The American Society for Radiation Oncology (ASTRO) has issued a new clinical practice statement on recommendations to customise neo-adjuvant and adjuvant radiation therapy for moderately advanced rectal cancer.
The statement also examines non-operative therapies for patients who are medically inoperable or refuse abdomino-perineal resection, taking into account the emerging technologies available for this subset of patients.
The standard of care for all patients with stage II-III rectal cancer has been a combined multi-modality approach of chemotherapy, radiation therapy (RT) and surgery, as established in a 1990 consensus statement from the National Cancer Institute (NCI). This standard, however, is based on data collected in the 1970s and 1980s, when both RT and chemotherapy were necessary to reduce the high risk of local recurrence following less sophisticated forms of surgery.
Advancements in treatment options over the past three decades – including more refined surgical techniques, more effective systemic agents and more focal and shorter-course RT options – have drastically lowered recurrence rates, creating situations where one or more modalities may be omitted and the side effects of treatment may be reduced.
“This statement provides practicing physicians with an idea of how to employ alternative treatment options for rectal cancer patients, such as short-course radiation therapy or non-operative management approaches. It also lets us identify patients who may be more amenable to different treatment sequencing options, rather than grouping everyone with stage II and III rectal cancer together for a single standard tri-modal treatment approach. There are cases where we can achieve the same survival benefit with less treatment,” said Dr Karyn A Goodman, an associate professor of radiation oncology at the University of Colorado and lead author of the practice statement’s executive summary.
The guideline was developed through the RAND/UCLA Appropriateness Method, where members of an independent, multidisciplinary expert panel rate the appropriateness of different treatment approaches for different clinical scenarios based on a systematic review of published research. Experts in oncology, gastroenterology and internal medicine rated more than 200 unique scenarios combining risk factors that influence treatment decisions with potentially appropriate treatment modalities.
Panelists individually scored each scenario on a nine-point scale that assessed the anticipated benefit versus harm for an average patient in that situation. Ratings from the 10-member panel were aggregated into three categories for the Clinical Practice Statement; therapeutic options were labelled as Appropriate for median panel ratings of seven to nine without disagreement, May Be Appropriate for median ratings of four to six or if there was disagreement, and Rarely Appropriate for median ratings of one to three without disagreement.
Scenarios and treatment recommendations were grouped into four sections, including (1) neo-adjuvant and (2) adjuvant therapies used in conjunction with rectal surgery as well as non-operative management approaches for (3) medically inoperable patients and (4) patients who refuse radical rectal surgery.
For neo-adjuvant therapy, panellists rated five treatment options, stratified by three patient characteristics: risk classification based on disease stage (intermediate-risk, moderately-high-risk or high-risk disease), distance from the tumour to the anal verge and distance from the tumour to the mesorectal fascia.
Neo-adjuvant chemo-radiation was rated Appropriate for all scenarios, while neo-adjuvant brachytherapy alone was rated Rarely Appropriate across all scenarios. Neo-adjuvant chemotherapy alone was rated May Be Appropriate for intermediate- and moderately-high-risk patients with non-threatened mesorectal fascia and Rarely Appropriate for the other scenarios. Forgoing neo-adjuvant therapy was rated potentially appropriate only for cases with higher tumours situated far from the mesorectal fascia, where there would be no concern for positive margins following surgery.
Goodman explained the importance of radiation in treatment sequencing for tumours situated closer to the anal verge. “Tumours that sit lower in the rectum are in a more narrow part of the pelvis and therefore tend to have a higher risk of positive margins. Lower tumours also have a somewhat higher rate of lymph node metastasis. In these cases, radiation therapy is particularly important to help reduce the risk of local recurrence following surgery by shrinking the tumor, which helps surgeons resect more cleanly, and by eliminating micro-metastatic disease that may remain in pelvic lymph nodes not removed during surgery,” she said.
Neo-adjuvant short-course radiation therapy (25 Gy across five fractions) was rated Appropriate for many intermediate- and moderately-high-risk cases with non-threatened mesorectal margins and May Be Appropriate for other scenarios. While short-course radiation is the standard of care for moderately-advanced cases in many Northern European countries, it is rarely used in the US, said Goodman, yet she sees this option as gaining traction domestically, as evidenced in part by the recommendations of this panel.
For adjuvant therapy, panelists assessed two treatment options, chemotherapy alone and chemo-radiation plus four or more months of chemotherapy, stratified by three patient characteristics: circumferential resection margin, distance from the anal verge and risk classification based on total postsurgical nodal count.
Adjuvant chemo-radiation therapy (CRT) plus chemotherapy was rated Appropriate for all patients with positive margins and for patients with negative margins but higher risk classification and/or lower tumours. Adjuvant chemotherapy alone was rated Appropriate only for patients with negative margins, moderately-high-risk disease and higher tumours; it was rated May Be Appropriate for all other scenarios.
For medically inoperable cases (elderly patients who are not strong surgical candidates), panelists considered five non-operative treatment sequences, stratified by three patient characteristics: performance status based on Eastern Cooperative Oncology Group score, presence or absence of local symptoms and distance from the anal verge.
Chemo-radiation was rated Appropriate for medically inoperable patients with good performance status and May Be Appropriate for those with poor performance status. External beam radiotherapy (EBRT) alone and chemotherapy alone were rated May Be Appropriate for all scenarios. Brachytherapy alone and brachytherapy combined with CRT were rated potentially appropriate for lower tumours but rarely appropriate for higher tumours.
The guidelines also assess definitive non-operative treatment for patients who experience a pathologic complete response following neo-adjuvant chemo-radiation and want to avoid radical surgery, particularly those with low-lying tumours who are at higher risk for a permanent colosotomy. Panelists considered three treatment options, including standard-dose chemo-radiation alone, chemo-radiation plus brachytherapy boost and chemo-radiation plus EBRT boost. Each approach was rated Appropriate for scenarios where patients refuse standard therapy.
The panel also considered the appropriateness of using intensity-modulated radiation therapy (IMRT) in place of three-dimensional conformal radiation therapy (3-D CRT) in neo-adjuvant and adjuvant settings. IMRT is an advanced RT technique that delivers more focal radiation doses and spares more radio-sensitive healthy tissue than with 3-D CRT. For each of the three treatment scenarios (neo-adjuvant RT alone, neo-adjuvant chemo-radiation, adjuvant chemo-radiation), panelists rated IMRT as May Be Appropriate, noting both upsides, such as reduced toxicity, as well as downsides, such as the higher financial costs, of using the technique.
Purpose: To summarize results of a Clinical Practice Statement on radiation therapy for stage II-III rectal cancer, which addressed appropriate customization of (neo)adjuvant radiation therapy and use of non-surgical therapy for patients who are inoperable or refuse abdominoperineal resection.
Methods and materials: The RAND/University of California, Los Angeles, Appropriateness Method was applied to combine current evidence with multidisciplinary expert opinion. A systematic literature review was conducted and used by the expert panel to rate appropriateness of radiation therapy options for different clinical scenarios. Treatments were categorized by median rating as Appropriate, May Be Appropriate, or Rarely Appropriate.
Results: In the neoadjuvant setting, chemoradiation was rated Appropriate and the ratings indicated short-course radiation therapy, chemotherapy alone, and no neoadjuvant therapy are potential options in selected patients. However, neoadjuvant endorectal brachytherapy was rated Rarely Appropriate. For adjuvant therapy, chemoradiation (plus ≥4 months of chemotherapy) was rated Appropriate and chemotherapy alone May Be Appropriate for most scenarios. For medically inoperable patients, definitive external beam radiation therapy and chemotherapy alone were rated May Be Appropriate, whereas endorectal brachytherapy and chemoradiation plus endorectal brachytherapy were possible approaches for some scenarios. The last option, definitive chemoradiation, was rated Appropriate to May Be Appropriate based on performance status. Finally, for patients with low-lying tumors refusing abdominoperineal resection, definitive chemoradiation alone, chemoradiation plus endorectal brachytherapy, and chemoradiation plus external beam radiation therapy were all rated Appropriate.
Conclusions: This Clinical Practice Statement demonstrated the central role of radiation therapy in stage II-III rectal cancer management and evaluated ways to better individualize its use in the neoadjuvant, adjuvant, and definitive settings. Ongoing trials may clarify areas of continuing uncertainty and allow further customization.
Karyn A Goodman, Caroline E Patton, George A Fisher, Sarah E Hoffe, Michael G Haddock, Parag J Parikh, John Kim, Nancy N Baxter, Brian G Czito, Theodore S Hong, Joseph M Herman, Christopher H Crane, Karen E Hoffman