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Sphincter Preservation for Rectal Cancer: Fact or Fiction?

Memorial Sloan-Kettering Cancer Center, New York, NY

ORGAN PRESERVATION IS one of the successes of the multidisciplinary management of cancer. Selected soft tissue sarcomas, and breast, head and neck, esophageal, anal, and prostate cancers are effectively managed with the goal of preserving the organ while achieving a similar outcome to radical surgery.

In recent years, preoperative therapy has gained acceptance as a standard adjuvant treatment for patients with clinical T₃ rectal cancer. From the viewpoint of sphincter preservation, the potential advantage of preoperative therapy is to decrease the volume of the primary tumor. When the tumor is located in close proximity to the dentate line, this decrease in tumor volume may allow the surgeon to perform a low anterior resection/coloanal anastomosis rather than an abdominoperineal resection (APR).

A traditional cornerstone of surgical oncology is that the operation required should not be modified regardless of the response to preoperative therapy. The use of sphincter preservation in a patient who is thought to require an APR challenges this dictum. At the present time, the most common method by which to determine if preoperative therapy increases sphincter preservation is to perform a prospective clinical assessment. In this setting, the operating surgeon examines the patient before the start of preoperative therapy and declares the type of operation required. There are a number of potential biases with this approach. First, this assessment is based solely on an office examination and may not accurately reflect the assessment when the patient is relaxed under general anesthesia. Second is patient selection, in that the ability to perform sphincter preservation in a thin female is more likely than an overweight or muscular male. Lastly, the surgeon’s skill and commitment to this approach will influence the choice of surgery.

Is there a more objective method to identify those patients for whom preoperative therapy improves the chance of sphincter preservation? Using the distance of the tumor from the anal verge is quite subjective except when the tumor directly invades the anal sphincter. In this setting, sphincter preservation is not possible even when a complete response is achieved. Transrectal ultrasound can accurately determine T stage; however, its role in identifying patients for sphincter preservation is unclear. Molecular markers have had varying success in helping to select those patients who may best respond to preoperative therapy. Therefore, the pretreatment clinical assessment, albeit crude, remains the best method.

No discussion of the preoperative therapy of rectal cancer, especially when examining its role in sphincter preservation, can avoid the heated controversy of the ideal radiation dose and technique. There are two broad approaches to preoperative therapy. The favored approach depends, in part, on which side of the Atlantic Ocean the patient lives.

The first option is intensive short-course radiation. This approach, most commonly used in Scandinavia and the United Kingdom, uses 25 Gy at 5 Gy/fraction (without chemotherapy) followed by surgery 1 week later. The Swedish Rectal Cancer Trial¹ is the only one of the 12 randomized trials using this technique that reported a survival advantage. Not only was this survival advantage not confirmed by the Dutch CKVO 95-04 trial,² but two recent meta-analysis have reported conflicting results.³ Does the intensive short-course regimen increase sphincter preservation? The brief answer is no. In the Dutch CKVO 95-04 trial, where the interval between radiation and surgery was 1 week, there was no downstaging. None of the other randomized trials of intensive short-course preoperative radiation address the issue of sphincter preservation, and this was not an end point of these trials. Two previously published Scandinavian trials of intensive short-course radiation suggested that downstaging was most pronounced when the interval between the completion of radiation and surgery was at least 10 days.⁴ Whether increasing the interval between the end of intensive short-course radiation and surgery to more than 4 weeks will increase downstaging is not known. This question is being addressed in an ongoing randomized trial in Sweden.

The second regimen for preoperative treatment is conventional radiation plus fluorouracil-based chemotherapy (combined-modality therapy). When the goal of preoperative therapy is sphincter preservation, conventional doses and techniques of radiation are recommended. These include multiple-field techniques to a total dose of 45 to 50.4 Gy at 1.8 Gy/fraction. Surgery should be performed 4 to 7 weeks after the completion of radiation. Unlike the intensive short-course radiation regimen, this conventional design allows for two important events to occur. First is the recovery from the acute side effects of radiation, and second is adequate time for tumor downstaging. Data from the Lyon R90-01 trial of preoperative radiation suggest that an interval of more than 2 weeks after the completion of radiation increased the chance of downstaging.⁵

Three randomized trials of preoperative versus postoperative combined-modality therapy for clinically resectable, T₃ rectal cancer have been developed. Two are from the United States (INT 0147 and NSABP R0-3) and one from Germany (CAO/ARO/AIO 94). All three used conventional doses and techniques of radiation therapy and concurrent fluorouracil-based chemotherapy and mandated a preoperative clinical assessment declaring the required operation. Unfortunately, low accrual resulted in the early closure of both the NSABP R-03 and INT 0147 trials. A preliminary report of the NSABP R-03 trial (with a median follow-up of only 1 year) revealed that the percent of patients who underwent sphincter sparing surgery and who were without evidence of disease was higher in the preoperative versus the postoperative arm (44% v 34%, respectively).⁶ Fortunately, the CAO/ARO/AIO 94 trial has completed the planned accrual of over 800 patients and will have adequate statistical power to address the issues of toxicity, efficacy, and sphincter preservation.⁷

In the absence of data from these randomized trials, we must rely on phase I/II trials for answers. Although there are many trials of preoperative therapy in patients with clinically resectable rectal cancer, only seven series have reported results in patients who underwent a prospective clinical assessment by their surgeon before the start of preoperative therapy and were declared to need an APR.⁸ All used conventional doses and techniques of radiation therapy. Three used radiation therapy alone, and four used combined-modality therapy. The incidence of sphincter preservation was only 23% in the NSABP R-03 trial⁹ and 44% in the Lyon 90-01 trial.⁵ The remaining five series reported rates of 66% to 89%.

It must be emphasized that sphincter preservation, without adequate function, is of questionable benefit. A well-functioning colostomy may offer a better quality of life than a poorly functioning sphincter. For example, in a series of 73 patients who underwent surgery, Grumann et al¹⁰ reported that the 23 patients who underwent an APR had a more favorable quality of life compared with the 50 who underwent a low anterior resection. In four of the seven phase I/II trials that examine functional outcome, the majority (approximately 75%) report good to excellent sphincter function.

Does conventional preoperative combined-modality therapy improve sphincter preservation in rectal cancer? As with most controversies in cancer treatment, there are believers and nonbelievers. The limited phase I/II studies are encouraging. However, the definitive answer to this question as well as others, such as functional outcome and local control and survival, await the outcome of the CAO/ARO/AIO 94 randomized trial. As with many clinical trials in oncology, phase I/II results frequently show promise, and phase III trials sometimes disappoint. Hopefully, the CAO/ARO/AIO 94 study will change this legacy. Until the randomized data are available, when sphincter preservation is desirable, conventional preoperative combined-modality therapy is the preferred approach.

REFERENCES

1. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336: 980-987, 1997[Abstract/Free Full Text]

2. Marijnen CAM, Nagtegaal ID, Kranenbarg EK, et al: No downstaging after short-term preoperative radiotherapy in rectal cancer patients. J Clin Oncol 19: 1976-1984, 2001[Abstract/Free Full Text]

3. Minsky BD: Adjuvant radiation therapy for rectal cancer: Is there finally an answer? Lancet 358: 1285-1286, 2001[CrossRef][Medline]

4. Graf W, Dahlberg M, Osman MM, et al: Short-term preoperative radiotherapy results in down-staging of rectal cancer: A study of 1316 patients. Radiother Oncol 43: 133-137, 1997[CrossRef][Medline]

5. Francois Y, Nemoz CJ, Baulieux J, et al: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: The Lyon R90-01 randomized trial. J Clin Oncol 17: 2396-2402, 1999[Abstract/Free Full Text]

6. Roh MS, Petrelli N, Weiand H, et al: Phase III randomized trial of preoperative versus postoperative multimodality therapy in patients with carcinoma of the rectum (NSABP R-03). Proc Am Soc Clin Oncol 20: 123a, 2001 (abstr 490)

7. Sauer R, Fietkau R, Wittekind C, et al: Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer. Strahlenther Onkol 177: 173-181, 2001[CrossRef][Medline]

8. Grann A, Feng C, Wong D, et al: Preoperative combined modality therapy for clinically resectable uT3 rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 49: 987-995, 2001[CrossRef][Medline]

9. Hyams DM, Mamounas EP, Petrelli N, et al: A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: A progress report of the National Surgical Adjuvant Breast and Bowel Project protocol R0-3. Dis Colon Rectum 40: 131-139, 1997[CrossRef][Medline]

10. Grumann MM, Noack EM, Hoffman IA, et al: Comparison of quality of life in patients undergoing abdominoperineal extirpation or anterior resection for rectal cancer. Ann Surg 233: 149-156, 2001[CrossRef][Medline]

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