Twelve-year outcomes of a Dutch study investigating the efficacy of preoperative radiotherapy with total mesorectal excision (TME) for rectal cancer are reported in the June issue of Lancet Oncology. They reconfirm the need to individualize treatments to prevent unnecessary suffering from toxicities.
The key finding of this landmark trial remains the same as from 10-year follow-up outcomes data, which the researchers presented last fall at a plenary session of the American Society for Radiation Oncology (ASTRO) 2010 annual meeting: that preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone. The rates of recurrence have improved slightly with this newly published report (Lancet Oncology, June 2011, Vol. 12:6, pp. 575-582).
The new paper indicates that at a median follow-up of 12 years, the 10-year cumulative incidence of local recurrence for patients who received radiation therapy was 5%, compared with 11% in the surgery-alone group. That compares to recurrence rates of 6.4% and 13.3%, respectively, at the 10-year mark in data provided in the ASTRO presentation by Dr. Corrie Marijnen, professor of radiation oncology at the Netherlands' Leiden University Medical Center.
TME has been the gold standard of treatment for rectal cancer for more than 20 years, and it offers the best resection option for sphincter preservation. This surgical procedure removes the cancer in its entirety, with its surrounding perirectal lymphatic tissue contained within a thin fascial layer. However, before MRI became a preoperative standard at many hospitals when staging rectal cancer patients, up to 45% experienced local recurrence, according to Marijnen.
Nearly 2,000 patients and 119 cancer treatment centers in Europe and Canada participated in this randomized clinical trial conducted by the Dutch Colorectal Cancer Group. From January 1996 through December 1999, 1,861 patients with localized resectable rectal cancer were randomized to undergo short-course radiation therapy prior to TME surgery or to have TME alone. Patients assigned to radiotherapy received five 5-Gy fractions, for a total radiation dose of 25 Gy over five to 10 days of treatment.
The cohort of eligible patients -- 987 patients (64% men) who received radiotherapy and TME and 908 (64% men) who received surgery alone -- were followed by the researchers through July 2010.
The benefit of radiotherapy differed among subcategories of patients based on their stage of cancer and its location, according to principal investigator Dr. Cornelis van de Velde, PhD, professor of surgery at Leiden University Medical Center, and colleagues. Overall, cancer recurrence was significantly less common in the irradiated group, with a 20% recurrence rate, than in the surgery alone group, with a 27% rate. The researchers also reported that the effect of radiotherapy became stronger as the distance from the anal verge increased.
Local and distant recurrence in subcategories of patients
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| RT = radiation therapy |
The effectiveness of radiotherapy in preventing local recurrences was significantly dependent on cancer tumor stage. It proved to be most beneficial for patients with TNM (Tumor, Nodes, Metastases) stage III disease. One patient would not develop a local recurrence for every nine to 10 other patients who underwent radiation therapy unnecessarily. By comparison, for patients with TNM stage I rectal cancer, this ratio was one patient for every 28 other patients.
Causes of death
The researchers reported that a total of 973 patients had died by the termination date for follow-up of July 15, 2010. They reported that the cumulative incidence of cancer-specific death at 10-year follow-up was 28% for the radiotherapy group and 31% for the surgery-only group. However, the rate for patients with a negative circumferential resection margin, a total of 634 patients, was 56% and 57%, respectively.
Although 10% fewer patients who received radiotherapy died of rectal cancer (38%, compared with 48% for the surgery-only group), a higher percentage died from other causes of death. This resulted in overall survival rates being comparable.
Toxicity analysis
In addition to analyzing the primary and secondary end points of the trial (local control, distant recurrence, overall survival, and cancer specific survival), the researchers also recorded acute and late toxicities experienced by both groups of patients. They were concerned about whether adverse effects caused by radiotherapy might outweigh the benefits of decreased local recurrence, and wanted to measure the impact of TME and TME with radiation therapy on the patients' health-related quality of life.
For logistical reasons, the research team limited the evaluation to patients who enrolled in the 84 participating Dutch centers. All 1,530 Dutch patients who remained cancer-free for up to 24 months after surgery were asked to complete a health-related quality of life questionnaire. These were to be completed before surgery and at three, six, 12, 18, and 24 months after surgery.
Patients who failed to complete two consecutive questionnaires were excluded, resulting in a total of 990 patients whose questionnaires were analyzed. This included 497 patients from the radiotherapy group, of whom 64% were male, and 493 from the surgery-only group, of whom 63% were male.
In a previous article on the same patient population published in 2005 in the Journal of Clinical Oncology, Marijnen and colleagues reported that patients who received radiotherapy experienced slower recovery of bowel and bladder function and had a greater degree of sexual dysfunction, compared with the surgery-only patients. At 24 months, more than half of the patients who had radiotherapy experienced fecal incontinence, compared with slightly more than one-third of the surgery-only patients (J Clin Oncol, 2005, Vol. 23:9, pp. 1847-1858).
Men who had the radiotherapy reported ejaculation disorders that deteriorated over time, and a decrease in erectile function for up to two years. The researchers attributed these conditions to irradiation of the seminal vesicles and late radiation damage to the small vessels, respectively. Women experienced vaginal dryness and pain during intercourse.
These conditions worsened a median of 5.1 years after surgery. In a subsequent study on patient quality of life, 708 patients from the group of 990 were mailed a questionnaire. The analysis of 597 patients who completed this questionnaire was also published in the Journal of Clinical Oncology (2005, Vol. 23:25, pp. 6199-6206).
Lead author Dr. K.C. Peeters, of Leiden University Medical Center's departments of surgery and clinical oncology, and colleagues wrote that 62% of patients who had the radiotherapy treatments reported fecal incontinence. By comparison, only 38% of the surgery-only group had this problem. Anal blood loss was almost four times higher (11% versus 3%, respectively) and mucus loss was almost double (27% versus 15%, respectively.) As with the first quality-of-life assessment, the respondents were almost evenly divided, with 306 having had radiotherapy and 291 having had surgery only.
Irradiated patients reported more signs of severe incontinence, as well as a greater impact of bowel dysfunction on their daily activities. Because of this, social activities were affected to a greater degree.
"The substantial additional long-term side effects of radiotherapy on bowel dysfunction indicate that radiotherapy should be administered to those patients who are most likely to benefit from it," the researchers stated in their article.
Although quality-of-life data were not updated in the 12-year outcomes report, the researchers remain deeply concerned. They expressed hope that improved imaging techniques, such as contrast-enhanced MRI scans to improve preoperative nodal staging, and new biomarkers could help identify patients who would benefit the most from radiotherapy.
"Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side effects favors gains, and simultaneously identify patients for whom radiotherapy can safely be omitted," they concluded.
