Cancer

Although surgery remains the central treatment of rectal cancer, the overall approach to treatment has changed dramatically over the last three decades. Surgical technique has been refined to become more focused and precise, with specific attention given to a locally more aggressive and meticulous technique. The modern multimodal therapy approach individ- ualizes rectal cancer care, thus offering the best and most appropriate treatment to every single patient. Local and distant staging guides the decision for adjuvant radiotherapy and/or chemoradiotherapy and for available surgical approaches, i.e., local excision or an abdominal procedure.

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Many prospective trials have demonstrated the beneficial effect of preoperative and postoperative radiation therapy in patients with rectal cancer who had surgery with curative intent.

The clinical benefits of radiotherapy in the treatment of rectal cancer can be broadly divided under four categories: first, radiotherapy lowers local failure rates and improves survival in resectable rectal cancer; second, radiotherapy allows surgery in nonresectable rectal cancer; third, it facilitates sphincter-preserving procedures in low-lying rectal cancer; and finally, it may offer a totally curative approach without major surgery.

Radiotherapy can either be used alone or in combination with chemotherapy. The numerous combinations and variations in radiotherapy and chemotherapy regimens make the evaluation and comparison of different multimodal therapy pathways difficult. In this section, we will review the results of various adjuvant treatment modalities in rectal cancer focusing on areas of clinical benefit. We will not discuss the role of curative radiation alone.

Benefit No. 1: Radiotherapy Lowers the Local Failure Rates and Improves Survival in Resectable Rectal Cancer

According to three recently published metaanalyses, there is no doubt that neoadjuvant treatment is superior to adjuvant treatment with regard to reduction in local failure rates and cancer-specific survival.^32–34The results of two of three other trials that specifically studied preoperative versus postoperative radiotherapy support the conclusions from the metaanalyses. The first report was the Uppsala trial in which short-course preoperative radiotherapy in all patients was compared with postoperative prolonged course only in patients with advanced cancers (Stages II and III).³⁵The other two trials compared neoadjuvant chemoradiotherapy with adjuvant chemoradiotherapy with the same schedules and doses. The results from the NSABP R-03 trial, which closed prematurely because of poor accrual, showed that 44% of patients having undergone preoperative chemoradiation were disease free at 1 year, compared with 34% of patients who had received postoperative chemoradiation.³⁶ The German CAO/ARO/AIO trial has randomized patients with T3-4, N0, or any T,N1 rectal cancer to neoadjuvant chemoradiation followed by surgery and additional postoperative chemotherapy or postoperative chemoradiation.³⁷In this study, surgery was performed according to the principles of sharp mesorectal excision. The rates of complete resection (R0) and sphincter- saving surgery were similar in both groups, but the 5-year cumulative rate of local relapse was 6% for patients assigned to preoperative chemoradiation and 13% for the postoperative chemoradiation group. Survival was similar in both treatment arms. Grade 3 or 4 toxicity occurred in 27% of patients in the preoperative chemoradiation group and 40% of patients in

the postoperative chemoradiation group. The results of this last study suggest that preoperative chemoradiation is the pre- ferred adjuvant treatment in patients with locally advanced rectal cancer.

Neoadjuvant Therapy: Radiation Alone Versus Chemoradiation

The potential advantages of neoadjuvant therapy include increased tumor radiosensitivity with decreased small bowel toxicity, decreased overall radiation-associated complications, and decreased risk of tumor seeding during surgery. The primary disadvantage of neoadjuvant therapy is the risk for overtreatment in patients with early-stage disease. New imaging modalities such as endorectal ultrasound³⁸and magnetic resonance imaging³⁹now allow for increasingly precise preoperative identification of patients with T2 and T3 tumors, thus minimizing the number of patients who would be overtreated by neoadjuvant therapy. Our ability to identify lymph node metastases preoperatively with any of these imaging modalities remains more limited.

A short course of preoperative radiation, 20–25 Gy given over 1 week is biologically equivalent to the traditional postoperative course of 45–55 Gy given over 5–6 weeks. It was long held that neoadjuvant radiation alone only improved local control but did not improve survival. In 1993, the randomized Swedish Rectal Cancer Trial (SRCT) demonstrated that a short course (25 Gy) of preoperative radiotherapy with surgery within the following week significantly reduced local recurrence from 27% to 12%, and improved 5-year survival rates from 48% to 58% when compared with surgery alone.⁴⁰ The main objection to all trials showing improvement in local recurrence and survival rates with radiotherapy, including the SRCT, was the high rate of local recurrence in the control arm that has been attributed to nonstandardized surgical technique.^32–34Case series from specialized centers have reported lower local recurrence rates with surgery alone using meticulous surgical technique compared with patients treated with radiation and surgery in prospective trials when surgery was not standardized.^41–43Several reports from different countries have confirmed that surgical skill is of utmost importance, thus opening for discussion the real role of radiotherapy when surgical technique is optimized.^44–47

The role of preoperative radiation in patients with rectal cancer treated with optimal surgery was addressed in the Dutch Rectal Cancer Trial. All participating surgeons had adopted the technical “gold standard” of total mesorectal excision (TME) before entering patients. In this randomized, multicenter study of 1861 patients with rectal cancer, 2-year local recurrence rates were significantly improved from 8.2%

to 2.4% when preoperative radiation was given before TME.⁴⁸ Five-year figures confirm a reduction in local recurrence rates from 11.4% after TME alone versus 5.6% for preoperative radiotherapy followed by TME but this does not translate into an improvement in 5-year survival rates (van de Velde,

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personal communication). Thus, it seems that neoadjuvant radiotherapy still has a place in the treatment of rectal cancer, even when surgical technique is optimized.

The advisability of adding chemotherapy to preoperative radiation (and therefore to use neoadjuvant combined chemoradiotherapy) is undergoing intense scrutiny. Additional 5-FU-based chemotherapy may theoretically act as a radiosensitizer at the high cost of increased hematologic and gastrointestinal toxicity. Neoadjuvant chemoradiotherapy is recommended for advanced disease (T4, N0-2), but there is no randomized phase III study comparing neoadjuvant radiotherapy versus neoadjuvant chemoradiotherapy in resectable rectal cancer (T2-3, N0-2). Only one study is currently under- way to examine this issue. In the EORTC 22921 trial, patients with T3, T4 NX rectal cancer are randomized to one of four treatment arms: preoperative radiotherapy followed by surgery only; preoperative radiotherapy followed by surgery and postoperative adjuvant chemotherapy; neoadjuvant chemoradiation followed by surgery only; and neoadjuvant chemoradiation followed by surgery and additional adjuvant chemotherapy.⁴⁹ The trial was closed in 2003 after enrolling 1100 patients. A preliminary analysis of acute toxicity has demonstrated that at the dose recommended in the trial, the addition of chemotherapy during the radiation increased the proportion of patients developing grade 2 diarrhea from 17% to 34%. However, compliance with the adjuvant therapy and the proportion of patients undergoing surgery did not change. The oncologic results of this trial have not yet been published.

Postoperative Adjuvant Therapy: Radiation Alone Versus Chemoradiation

The advantage of reserving adjuvant treatment for the postoperative setting is the ability to restrict its use to patients who are at identified risk for failure, based on their histopathologic staging. In the German CAO/ARO/AIO trial, 18% of patients diagnosed with Stage II or III rectal cancer based on endorectal ultrasound had pathologic Stage I disease and were probably overtreated. The disadvantages include the higher incidence of radiation-related complications, particularly small bowel radiation injury and a higher number of patients unable to complete the entire course of therapy because of treatment side effects. Other reasons are the relative radiore- sistance of the hypoxic surgical bed and the risk for repopu- lation of tumor cells from surgery to the start of radiotherapy.

Postoperative adjuvant radiation therapy alone decreases local recurrence, although not to the same extent as neoadjuvant treatment, and does not improve survival.^50–52 Several early studies revealed that the addition of 5-FU-based chemotherapy to postoperative radiotherapy increased local control (Mayo Clinic/NCCTG 79-47-51⁵³) and significantly improved survival by 10%–15% (Gastrointestinal Tumor Study Group⁵⁴ and Mayo/NCCTG⁵³). Despite the fact that all those trials were heavily underpowered, these findings prompted the National Cancer Institute Consensus

Conference of 1990 to recommend combined modality chemoradiotherapy as the standard postoperative adjuvant treatment for patients with Stage II and Stage III rectal cancer.⁵⁵ Although a recently published Norwegian trial confirmed⁵⁶these findings, many countries, especially in Europe, did not follow those recommendations mainly because by then neoadjuvant radiotherapy had been proven to be more efficacious.

Benefit No. 2: Radiotherapy Allows Surgery in Nonresectable Rectal Cancer

The definition of a nonresectable rectal cancer is controversial. These tumors are clinically tethered or fixed but it is often difficult to predict whether fixation is the result of fibrotic adhesions or tumor infiltration of the pelvic sidewalls or adjacent organs.⁵⁷Such tumors probably involve the fascia propria of the rectum, and a standard surgical resection following the principles of sharp mesorectal excision often results in tumor involvement of the circumferential resection margin. For the purpose of this section, we will define a nonresectable rectal cancer as a tumor that cannot be resected without a very high risk of local recurrence. Magnetic resonance imaging is particularly useful to determine the relation- ship of the tumor with the fascia propria of the rectum, and it may be the best imaging modality for the preoperative staging of patients with fixed tumors. Based on available data, patients with such locally advanced rectal cancer tumors benefit from preoperative radiotherapy with the aim of downsizing the tumor. Approximately 10%–15% of all patients with rectal cancer fall into this category; half of those patients have no metastases, indicating that there is potential for a curative procedure.²⁶Based on tumor characteristics, surgery alone is unlikely to be curative and it is indicated to offer radiotherapy to those patients.

It must be emphasized that short-course radiotherapy is not an option in unresectable rectal cancer; a standard dose of 45–55 Gy over 5–6 weeks must always be given.

Radiotherapy is used to downsize tumors in this group of patients. After completion of standard-dose radiotherapy, a 6- to 8-week waiting period allows the tumor to shrink, increasing the possibility for a curative procedure.

The role of additional chemotherapy remains unclear in this context. There is very little solid evidence from randomized trials using chemoradiotherapy. One old trial (1969) reported positive results from chemoradiotherapy in locally unresectable rectal cancer.⁵⁸Two other negative trials, published in the late 1980s, reported increased toxicity.^59,60One underpowered Swedish trial (2001) showed improved local recurrence rate and overall survival in patients randomized to chemoradiotherapy versus radiotherapy alone followed by surgery.⁶¹ Several phase II trials have reported a reduction in local recurrence rates and impressive data regarding survival^62,63; prob- lems with interpretation of case-mix and definition of

“nonresectability” make the results of those trials difficult to

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interpret. The LARCS Nordic trial, which randomized patients with unresectable rectal cancer to receiving either 50 Gy preoperatively or 50 Gy and chemotherapy preoperatively just closed and will help to shed some light on this question.

At this time, there is no good evidence supporting the use of chemotherapy in addition to radiotherapy for unresectable rectal cancer. Despite the lack of data and scientific evidence, most radiotherapists and medical oncologists have more or less accepted the concept of using chemoradiotherapy for nonresectable rectal cancer patients. It is likely that the trend will continue, until ongoing trials answer that question. The newer chemotherapeutic agents currently in use or under study for treatment of locally advanced and metastatic colon cancer (e.g., irinotecan, capecitabine, and oxaliplatin) will doubtless be evaluated for their usefulness in neoadjuvant and adjuvant treatment of rectal cancer in the near future. Their efficacy and usefulness is unknown at this time.⁶⁴

Benefit No. 3: Radiotherapy Facilitates Sphincter-preserving Procedures in Low-lying Rectal Cancer

Several series claim that preoperative radiotherapy (and preferably chemoradiotherapy) downsizes tumors to the extent that it is possible to increase the number of patients in whom the sphincters can be preserved.^65–69 There is even a report showing complete response to chemoradiotherapy in some patients with T4 tumors; some of these patients were not operated on and reportedly remain alive and well.⁷⁰ Caution must be exercised when reading these studies. First, rates of sphincter preservation do not tell the entire story; second, the main criticism of these studies is that modern thera- pies are compared with historical controls. The dramatic recent changes in surgical technique (TME, staplers) and the modern approach to rectal cancer treatment may partially explain the increased rate of sphincter preservation. We now accept a 5- to 10-mm distal margin as curative procedure if a stapled anastomosis is done.^71,72 Modern randomized trials must be done to verify the sturdiness of the conclusions. In the French R9001 trial, patients with T2 and T3 tumors received preoperative 39 Gy (13 ×3 Gy) and were randomized to immediate surgery or surgery 5 weeks after irradiation. Surgeons were asked before any treatment to evaluate the possibility to preserve the sphincters. Delaying surgery for 5 weeks after the end of radiation only slightly increased the rate of sphincter preservation.⁷³This small trial indicates that there might be a downstaging and downsizing effect, which in turn might increase the rate of sphincter preservation. Of note, the overall recurrence rate in the trial was 9%, which is considered a high figure; more crucially, the local recurrence rate was 12% among the patients in whom the surgeon had origi- nally planned an abdominoperineal excision but changed intraoperatively to a sphincter-preserving procedure because of the downsizing effect of radiotherapy.⁷³

The German trial (CAO/ARO/AIO trial), in which patients were randomized to pre- or postoperative chemoradiotherapy, has shown a clear tendency to more favorable stage in patients having had preoperative treatment compared with postoperative chemoradiotherapy. In a subgroup analysis of patients determined by the surgeon before randomization to require an abdominoperineal resection, the proportion of sphincter preservation rate was 39% in the preoperative chemoradiation group and 18% in the postoperative chemoradiotherapy group.

In a recent Polish study, more than 300 patients were randomized to either short-course radiotherapy (25 Gy) with immediate surgery or long-course chemoradiotherapy and delayed surgery. T3 or resectable T4 tumors located within the reach of the examining finger, without evidence of sphincter involvement, and resectable with a 1-cm macro- scopic distal margin were included in the study. Sphincter preservation and local recurrence rates were analyzed.

Sphincter preservation rates were identical in both groups (61% in the short-course radiotherapy with immediate surgery versus 59% in the prolonged chemoradiotherapy course and delayed surgery).⁷⁴ This trial was conducted to determine whether chemoradiotherapy and delayed surgery had an impact on sphincter preservation. Accordingly, this is not a subset analysis of the data from the trial, indicating the strength of the results. At this time, there is no evidence that prolonged-course radiotherapy combined with chemotherapy with delayed surgery impacts sphincter preservation. It is possible that increasing the waiting time from end of radiotherapy to surgery will achieve further downsizing, which might improve sphincter preservation.

An important consequence of increased sphincter preservation is poor function. Poor quality of life may be the price to pay for intact sphincters: up to 20% of all patients who undergo a low anterior resection are incontinent of solid stool.⁶⁸This contrasts with reports that patients with a stoma had a better quality of life compared with those with an anterior resection.⁷⁵This must be considered when selecting surgical options for individual patients.

Adjuvant Chemotherapy Alone in Rectal Cancer

In contrast to colon cancer, chemotherapy alone as adjuvant treatment in rectal cancer remains questionable. In the early 1980s, underpowered United States radiotherapy trials concluded that chemotherapy improved survival compared with surgery alone. Two large randomized trials comprising more than 4000 patients have studied the value of chemotherapy versus surgery alone in colon and rectal cancer patients.

Combination 5-FU/levamisole and 5-FU/LV were found to improve survival in patients with colon cancer, but showed no benefit in patients with rectal cancer.^76,77These results under- score the difference in chemotherapy effectiveness for rectal cancer and colon cancer. The reasons for this are unclear:

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different tumor profiles or lack of proper surgical technique at the time of these trials may partly explain the results. At this time, adjuvant chemotherapy alone is not acceptable in rectal cancer. However, postoperative chemotherapy is currently used to reduce the risk of distant relapse in patients with rectal cancer treated with pre- or postoperative chemoradiation and radical surgery.

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