This practice guideline was developed by the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI), using the methodology of the Practice Guidelines Development Cycle [5
]. Evidence was selected and reviewed by four members of the CCOPGI's Gastrointestinal Cancer DSG and methodologists. This practice guideline report is a convenient and up-to-date source of the best available evidence on preoperative RT for clinically resectable rectal cancer, developed through systematic reviews, evidence synthesis and input from practitioners in Ontario. External review by Ontario practitioners was obtained through a mailed survey consisting of items that address the quality of the draft practice guideline report and recommendations, and whether the recommendations should serve as a practice guideline. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee (PGCC).
The report is intended to promote evidence-based practice. The Practice Guidelines Initiative is editorially independent of Cancer Care Ontario and the Ministry of Health and Long-Term Care. The CCOPGI has a formal standardized process to ensure the currency of each guideline report. This consists of periodic review and evaluation of the scientific literature, and where appropriate, integration of this literature with the original guideline information.
Examination of the evidence
Literature search strategy
MEDLINE (1966 to April 2003), CANCERLIT (1983 to April 2002) and the Cochrane Library (Issue 1, 2003) were searched with no language restrictions. "Rectal neoplasms" (Medical subject heading [MeSH]), "colorectal neoplasms" (MeSH) and the text word "rectal cancer" were combined with "radiotherapy" (MeSH) and the following phrases used as text words: "preoperative"; "neoadjuvant"; "radiotherapy"; "radiation"; "irradiation". These terms were then combined with the search terms for the following study designs or publication types: practice guidelines, meta-analyses, and randomized controlled trials. The proceedings of the 1998 to 2002 annual meetings of the American Society of Clinical Oncology (ASCO) and the 1999 to 2002 annual meetings of the American Society for Therapeutic Radiology and Oncology (ASTRO) were searched for reports of new or ongoing trials. Relevant articles and abstracts were selected and reviewed and the reference lists from these sources were searched for additional trials. A search of personal reprint files was also conducted.
Study selection criteria
Trials of preoperative RT in resectable rectal cancer are characterized by multiple methodological problems because two treatments are combined (RT and surgery) to affect a heterogeneous condition (various populations and stages of rectal carcinoma) and to achieve a variety of goals (downstaging, improving resectability, decreasing local and possibly distant recurrences and improving survival). Cummings [6
] detailed many of the pitfalls that marred early trials, including deficiencies in trial design, eligibility criteria, treatment standardization and reporting of results. We used this critique to develop standard criteria for the selection of trials of preoperative RT for rectal cancer. Studies were included in this systematic review of the evidence if they met all of the following criteria:
1. Patients were randomly assigned to preoperative RT versus surgery alone or an alternative treatment.
2. The study population was well defined. Studies preferably included only rectal carcinoma, defined by tumors located within 15 cm of the pectinate line or anal verge on sigmoidoscopy, or rectosigmoid tumors. Patients were screened for metastases and co-morbidity by clinical and imaging procedures and were assessed as surgically resectable for cure.
3. Treatments were described clearly, including RT dose, fractionation, duration, field size and portals of irradiation. Timing of surgery after completion of RT was clearly set. General surgical principles were described.
4. Compliance with treatments and follow-up were described.
5. Treatment outcomes were reported for overall survival and / or local failure. Other outcomes such as adverse effects (morbidity and mortality), downstaging (decrease in the proportion of cases with stage III disease), and resectability (total and curative) were recorded if available.
Synthesizing the evidence
Trials of preoperative RT versus surgery alone were pooled using Review Manager 4.2.1 (© Update Software), which is available through the Cochrane Collaboration. Overall mortality, local failure, tumor resectability, tumor downstaging, and adverse effects were pooled in separate analyses for all studies, where data was available. Reported figures or estimates obtained from tables or graphs were used. For calculation of survival and local failure, all eligible patients were considered in the denominator, based on intention to treat. All deaths at the time of reporting, regardless of cause, were included in survival calculations. Patients with local failure included those with non-resected as well as those with recurrent disease. Only resected cases were considered in the calculation of downstaging.
Data were pooled using the random effects model as the more conservative estimate of effect [7
]. Results were expressed as relative risk ratios (RR) with 95% confidence intervals (CI), where a RR less than 1.0 favors preoperative RT and a RR greater than 1.0 favors surgery alone. Odds ratios (OR) and absolute risk differences (RD) were also calculated.
Heterogeneity of results among trials was expected in view of the different treatments used and populations tested, as well as the wide time interval and geography across which these trials were conducted. For example, the RT prescription may affect the results. RT doses greater than 30 Gy10
are considered necessary and pelvic fields are as effective as extended fields. Moreover, the use of three or more RT beams will lessen toxicity and short delays of surgery after RT will not demonstrate downstaging. Thus, these factors were investigated with sensitivity analyses to see whether there was an impact on results. Outcomes of predetermined groups of patients were examined initially by the graphic method described by L'Abbe et al.
] and RR calculated. For sensitivity analyses the following factors were examined:
• Biologically effective dose (BED) of RT (less than 30 Gy10
versus equal to or greater than 30 Gy10
). BED was calculated using the linear quadratic formula [9
] and the parameters suggested for time correction [10
BED time = nd (1+d/α/β) - γ/α (T - Tk)
where n = number of fractions, d = dose per fraction, α/β = 10 for tumor effect and acute reactions and α/β = 3 for late reactions, γ/α = repair rate set at 0.6 Gy/day, T = total treatment time and Tk = initial delay time set at 7 days;
• RT fraction size (standard fractions up to 2.5 Gy/day versus high fractions of 5 Gy/day);
• Contemporary RT prescription, defined as studies employing multiple-field technique and target volume confined to the pelvis (i.e. excluding studies employing parallel pair arrangements or including para-aortics); and
• Delay of surgery after completion of RT (less than seven days versus eight or more days).
• Studies including a range of rectal cancer cases versus those including only advanced disease.
Sensitivity analyses were also performed for all five of the meta-analyses (overall survival, local failure, tumor resectability, downstaging, and adverse effects) considering only trials with high design quality. The quality of the 14 eligible randomized trials of preoperative RT versus surgery alone in operable rectal cancer was scored independently. Five assessors assessed each trial using the Detsky instrument [11
]. This questionnaire addresses five domains of study quality: randomization process, outcomes measure, patient eligibility, treatment description, and statistical procedures. The 14 questions on the Detsky instrument can be answered "adequate", "inadequate", or "partial" and scored 1, 0, or 0.5, respectively. The final score of each trial is a ratio of the observed points divided by the total number of questions answered. The results from the five assessors were averaged for a final score. Trials with Detsky instrument scores greater than 0.5 were considered to be of high quality.