The Impact of Short Course Pre-Operative Radiotherapy on Patients
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 22 de septiembre de 2008
Presenter: D. Sebag-Montefiore, MD
Presenter's Affiliation: Medical Research Council Clinical Trial Unit, CR07 Trial Management Group
Type of Session: Plenary
- The current standard of care for treatment rectal cancer involves surgery; however, there is a high incidence of local recurrence seen after surgery due to failure to remove all tumor-bearing tissue.
- Local recurrence is a major problem in the treatment of rectal cancer, since recurrence often leads to disabling and severe symptoms, and is challenging to treat.
- Previous studies have shown that the addition of radiation therapy to surgery has helped to significantly improve local control. The Swedish Rectal Cancer Trial published in NEJM in 1997 which randomized patients to preoperative radiotherapy and surgery vs. surgery alone showed that preoperative radiotherapy improved 5-year LR and 5-year OS significantly.
- It has also been established that preoperative radiation therapy is superior to postoperative radiation therapy. In 2004, the German Rectal Cancer Study Group published a randomized trial comparing preoperative and postoperative radiation therapy for patients with locally advanced rectal cancer, and demonstrated that preoperative radiation therapy improved the 5-year local control rate (6% vs. 13%), increased the rate of sphincter saving surgeries, and decreased grade 3-4 toxicity.
- The role of pelvic radiation therapy in rectal cancer is primarily for improvement of local control, however this often can come at a price of long term-morbidity associated with the side effects of radiation. Although local control and survival data have been recognized in the literature, the long term outcome data has not been well studied.
- One of the largest studies which has evaluated outcomes data in patients receiving preoperative radiaton therapy for rectal cancer was performed by the Dutch Colorectal Cancer Group, and quality of life (QOL) measures such as male sexual functioning and bowel problems were studied.
- The present study, MRC CR07/ NCIC CTG CO16, is a randomized, collaborative trial to compare local recurrence and disease free survival for locally operable rectal cancer patients who received short course pre-operative radiotherapy using 25 Gy in 5 fractions (PRE) vs. surgery followed by selective post-op chemo-radiotherapy (SEL POST) which was 45 Gy in 25 fractions for patients with a positive circumferential resection margin (CRM+ive). The initial data on these endpoints was presented in abstract form at the ASCO 2006 Annual Meeting.
- The authors have also attempted to assess the impact of the PRE policy on measures, mainly male sexual function and bowel function (which were also studied in the Dutch trial), which are the main data presented in this abstract.
- Between March 1998 and August 2005, 1350 patients from 52 centers with non-metastatic operable adenocarcinoma of the rectum (<15 cm from the anal verge) were randomized to either short course pre-operative radiotherapy (PRE) versus surgery followed by selective post-op chemo-radiotherapy (SEL POST) for patients considered to be at high risk for local recurrence, those with positive surgical margins.
- The primary endpoint of the trial was local control and secondary endpoint was disease free survival.
- In this analysis, the authors have analyzed quality of life data for the trial patients using patient questionnaire data. To assess the impact on QOL, patients were all asked to complete the SF-36 and the EORTC QLQ-CR38 instruments (detailed questionnaires) at baseline, 3 months to 1 year, and every 6 months to 3 years. Data was combined and scores were normalized to a 0-100 point scale, with a higher score indicating worse QOL.
- An intent-to-treat analysis was performed.
- Median follow-up was 3 years. There were 674 patients in the PRE group vs. 676 patients in the SEL POST group.
- The local recurrence rate for the PRE group was 4.4% versus 10.6% in the SEL POST group at 3 years, with an absolute difference of 6.2 %, HR=0.39, and p=0.000004.
- The disease free survival rate for the PRE group was 77.5% versus 71.5% in the SEL POST group at 3 years, with an absolute difference of 6%, HR=0.76, and p=0.0013.
- Completion of QOL questionnaires fell from 87% at baseline to 50% at 2 years. However, this did not differ between the treatment arms. The compliance rate for completion of forms on male sexual functioning was lower at 38% at 2 years.
- Male sexual functioning (MSF) was found to have deteriorated at 3 months, however it seemed to be due to surgery. The mean score at baseline was 26.0 vs. 58.4 at 3 months, p=<0.001, with no difference between treatment arms. However, there was a further lowering of MSF scores seen in the PRE group at 6 months. The MSF mean score for the PRE group was 63.3 vs. 55.4 for the SEL POST group, p=0.030 at 6 months, which continued to 3 years.
- In a subset analysis examining the impact of type of surgery, MSF was found to be worse in those patients who had an abdominoperioneal excision (APER) vs. an anterior resection (AR). The mean MSF score for APER at 3 months was 67.1 vs. 52.8 for AR, p=0.020.
- Scores for overall bowel function were not different between the two arms. However, when examining the specific outcome of "unintentional release of stools," the PRE group had a higher score of 52.4 vs. 38.7 for the SEL POST group, p=0.015.
- Both arms showed patient reports of decreased physical function at 3 months, but this returned to its baseline level soon thereafter.
- This trial and other previous trials have shown that preoperative radiation therapy reduces local recurrence and increases disease-free survival, although there is no overall survival difference seen.
- The quality of life (QOL) data presented in this study is similar to that of the previously mentioned Dutch trial.
- Although the deterioration in MSF appears to be due to surgery (worse with APER vs. AR), this effect is further exacerbated the pre-operative radiotherapy.
- In addition, although overall bowel function did not differ between the 2 groups, the PRE group did lead to worse fecal incontinence scores.
- The results of this QOL study should help patients and physicians make decisions on the risks and benefits of pre-operative radiation for an individual patient.
- Rates of local control after surgery for rectal cancer in the literature vary widely, but have been reported as 15 to 45%.
- The value of radiation therapy when used in addition to surgery for rectal cancer has been well established to improve these local control rates. Previous studies comparing preoperative and postoperative radiation therapy clearly show that local recurrence rates are lower for those patients treated preoperatively.
- This prospective randomized trial further demonstrates that preoperative radiation (which was hypo fractionated short course) is superior to postoperative radiation in terms of local control. However, this needs to be balanced against the potential negative side effects of this treatment. This area has traditionally not been emphasized in the literature and this study makes a valiant attempt to address this issue.
- In order to assess outcomes data, one needs validated instruments, a comparison to a baseline assessment, and a way to handle missing data, especially since compliance rates for questionnaires can be low. One of the strengths of this trial is that they used QOL instruments which have a proven quality and reliability. In addition, they measured outcomes at baseline and multiple time points, and used an intent to treat analysis with a very large number of patients enrolled.
- The authors clearly reported that quality of life measures such as MSF and fecal incontinence scores were worse for the short course pre-operative group, even though local recurrence and disease free survival and significant improved. These outcomes were similar to the previously reported Dutch study.
- There is a strong concern that these side effects are exacerbated by the fact that the radiation was given as short course hypofractionatedradiation, instead of traditional 5 week preoperative radiation therapy. This may have caused an increased in the toxicities seen in this group, but this was not addressed by the authors of this study.
- In terms of the clinical implications of these results, the big question becomes, how does one balance the clear benefit of preoperative radiation on tumor control with the risk of long-term morbidity? The goal when choosing treatments for patients is to maximize cure rate with the least toxicity possible.
- Based on these results, we can conclude that short-term preoperative radiation is more effective than postoperative XRT to improve local control and disease free survival, however we must take into account the negative side effects of this treatment when discussing this therapy with our patients.