By Ehsan Balagamwala, MD, and Benjamin J. Moeller, MD, PhD
In 2011, ASTRO published a guideline on palliative thoracic radiation therapy
(RT) which covered dose and fractionation for external beam radiation therapy (EBRT) and the roles of endobronchial brachytherapy (EBB) and chemotherapy given concurrently with EBRT. Pertinent to the update discussed below, the original guideline task force concluded that there was no role for concurrent chemotherapy with palliative EBRT for lung cancer. This recommendation was based on a single randomized control trial (RCT) by Ball et al.,
which showed improved overall response rates with concurrent chemotherapy. However, it also reported increased esophageal toxicity, as well as no improvement in overall survival, progression-free survival or symptom palliation.
ASTRO’s current guideline methodology includes periodic review of published guidelines for consideration of revision based on new data. A task force was convened in 2016 to review the palliative thoracic guideline briefly summarized above and they issued the results of this review in a guideline update published in the July-August issue of Practical Radiation Oncology
. An updated literature review was performed for all three original key questions. The task force felt that the original statements on the questions of EBRT dose and fractionation, as well as those on EBB should be left intact. However, new data on the utilization of concurrent chemotherapy with palliative EBRT prompted the task force to recommend revising its guidance on this question.
For patients with stage IV lung cancer, the recommendation against concurrent chemoradiation was unchanged. However, recommendations on the palliative management of incurable stage III non-small cell lung cancer (NSCLC) were revised based on two additional RCTs published after the original guideline was released: one by Nawrocki et al.
, and another by Strom et al.
Both of these trials had two strengths lacking in the study by Ball and colleagues: First, protocol-specified definitions of incurable stage III NSCLC (Ball et al., did not have well-defined eligibility criteria) and second, utilization of platinum-containing multiagent chemotherapy, which has been shown to have the most activity in NSCLC (Ball et al., utilized single agent fluorouracil).
With the addition of chemotherapy, both Nawrocki et al., and Strom et al., showed improvement in overall survival, albeit with increased risk of grade 3-4 toxicity (neutropenia and esophagitis) with concurrent chemoradiation. Based on these new trials, the task force recommended that a subset of patients (chemotherapy candidates, Eastern Cooperative Oncology Group performance status 0-2, and life expectancy ≥ 3 months), who are not candidates for either definitive concurrent chemoradiation or sequential chemoradiation, would benefit from concurrent chemotherapy with moderately hypofractionated RT.
In the months since this guideline was released, there has been engaging discussion via social media and scientific meetings, largely aimed at clarifying two important points:
- How should the guideline reader define “incurable” stage III NSCLC?
- How can the guideline reader be reassured as to the safety of concurrent chemotherapy with palliative thoracic EBRT?
Though data demonstrate that many patients with stage III NSCLC are managed with palliative intent, no validated criteria have been defined for which patients are best treated this way, which complicates clinical research done in this space. The two studies primarily informing this update used largely non-overlapping criteria for defining incurable stage III NSCLC and, therefore, could not be used as a basis for this definition. Further, developing a definition of incurability was beyond the scope of this guideline update. Therefore, we chose to leave it to the discretion of the treating physician to determine candidacy for curative therapy in this context. The recommendation to utilize concurrent chemotherapy would apply only to those stage III NSCLC patients who they have deemed incurable in their individual practices (i.e., those patients that are treated with palliative intent and will receive only palliative RT and/or chemotherapy as a part of their treatment course).
When recommending escalating treatment intensity in the palliative care arena, treatment toxicity is an important consideration. Specific to the question of concurrent palliative thoracic chemoradiation is the risk for esophagitis. Ball et al., reported grade 3 esophagitis in 3 percent for RT alone versus 12 percent for chemoradiation (p<0.01). Nawrocki et al., did not find a statistically significant difference in risk for grade 3 esophagitis (0 percent RT versus 2 percent chemoradiation) but did find increased risk for grade 3 or 4 neutropenia with concurrent chemotherapy. Finally, Strom et al., found increased risk of grade 3 esophagitis with chemoradiation (1.5 percent versus 30 percent, p<0.01). Overall, the task force members concluded that the modest increase in the risk of acute esophagitis was outweighed by significant improvements in not only response rates and survival but also symptom control and quality of life with the addition of concurrent chemotherapy to palliative thoracic EBRT.
Finally, we applaud the investigators involved in all the referenced trials. Randomized clinical studies focused on palliative radiotherapy are relatively uncommon, partly due to the difficulties involved in conducting them. Given the prevalence of palliative care in our field and its understood value for our patients, we appreciate these efforts and encourage more investigation to further clarify these important issues.
Dr. Balagamwala served as the resident representative on the task force for this guideline; he recently completed his residency at the Cleveland Clinic, where he is now an attending physician in the Department of Radiation Oncology. Dr. Moeller chaired the update to the ASTRO guideline on palliative thoracic radiation therapy and is a member of the ASTRO Guidelines Subcommittee. He works at Southeast Radiation Oncology Group in Charlotte, North Carolina.