This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tepper, J. E. Search for Related Content PubMed PubMed Citation Articles by Tepper, J. E. Social Bookmarking                            What's this?

Adjuvant Radiation Therapy of Rectal Cancer

University of North Carolina School of Medicine, Chapel Hill, NC

FOR MORE THAN A decade there has been general agreement in the United States that adjuvant radiation therapy (RT) is appropriate therapy for patients with T3, T4, or N+ rectal cancer to decrease the risk of local failure.¹ Virtually all studies have demonstrated less local failure with either pre- or postoperative irradiation, with further improvement with the use of concurrent fluorouracil-based chemotherapy.

The impact of pelvic RT alone on improving survival is less clear, with no consistent evidence of a survival advantage after postoperative RT. A recent large randomized study from the National Surgical Adjuvant Breast and Bowel Project (NSABP) has raised questions regarding the necessity of routine adjuvant RT in this population. In this trial, there was a modest decrease in local recurrence with postoperative chemotherapy and RT compared with fluorouracil-based chemotherapy alone but no significant improvement in disease-free or overall survival.²

The NSABP study showed a local recurrence rate (as first site of recurrence) of 14% versus 8% without and with RT, respectively. If the baseline recurrence rate is very low, is RT indicated at all? However, the true local failure rate after conventional surgery may be higher than that reported by the NSABP, which reported only first site of failure in a selected group of patients. The contemporaneous Intergroup rectal adjuvant trial, which tested different chemotherapy regimens but with all patients receiving pelvic RT, demonstrated an actuarial risk of local failure of 14% at 5 years, compared with 8% reported in the NSABP trial.³ This risk increased to 17% at 7 years, despite the use of chemoradiation. High- and low-risk groups could be identified. Specifically, patients with T1N1, T2N1, or T3N0 disease had a relatively low risk of failure (8% to 9%), whereas patients with T3N+ or T4 tumors had a much higher risk (18% and 24%, respectively). Despite this substantial risk of local failure, even with RT in high-risk patients, are there subsets of T3 to T4 or N+ patients for whom radiation therapy may not be necessary?

The surgeon and the surgical procedure have been found to be important prognostic factors in outcome after rectal cancer surgery. Studies have clearly demonstrated that local recurrence rates decrease substantially when total mesorectal excisions (TME) are performed,^4,5 and recurrence rates are lower when an experienced surgeon performs the operation. However, although TME is important, it will certainly not solve the problem of local recurrence entirely. A Dutch trial has completed accrual, testing whether preoperative RT plus TME is superior to TME alone when there is good surgical quality control. It will be of interest to determine how much impact RT has under this clinical situation. It is likely that local recurrence rates will be lower than in historical data, but local recurrences will still occur and RT is almost certain to improve local control.

Another important factor in outcome is the pathologic evaluation. Studies by Quirk et al^6,7 have shown that careful analysis of the circumferential margin can predict patients at high risk of local failure. The data suggest that a circumferential margin of at least 2 to 5 mm may be sufficient to ensure a low risk of local failure. The pathologist is also important in the evaluation of lymph nodes. A number of investigators have demonstrated that the number of nodes found by the pathologist is an important indicator of outcome. Data from the gastrointestinal Intergroup trial showed that, for rectal cancer patients categorized as node-negative, patients who had 14 or more nodes reviewed by the pathologist had a far better outcome than patients with fewer nodes in the specimen.⁸

Interestingly, although the survival advantage from postoperative radiation therapy does not seem to be large, the data suggest that there may be a greater survival benefit with preoperative therapy.⁹ A recent meta-analysis showed improvement in local control, survival, and disease-free survival with preoperative RT.¹⁰ Two United States trials that attempted to compare the relative benefit of preoperative versus postoperative combined-modality therapy could not accrue sufficient patients and were closed. An ongoing European study asking the same question has accrued patients, but data are not yet available.

Another critical issue in determining when RT is appropriate is balancing the acute and chronic morbidity of RT against the benefits in local control and survival. There have been a number of studies showing toxicity from RT, but technique can influence outcomes. Some early studies demonstrated a high rate of late toxicity using large anterior-posterior fields or high dose per fraction.^11-15 There is clear evidence that there are fewer side effects with improved technical approaches in field design, minimizing the amount of small bowel irradiated, and modifying dose per fraction.¹⁶ Although not proven in randomized trials, some investigators believe that preoperative therapy produces fewer late complications because the small bowel is not fixed in the pelvis secondary to surgical adhesions and because much of the irradiated bowel is removed at the time of operation and, therefore, cannot produce late side effects.

Given all of this information, it is perhaps clear why the report by Schrag et al¹⁷ in this issue of the Journal of Clinical Oncology shows that elderly patients are not routinely receiving adjuvant irradiation. But it also shows, as Schrag suggests, that adjuvant RT should still be considered, even for the elderly. RT should not be denied to patients purely because of their age. A 75-year-old has a greater than 10-year life expectancy. As is always the case in medicine, the use of a therapy is a balance of risk versus benefit. Elderly patients are sometimes frail, can have substantial comorbidities, can have less physiologic reserve, and can be less willing to go through an extended course of either RT or chemotherapy, especially if they do not perceive a major therapeutic benefit. However, it is important to evaluate fully the recurrence risk for each patient and then make treatment recommendations based on that information. The study from Schrag et al shows that patients with low-lying tumors (requiring an abdominal perineal resection), higher-stage tumors, and lower age all had a higher likelihood of receiving adjuvant RT than patients without these characteristics, consistent with the interpretation that physicians are already making judgments based on risk of local failure. Additional studies may allow us to characterize more precisely this risk of failure by clinical, surgical, and pathologic characteristics so that these decisions are based on good data rather than individual physician whim.

Given the information available, what should be standard practice at the present time? First, adjuvant chemoradiation therapy is still the standard in the United States for T3, T4 or N+ rectal cancer. It is critical that we distinguish patients who have true rectal cancer (ie, a tumor located at or below the peritoneal reflection) with a higher risk of local recurrence from a colon cancer patient who is unlikely to need RT. Second, the surgical procedure must be optimized. Surgeons who are trained in TME should perform rectal cancer surgery, and we should confirm that a TME was performed. It is inappropriate to extrapolate the data from published series and to expect that similar results will be obtained by inadequately trained surgeons. Third, the pathologic evaluation must be complete. We may be able to identify low-risk patients who will not derive substantial benefit from RT if the patients are known to have wide circumferential margins, but this can only be done if the pathologist formally assesses and reports this factor. An adequate number of nodes must be analyzed to be confident that a patient staged as N0 is truly node-negative and, therefore, may not be at high risk of local failure. T1/2N1 and T3N0 patients seem to be at relatively lower risk for failure as are patients with high rectal cancers, and this can be considered in the management decision if there is good surgical and pathologic information. Fourth, RT must be given by physicians who are willing to expend the effort to minimize toxicity and are knowledgeable as to how to do so. Last, we need to determine whether there are truly advantages to preoperative RT compared with postoperative treatment. With attention paid to factors such as these, we may then be able to make better recommendations to patients, both young and elderly, so that they can make intelligent risk-benefit decisions regarding adjuvant therapy.

REFERENCES

1. NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264: 1444-1450, 1990[Abstract/Free Full Text]

2. Wolmark N, Wieand HS, Hyams DM, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92: 388-396, 2000[Abstract/Free Full Text]

3. Tepper JE, O’Connell MJ, Niedzwiecki D, et al: Final report of INT 0114–Adjuvant therapy in rectal cancer: Analysis by treatment, stage and gender. Proc Am Soc Clin Oncol 20: 123a, 2001 (abstr 489)

4. Heald RJ, Moran BJ, Ryall RD, et al: Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 133: 894-899, 1998[Abstract/Free Full Text]

5. Enker WE: Total mesorectal excision with sphincter and autonomic nerve preservation in the treatment of rectal cancer. Curr Tech Gen Surg 5: 1-8, 1996

6. Quirke P, Durdey P, Dixon MF, et al: Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histopathological study of lateral tumour spread and surgical excision. Lancet 2: 996-999, 1986[Medline]

7. Scott N, Jackson P, al-Jaberi T, et al: Total mesorectal excision and local recurrence: A study of tumour spread in the mesorectum distal to the rectal cancer. Br J Surg 82: 1031-1033, 1995[Medline]

8. Tepper JE, O’Connell MJ, Niedzwiecki D, et al: Impact of number of nodes retrieved on outcome in patients with rectal cancer. J Clin Oncol 19: 157-163, 2001[Abstract/Free Full Text]

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

10. Camma C, Giunta M, Fiorica F, et al: Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA 284: 1008-1015, 2000[Abstract/Free Full Text]

11. Preoperative short-term radiation therapy in operable rectal carcinoma: Stockholm Rectal Cancer Study Group. Cancer 66: 49-55, 1990[Medline]

12. Holm T, Singnomklao T, Rutqvist LE, et al: Adjuvant preoperative radiotherapy in patients with rectal carcinoma: Adverse effects during long term follow-up of two randomized trials. Cancer 78: 968-976, 1996[Medline]

13. Ooi BS, Tjandra JJ, Green MD: Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer. Dis Colon Rectum 42: 403-418, 1999[Medline]

14. Kollmorgen CF, Meagher AP, Wollf BG, et al: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg 220: 676-862, 1994[Medline]

15. Letschert JG, Lebesque JV, Aleman BM, et al: The volume effect in radiation-related late small bowel complications: Results of a clinical study of the EORTC Radiotherapy Cooperative Group in patients treated for rectal carcinoma. Radiother Oncol 32: 116-123, 1994[Medline]

16. Gallagher MJ, Brereton HD, Rostock RA, et al: A prospective study of treatment techniques to minimize the volume of pelvic small bowel and reduction of acute and late effects associated with pelvic irradiation. Int J Radiat Oncol Biol Phys 12: 1565-1573, 1986[Medline]

17. Schrag D, Gelfand SE, Bach PB, et al: Who gets adjuvant treatment for stage II and III rectal cancer? Insight from Surveillance, Epidemiology, and End Results–Medicare. J Clin Oncol 19: 3712-3718, 2001[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				F. L. Greene, A. K. Stewart, and H. J. Norton New Tumor-Node-Metastasis Staging Strategy for Node-Positive (stage III) Rectal Cancer: An Analysis J. Clin. Oncol., May 15, 2004; 22(10): 1778 - 1784. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tepper, J. E. Search for Related Content PubMed PubMed Citation Articles by Tepper, J. E. Social Bookmarking                            What's this?