ASCO’s endorsement of the American Society for Radiation Oncology (ASTRO) guidelines on the role of radiotherapy in locally advanced non–small cell lung cancer (NSCLC) is an important summary of the best evidence on the appropriate role and techniques for radiotherapy in this disease.¹ These guidelines—reviewed in this issue of The ASCO Post—have been developed through a rigorous ASCO Clinical Practice Guideline Committee review process to ensure the highest quality of guideline endorsement possible.

Clinical guidelines serve practitioners by improving the consistency of care, avoiding unnecessary or harmful interventions, informing patients about their choices, and providing orientation points for policy makers and insurance carriers. If followed, clinical guidelines should benefit patients and the health-care system as a whole.²

However, clinical guidelines cannot replace the individual treatment approach to a given patient, taking into consideration his or her unique set of comorbidities, beliefs, and willingness to undergo more- or less-aggressive treatment. Guidelines also cannot provide comprehensive details of ­radiation treatment planning and execution, which have a significant impact on the quality of the radiation treatment delivered. Guidelines cannot take into account the expertise of specific disciplines at a given institution, which may have a significant impact on the quality of care. Lastly, they may not fully explore areas of uncertainty where evidence is lacking, and decisions must be made based on best oncologic principles and judgment. Thus, guidelines have to be applied to clinical practice in a thoughtful manner.

Key Points of the ASCO Endorsement

Patients with stage II or III NSCLC can be managed with curative-intent radiotherapy or surgical resection, depending on the technical resectability of the tumor and the medical comorbidities of the patients. Chemotherapy should be added to the treatment paradigm for all eligible patients, either concurrently/sequentially with curative-intent radiotherapy or neoadjuvantly/adjuvantly with surgical resection. Postoperative radiotherapy is recommended for patients with incomplete resection and may be recommended for patients with pathologic N2 nodal involvement. The standard dose for curative-intent radiotherapy is 60 Gy in 2-Gy daily fractions, and ideally this should be delivered with concurrent chemotherapy in all patients who are candidates for this approach.

Areas of Uncertainty

Curative-Intent Radiotherapy

Concurrent chemoradiotherapy has resulted in the best outcomes for inoperable patients with locally advanced NSCLC. However, determining who can tolerate concurrent vs sequential chemoradiotherapy is more challenging and less well defined. Factors that should be considered are the patient’s performance status, weight loss, age, esophageal or pulmonary comorbidities, oxygen desaturation on exertion, and patient preference regarding the aggressiveness of treatment.

The recent RTOG 0617 trial demonstrated that a dose of 74 Gy is inferior to 60 Gy when treating the entire tumor volume with concurrent chemoradiotherapy.³ However, it remains unknown whether the optimal radiotherapy dose may lie between 60 Gy and 74 Gy. The challenge of identifying the optimal radiotherapy dose in this setting is that locally advanced NSCLC can vary greatly in tumor volume, disease extent, and proximity to organs at risk, and these factors all play a role in determining what radiotherapy dose is safe and most effective. RTOG 0617 newly identified a radiation dose to the heart as predictive of survival. The pathophysiologic mechanism for this finding remains to be elucidated.

The results of RTOG 0617 do not settle the question of the optimal radiotherapy dose in patients who receive sequential chemoradiotherapy or radiotherapy alone (for patients who are not candidates for chemotherapy at all). Thus, it remains unclear what the radiotherapy dose in this patient population should be and whether doses above 60 Gy in the absence of concurrent chemotherapy are beneficial or not.

Although RTOG 0617 demonstrated higher-than-expected rates of survival, even with standard-dose radiotherapy, rates of intrathoracic tumor control with 60 Gy are suboptimal.⁴ Thus, other strategies to improve local tumor control by escalating the radiotherapy dose have been pursued. They include increasing the dose to subportions of the tumor volume based on mid-treatment positron emission tomography scans (RTOG 1106/ACRIN 6697; http://clinicaltrials.gov, NCT01507428) or escalating the radiotherapy dose to the point that the expected risk of toxicity is the same across patients—ie, isotoxic treatment (IDEAL-CRT; http://public.ukcrn.org.uk, UKCRN ID 6961). Proton therapy can often minimize the radiotherapy dose to organs at risk, in particular the heart, lungs, and esophagus, and whether this translates to a clinical benefit over conventional photon therapy is currently being investigated in the RTOG 1308 randomized trial.

Pre- and Postoperative Radiotherapy

The guidelines recommend management by a multidisciplinary team, evaluating each individual patient for resectability and taking into account technical feasibility and medical comorbidities. Whether to utilize radiotherapy in the preoperative vs postoperative setting remains an unanswered question. The optimal approach for an individual patient will depend on the expertise of the treatment team as well as the tumor location, size, and involvement of adjacent structures. For superior sulcus tumors, preoperative chemoradiotherapy is recommended, since complete resection and long-term local tumor control are likely even more critical given the proximity to the brachial plexus and severe morbidity of a potential local recurrence.⁵

There is substantial evidence suggesting a benefit of postoperative radiotherapy in patients with completely resected N2 disease, but not with N0-1 disease. Whether postoperative radiotherapy is indicated in patients with N2 involvement at presentation, but not after response to induction chemotherapy, remains controversial.⁶

Currently, there is no good evidence for the optimal design of the target area for postoperative radiotherapy. We typically treat the involved lymph node stations as well as the ipsilateral hilum and bronchial stump. The contouring guidelines of an ongoing European randomized trial of postoperative radiotherapy (Lung ART; http://clinicaltrials.gov, NCT00410683) recommend treating one level above and below the involved nodal levels.⁷ It is hoped that this trial will provide level 1 evidence on the benefit of postoperative radiotherapy in N2 disease and further insight into which factors determine the outcome of patients undergoing postoperative radiotherapy.

Future Outlook

The future management of locally advanced NSCLC with radiotherapy will undoubtedly have to take into account the advances in our understanding of the genomic changes in NSCLC. Tyrosine kinase inhibitors against sensitizing EGFR mutations and ALK rearrangement have demonstrated the effectiveness of targeted therapies in extending progression-free and overall survival. RTOG 1306 is one of the first studies to incorporate these therapies in combination with concurrent chemoradiotherapy. More studies will be needed to determine how to maximize the benefit of targeted therapies and radiotherapy in selected patient populations.

Lastly, immunotherapy has resulted in impressive and prolonged responses in advanced NSCLC. There is increasing evidence that radiotherapy may serve as an in situ vaccine to expose tumor antigens and thus may have synergistic effects in combination with immunotherapy. Studies investigating immunotherapy in the neoadjuvant or adjuvant setting in locally advanced NSCLC have been initiated and raise hopes for significant improvement in the outcomes of patients with this diagnosis. ■

Disclosure: Dr. Rimner reported no potential conflicts of interest.

References

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2. Woolf SH, Grol R, Hutchinson A, et al: Clinical guidelines: Potential benefits, limitations, and harms of clinical guidelines. BMJ 318:527-530, 1999.

3. Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial phase 3 study. Lancet Oncol 16:187-199, 2015.

4. Machtay M, Paulus R, Moughan J, et al: Defining local-regional control and its importance in locally advanced non-small cell lung carcinoma. J Thorac Oncol 7:716-722, 2012.

5. Rusch VW, Giroux DJ, Kraut MJ, et al: Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: Long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 25:313-318, 2007.

6. Amini A, Lou F, Correa AM, et al: Predictors for locoregional recurrence for clinical stage III-N2 non-small cell lung cancer with nodal downstaging after induction chemotherapy and surgery. Ann Surg Oncol 20:1934-1940, 2013.

7. Spoelstra FO, Senan S, Le Péchoux C, et al: Variations in target volume definition for postoperative radiotherapy in stage III non-small-cell lung cancer: Analysis of an international contouring study. Int J Radiat Oncol Biol Phys 76:1106-1113, 2010.