Guidelines for stereotactic body radiation therapy treatment of lung cancer highlight important research questions: what is the next step?

Over the past decade, stereotactic body radiation therapy (SBRT) has become increasingly accepted as a safe and effective therapy for stage I lung cancer for medically inoperable patients. The American Society for Radiation Oncology (ASTRO) clinical guidelines concerning the use of SBRT for the treatment of stage I non-small cell lung cancer (NSCLC) were recently endorsed by the American Society of Clinical Oncology (ASCO) (1,2). Both the ASTRO guidelines and the ASCO endorsement are thorough and clear, and summarize the current state of evidence. ASCO has recommended certain modifications and qualifications that emphasized the importance of the multidisciplinary cancer care team discussions, shared decision-making, and the importance of adequate staging. An underappreciated advantage of establishing clinical guidelines is the resultant light that is shined on the many unanswered questions, which should guide the focus of further clinical research.

Of the 4 key questions addressed by the guidelines (Table 1), the first question is the most important and potentially controversial: “When is SBRT appropriate for patients with T1-2 N0 NSCLC who are medically operable?” Traditional first line treatment for this cohort of patients is surgical resection with lobectomy and systematic lymph node evaluation, a recommendation endorsed by all major guidelines, including the National Comprehensive Cancer Network (NCCN), and now by ASTRO and ASCO. Concerning trends, however, have shown increased use of SBRT with a concomitant decrease in surgical utilization (3), suggesting that patients with potentially operable early stage NSCLC are choosing SBRT over surgery. As thoracic surgeons, it is gratifying to see that 2 of the major organizations for our colleagues in cancer care recognize that the current state of research does not yet support recommending the use of SBRT instead of surgery for operable patients outside of clinical trials.

Table 1 Summary of ASTRO guidelines concerning SBRT use for stage I lung cancer, with ASCO additions in bold print (in parentheses, strength of recommendation, quality of evidence)
Full table

Two areas highlighted by the ASCO proceeding are in need of further research: (I) importance given to invasive tissue diagnosis for biopsy and staging; and (II) use of SBRT in operable high risk patients. The importance of invasive staging of the hilum and mediastinum before SBRT, especially in the case of central tumors and multiple primary lung cancers (MPLC) is emphasized in the ASCO qualifying statements. Increasing the accuracy of staging for patients considered for SBRT can be predicted to improve appropriate management strategies and decrease inappropriate usage of SBRT in cases more advanced than stage I. Reciprocally, whether the upstaging of medically inoperable patients with suspected stage I NSCLC, who are less able to tolerate any invasive procedure, will improve long-term outcomes is an area in need of clinical research.

The next area in need of more evidence is the recommendation for the potential use of SBRT in medically operable patients with stage I lung cancer. Although the guidelines state that surgical resection remains the treatment of choice at this time, both ASTRO and ASCO agree that SBRT can be considered for patients with “high” operative risk (Table 1, recommendation 1c). However, it is well recognized among physicians caring for cancer patients that risk assessment can be subjective. The ASTRO guideline recommendation states: “Operative risk should be assessed by a thoracic surgeon who specializes in lung resection”, and defined standard operative risk as “anticipated operative mortality <1.5%;” while further elaborating on “high operative risk” by risk factors used for clinical trials, including “FEV1 <50% predicted, DLCO <50% predicted, or a combination of advanced age, impaired pulmonary function, pulmonary hypertension, and poor left ventricular function”. ASCO removed the mortality risk definition in their endorsement and added “there is no universally accepted definition,” to the definition of high operative risk, and also added further qualifying statements: namely, emphasizing that limited lung resection is more often selected than SBRT in patients with high operative risk, and adding the longer term data from RTOG 0236 phase II trial of inoperable stage I NSCLC to the discussion points (with overall survival at 5 years 40% with SBRT) (4).

In sum, we find the ASCO proceeding to present a balanced view of the current state of the literature concerning operable patients. But it is clear that more data is needed. No large multicenter phase III clinical trial comparing results of surgical resection to SBRT for lung cancer has been completed. Recent attempts at randomized comparisons of SBRT to surgery were not able to accrue patients and were published as only underpowered, preliminary findings (5). Nevertheless, innumerable retrospective analyses comparing the 2 treatments continue to be published (6,7). Despite propensity matching and use of large databases, the effect of selection bias and residual confounding can never be eliminated in looking at retrospective data. SBRT has traditionally been reserved for patients with comorbidities, poor performance status, poor lung function, and high to prohibitive surgical risk and thus shorter life expectancies. Meanwhile, data is accumulating for first-line SBRT in operable patients. Series report 5 years overall survivals of 51% to 74% for SBRT, which rivals surgical results (8-12).

Three ongoing clinical trials are expected to provide a higher level evidence regarding SBRT for medically operable patients with stage I NSCLC: the VA Clinical Studies Program VALOR (Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy NCT02984761) trial, POSTILV (Radical Resection vs. Ablative Stereotactic Radiotherapy in Patients with Operable Stage I NSCLC NCT01753414) and STABLE-MATES (A Randomized Phase III Study of Sublobar Resection vs. Stereotactic Ablative Radiotherapy in High Risk Patients with Stage I NSCLC, NCT01622621). It is critically important that clinicians of all disciplines who treat lung cancer patients support and enroll in these trials which may become the basis for the standard of care in early stage NSCLC.

The ASTRO and ASCO guidelines point to inadequate data for evidence-based decision-making for stage I NSCLC. These and critical research questions must be answered for us to honestly and completely inform our patients. Cancer care should always be centered on options for enrollment in clinical trials, so that we can continue to improve and enhance treatment paradigms. The collaboration of thoracic surgeons, radiation oncologists, medical oncologists, pulmonologists, and radiologists is necessary at this time to maximize our ability to answer these important questions.

Acknowledgements

K. Macellaro, PhD, a member of the Baylor College of Medicine Michael E. DeBakey Department of Surgery Research Core Team, assisted with the editing of this editorial.

Footnote

Conflicts of Interest: Dr. Cornwell receives research funding from the Department of Veteran Affairs Cooperative Studies Program at the Michael E. DeBakey VA Medical Center in support of the VALOR trial. The other authors have no conflicts of interest to declare.

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