1. For a non-biopsied pulmonary nodule, evidence of progressive growth on Positron Emission Tomography (PET) scans and/or serial CT scans indicating a high likelihood of malignancy is required.

1. N2 disease clinically or by mediastinoscopy with planned lobectomy
2. T3 or T4 primary lesion
3. Superior sulcus tumors

1. Any mediastinal nodes positive for tumor
2. No surgical sampling of mediastinal nodes
3. Margins of the resected specimen are positive or close
4. Depending on the extent of residual disease, a dose of 50-54 Gy in 25-28 fractions (negative margins) to 60-70 Gy in 30-35 fractions (gross residual disease) is recommended.

1. The use of up to 15 fractions of a 3D conformal technique is medically necessary.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[INFORMATIONAL NOTE:
I. Treatment of stage III non-small cell lung carcinoma

Approximately one-third of individuals with non-small cell lung carcinoma present with locally advanced disease that is considered unresectable due to clinically apparent involvement of mediastinal lymph nodes or T4 disease. Until the mid-1990s, such individuals were treated with radiation therapy alone. RTOG 73-01 (Perez et al., 1987) was designed to assess the optimal dose of radiotherapy for patients with locally advanced disease, including those with poor performance status and/or significant weight loss. Local control and 2-year survival were better with 60 Gy in 6 weeks compared with lower doses. The seminal study of Dillman et al. from the Cancer and Leukemia Group B (CALGB) was published in 1996 and was the first study to demonstrate a survival benefit with the use of induction chemotherapy followed by external beam photon radiation therapy for patients with good performance status and weight loss of less than 5%. Cisplatin-vinblastine for two cycles followed by thoracic external beam photon radiation therapy to a dose of 60 Gy in 6 weeks was compared with the same external beam photon radiation therapy alone in 155 randomized patients. Induction chemotherapy improved median survival, and 3- and 7-year overall survival (OS). These results were confirmed in RTOG 88-08 (Sause et al., 2000), a study of 458 patients with Stage III NSCLC randomized to the positive arm of the CALGB trial (induction vinblastine-cisplatin followed by external beam photon radiation therapy) versus hyperfractionated external beam photon radiation therapy to 69.6 Gy versus standard fractionation external beam photon radiation therapy of 60 Gy in 6 weeks. These and other trials established the use of induction chemotherapy followed by standard fractionation of external beam photon radiation therapy as superior to external beam photon radiation therapy alone, and such therapy became the standard of care in the early 1990’s for inoperable patients with Stage III disease and good performance status. Use of concurrent chemoradiotherapy was also evaluated. RTOG 9410 is the largest trial assessing the value of concurrent versus sequential chemoradiotherapy. In this trial, 610 patients with Stage III disease were randomized to three arms: the positive arm of the CALBG trial reported by Dillman et al. (induction cisplatin-vinblastine for two cycles followed by external beam photon radiation therapy to 63 Gy) versus the same chemotherapy given concurrently versus a third arm of oral etoposide and weekly cisplatin given concurrently with 69.6 Gy hyperfractionated external beam photon radiation therapy (HART). Local control was better with concurrent HART, however, the best survival was seen with concurrent cisplatin-vinblastine and standard fractionated external beam photon radiation therapy. The use of concurrent external beam photon radiation therapy was associated with a significantly increased acute esophagitis as compared to sequential therapy, and concurrent HART was associated with even more frequent severe esophagitis.

The use of 3DCRT techniques, which are now standard, has made possible a decrease in normal tissues receiving high doses. 3DCRT techniques allow the development of complex multiple field radiotherapy plans that decrease the amount of normal tissue exposed to high doses. Better delineation of the target volume can be achieved with F-fluorodeoxyglucose-Positive Emission Tomography (FDG-PET). If FDG-PET has not been done for prior staging purposes, use of FDG-PET for staging and radiation planning is appropriate. Incorporating the information from PET/Computed Tomography (CT) can change the target volume in a significant proportion of patients as compared with CT alone. The radiotherapy target volume can decrease (due to the ability of PET to differentiate atelectatic lung from tumor) or increase (due to FDG uptake at mediastinal lymph nodes that were not positive by CT size criteria alone). In the increasingly common situation today when elective nodal irradiation is avoided, more accurate definition of involved sites of disease with PET decreases the likelihood that tumor-bearing nodes will not be encompassed in the target volume.

The use of techniques that account for mobility of the tumor with respiration takes on greater importance when 3DCRT treatment planning is utilized. By accounting for tumor motion on an individualized basis, smaller margins can be utilized thereby decreasing exposure to normal lung tissue. One approach to this problem is the use of respiratory gating or breath-hold technique. Gating the treatment with the respiratory cycle or treating with breath hold can help to reduce the planning target volume or avoid marginal miss. Another method incorporates so-called four-dimensional (4D) imaging. Use of rapid spiral CT scanning and acquisition of multiple images during breathing allows for better definition of the target volume, so that changes in the shape and location of the tumor during the breathing cycle can be taken into account in radiation delivery. With this technique temporal changes in tumor position and anatomy are incorporated into the treatment planning process. External beam photon radiation therapy delivery that adjusts in real-time to changes in tumor and normal anatomy holds further promise to decrease the necessary tumor margin and exposure to uninvolved lung.

Use of IMRT is also being studied. With this technique, the intensity of the beam is spatially varied in real time and delivery is accomplished using multiple fields at different angles or with rotational arc therapy. The primary disadvantage is that a greater volume of normal tissue gets low doses. Since the normal lung has low tolerance to even small doses, this technique is not appropriate in the majority of cases of locally advanced non-small cell carcinoma. IMRT may offer advantages in the treatment of an individual with bilateral mediastinal nodal involvement or in the treatment of an individual with definitive radiotherapy (without surgery) for superior sulcus tumors or paraspinal tumors. Recent attempts (Harris et al., 2014) to support the use of IMRT concluded that IMRT is “as effective as” but is “not better than” 3D.

Dose and fractionation regimens are evolving in the definitive treatment of locally advanced NSCLC, but no randomized trial has shown a benefit to doses higher than 60 Gy. The results of RTOG 0617, in which patients with stage IIIA or IIIB non-small cell lung cancer were randomized to standard-dose external beam chemoradiation (60 Gy) or high-dose chemoradiation (74 Gy) revealed that OS was 28.7 months in the standard-dose population vs. 20.3 months in those receiving high-dose radiation therapy. There was a trend towards increased treatment-related deaths in the high-dose population (8 vs. 3), and severe esophagitis was significantly increased in the high dose population 21% (43/207) vs. the standard-dose population (7% (16/217). The authors concluded that high-dose radiation for individuals with stage IIIA or stage IIIB non-small cell lung cancer was not better and might actually be harmful. Following publication of the official results of 0617, several additional analyses of the data emerged which have provoked controversy in the literature.

The study does not include in its primary or secondary objectives a comparison of randomized IMRT and 3DCRT treatment techniques. Indeed in the Treatment Planning section, the study states: “IMRT is allowed as long as the participating institution is credentialed by the RTOG for intra-thoracic IMRT Treatments.” Hence, there is no formal randomization.

Chun et al. (2017a) published a secondary analysis of 0617 in which they compared IMRT to 3DCRT. With a follow-up time period of two years, they noted no difference in overall survival (OS), progression free survival (PFS), local failure, and distant metastasis-free survival between the two techniques. They did conclude however that IMRT produced statistically significant lower heart doses than 3DCRT and that the volume of the heart receiving 40 Gy was also statistically significant in affecting OS. They recommended continued follow-up of the IMRT cardiac effects as the time period might be too short to measure them accurately. In their evaluation of pulmonary toxicity, the authors stated no difference in survival. They noted however that IMRT patients generally had larger tumor volumes, more advanced stage, and worse socio-economic status. IMRT was associated with statistically significant fewer cases of grade 3 pneumonitis though it is noted that the lung V20 was not different between the IMRT and 3D groups. Grade 3 esophagitis, dysphagia, weight loss and cardiovascular toxicity were not different. The lung V5 was significantly larger in the IMRT cases but was not associated with grade 3 toxicity. The article concluded that IMRT should be used routinely to treat locally advanced NSCLC.

Eaton et al. (2016) published a review of 0617 based on institutional accrual. They noted that patients treated at High Volume Centers (HVCs) were more often treated with IMRT than 3DCRT (54.0% vs. 39.5%) with lower mean esophageal and cardiac doses. HVCs had a more statistically significant acceptability rating on Protocol review than Low Volume Centers (LVCs) as well. In acknowledging the importance of reduced cardiac dose with IMRT, the authors noted that the volume of heart receiving 50 Gy or more was an independent predictor of adverse events. In summarizing their review the authors stated: “The differences in treatment technique, however, cannot solely account for the statistically significant longer OS demonstrated at HVCs as IMRT itself was not found to be associated with clinical outcome. Although a greater proportion of patients treated at HVCs were randomly assigned to the 60 Gy dose level, treatment at an HVC was associated with longer OS even among the subsets of patients randomly assigned to 60 Gy.” They concluded that institutional accrual volume should be considered in future clinical trials.

In correspondence to the Journal of Clinical Oncology, Ball et al. (2017) pointed out that there were only two grade 5 toxicities due to pneumonitis in 0617. In their editorial, they questioned whether the 0617 analysis was a true planned secondary evaluation and noted that interstitial lung disease, as well as other risk factors, were not taken into account. They noted institutional settings might have played a role in the determinations. For some patients and in less experienced centers the authors felt that 3DCRT might actually result better and safer treatment. Their editorial concluded that it was premature to recommend IMRT routinely for all patients based on the 0617 paper. In their reply to Ball et al, Chun (2017b) agreed that the secondary analysis did not provide the same level of evidence as a properly randomized Phase III study intentioned to address the different techniques. They stated that RTOG 0617 “…used stratified blocked randomization, with radiation technique as one of the stratification factors…”and that it has “…long been the intent to perform a secondary analysis.” They pointed out that IMRT has been adopted for other cancers without randomized studies and that the evidence provided in 0617 was sufficient to recommend the routine use of IMRT in locally advanced NSCLC.

The described literature does indeed raise important questions. In the formally-stated objectives of 0617, the stratification and endpoints to not necessarily support the concept of a sub-analysis, especially since IMRT was “permitted.” Given the difference in plan acceptability between HVCs and LVCs and the better survival of patients regardless of technique at an HVC, there may indeed be an overall difference and possible unintentional bias not only in treatment but also in the supportive care and treatment of side effects. Kong and Wang (2015) reviewed the non-dosimetric risk factors for radiation-induced pulmonary toxicity. Age, sex, smoking status, pre-existing lung disease, pulmonary function, tumor location, volume stage, and biologic and genetic factors may also play a strong role in radiation treatment toxicity and possible outcomes. The 0617 study does not include all of these risk factors. Similarly, in assessing cardiac effects, current cardiac status and potential cardiac risk factors should be taken into account in trial design. As such, until additional evidence is available from properly designed studies, 3DCRT remains the usual and customary treatment for locally advanced lung cancer. However, as NCCN [recognizes] that IMRT is preferred over 3DCRT for stage III, IMRT is also considered medically necessary.

An individual with Stage IIIA disease based on ipsilateral mediastinal nodal involvement has traditionally been considered unresectable, as outcome with surgery has generally been poor when there has been clinically apparent mediastinal involvement, particularly when multiple station N2 disease is present. However, with improvements in modern staging and more generalized use of multimodality therapy, there may be subsets of individuals with clinical N2 disease who might benefit from surgery. Attempts have been made to “downstage” individuals with preoperative chemoradiotherapy. The dose of radiation in the preoperative setting is generally 45 Gy in 25 fractions of external beam photon radiation therapy. 3DCRT techniques may be helpful, even at these lower doses, to reduce the dose to normal lung. Similarly, respiratory gating techniques may also be helpful, particularly for lower lobe primary tumors.

Postoperative radiotherapy (PORT) with external beam photon radiation therapy improves locoregional control as demonstrated by an early trial conducted by the Lung Cancer Study Group; however, this did not translate into an overall survival benefit. Enthusiasm for postoperative external beam photon radiation therapy diminished after the publication of the PORT meta-analysis, which included 2,128 patients with stage I to III non-small cell lung carcinoma enrolled in 9 randomized trials from 1966 to 1994. In the entire group of patients, there was a 7% absolute reduction in survival for patients who received external beam photon radiation therapy. The trials included in the meta-analysis have a variety of serious pitfalls, including the inclusion of ineligible patients, inadequate staging work-up, inclusion of node-negative patients, and techniques that today would be expected to produce deleterious outcomes. Most of the trials used higher total dose (> 50 Gy) or high dose per fraction (e.g. 2.5 Gy per fraction). In many of the trials, opposed off-cord lateral fields were used, which exposes a significant volume of normal lung to intolerable radiation volume, dose per fraction, and total doses. Additionally, systemic therapy was not used, and improved local control is more likely to translate into a survival benefit if effective systemic therapy is available. An individual with N2 disease is likely to achieve a significant local control benefit from postoperative external beam photon radiation therapy, and with modern techniques the individual may accrue a survival benefit. An American Intergroup trial and a European Organisation for Research and Treatment of Cancer (EORTC) trial are presently underway to re-evaluate the role of external beam photon radiation therapy for patients with N2 disease.

Twenty to 50% of individuals with clinical Stage III non-small cell lung carcinoma will develop brain metastases during the course of the disease and in individuals who have responded to prior multimodality therapy, a significant proportion experience relapse in the brain as the first or isolated site of failure. Early trials of PCI (Russell et al., 1991) showed greater than 50% relative risk reduction in the incidence of brain metastases with PCI, however, this did not translate into a survival benefit in any of the trials. Concerns of neurocognitive morbidity from PCI are largely related to the early experience with the use of PCI for small cell carcinoma, which is associated with a significant proportion of patients having neurocognitive dysfunction prior to radiation. More modern trials (Gregor et al., 1997) that employ lower dose per fraction and avoid concurrent chemotherapy have not found any impact of PCI on neurocognitive function. The RTOG conducted a study (Gore et al., 2009) of patients with Stage III non-small cell carcinoma who did not have progressive disease to evaluate the potential benefit of PCI. Patients were randomized to 30 Gy in 15 fractions versus observation after definitive local therapy. The primary endpoint was survival, and secondary endpoints were the rate of CNS metastasis, quality of life, and neurocognitive effects. The trial was negative for survival, but decreased local failure. Results of effects on neuropsychological function and quality of life are not yet available. Outside of a clinical trial, PCI for NSCLC is considered not medically necessary.

External beam photon radiation therapy is appropriate for curative intent treatment of an individual with Stage I and II NSCLC who is medically inoperable. An individual with hilar nodal involvement should be treated with standard fractionation (e.g. 60 Gy in 6 weeks) and 3DCRT techniques are preferred. For node negative Stage I and Stage II non-small cell lung cancer in an individual who is medically inoperable or who refuses surgery, SBRT is an appropriate option. Treatment is generally delivered in 3 to 5 fractions. SBRT is an appropriate technique for patients with node-negative peripheral lung cancers less than 5 cm in maximum dimension. Patients with central tumors can experience excessive toxicity when higher fraction sizes and fewer fractions (e.g. 3) are utilized. Use of mediastinoscopy is appropriate for staging of clinical stage T2N0 patients prior to definitive SBRT. IGRT may also improve the therapeutic ratio. Accurate set-up of the individual with the use of radiopaque markers placed in the tumor or use of daily CT scan imaging can essentially eliminate any additional margin that might otherwise be needed for daily individual set-up variability.

Lung cancer may present in an intermediate phase where cancer may be limited to the primary region with three or fewer metastatic sites that are also amenable to definitive treatment. Requests for definitive radiation treatment to the primary site will be considered on a case-by-case basis. Please refer to a separate policy on 'Radiation Therapy for Oligometastases'.

Similarly, a small subset of patients may present with Alk+; ROS1+ or EGFR+ mutations (exon 21, exon19) that have longer durable responses to targeted agents despite a significant metastatic disease burden. Alk+ tumors with CNS metastases may have survival in excess of 40 months. As such, circumstances may present where a more protracted radiation therapy regimen may benefit these patients rather than a short-term palliative regimen when substantial benefit has been gained from systemic therapy. These requests will also be reviewed individually. In the case of EGFR+ mutations it should be noted that exon 20 mutations are not associated with this benefit.

Additionally, the use of anti-PD-1 and PDL-1 agents such as Pembrolizumab are now being used as first line therapy in both metastatic squamous and adenocarcinomas which have a positive test of 50% or greater for PDL-1. The use of radiation therapy in this setting will also be reviewed on a case-by-case basis.

Please see the current NCCN Non-Small Cell Lung Cancer Guidelines® for additional discussion.

An individual with localized disease but with significant co-morbidities, poor performance status, or significant weight loss may be appropriate for external beam photon radiation therapy as definitive treatment with a hypofractionated schedule, use of split-course treatment, or use of more conventional fractionation alone (e.g. 60 Gy in 6 weeks). In addition, external beam photon radiation therapy is effective in the palliation of symptoms due to local tumor, such as hemoptysis, cough, or imminent endobronchial obstruction. Approximately 40% of individuals with NSCLC present with Stage IV disease. One multi-institutional phase III randomized study (Simpson et al., 1985) examined a variety of fractionation schemes including 40 Gy split course, 30 Gy in 10 fractions, and 40 Gy in 20 fractions. There was no difference between arms, and 60% of patients achieved symptom relief. Bezjak et al. (2002) reported a phase III trial of 231 patients randomized to 20 Gy in 5 fractions versus 10 Gy in 1 fraction. Similar palliation was seen in both arms, although patients in the 20 Gy arm had longer median survival. The Medical Research Council compared 17 Gy in 2 fractions (one per week) with 30 Gy in 10 fractions over 2 weeks. There was no difference in survival or palliation of symptoms. Hemoptysis was relieved in 86% of patients, cough in approximately 60% of patients, and pain in approximately 50% of patients. Therefore, data supports the use of short hypofractionated regimens, and there is generally no general role for more protracted schemes beyond 10 or 15 fractions. Endobronchial (EBB) radiation has also been found in retrospective studies to be effective in the palliation of symptoms due to intraluminal tumor, including obstruction, dyspnea, and cough. The procedure requires bronchoscopic guidance of the brachytherapy catheter. There is no proven role for more than 3 applications. EBB will be considered medically necessary after a failed course of external beam photon radiation therapy. American Society for Radiation Oncology (ASTRO) has published an evidence-based guideline for palliative lung cancer that reviews the various dose and fractionation regimens and the role of EBB. The ASTRO guideline specifically states that there is no benefit to adding concurrent chemotherapy to external beam photon radiation therapy in the palliative setting.]

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3. Ball D, Manus MM, Siva S, et al. Correspondence: Routine use of intensity-modulated radiotherapy for locally advanced non-small-cell lung cancer is neither choosing wisely nor personalized medicine. J Clin Oncol 2017 May; 35(13):1492-1493.

4. Bezjak A, Dixon P, Brundage M, et al. Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):719-728.

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6. Bradley J, Schild, Bogart, J, et al. RTOG 0617/NCCTG N0628/CALGB 30609/ECOG R0617. A randomizedphase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal radiotherapy with concurrentand consolidation carboplatin/paclitaxel +/- cetuximab (IND #103444) in patients with Stage IIIA/IIIB non-small cell lung cancer. NRG Oncology. Study Team 1/19/16.

7. 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. Lance Oncol. 2015 Feb; 16(2):187-199.

8. Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer. J Clin Oncol. 2013 May 20; 31(15) (suppl; abstr 7501).

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10. Chun SG, Hu, C, Bradley JD. Correspondence: Reply to D. Ball et al. J Clin Oncol. 2017 May 1;35(13):1493- 1494.

11. Chun SG, Hu C, Choy H, et al. Comparison of 3-D conformal and intensity modulated radiation therapy outcomes for locally advanced non-small cell lung cancer in NRG Oncology/RTOG 0617. Int J Radiat Oncol Biol Phys. 2016 Nov 1; 93(3 supplement):S1-S2.

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13. Curran WJ, Scott CB, Langer CJ, et al. Long-term benefit is observed in a phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresected stage III NSCLC: RTOG 9410. Proc Am Soc Clin Oncol. 2003; 22:621a. Abstract 2499.

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15. Eaton BR, Pugh SL, Bradley JD, et al. Institutional enrollment and survival among NSCLC patients receiving chemoradiation: NRG oncology radiation therapy oncology group (RTOG) 0617. J Natl Cancer Inst. 2016 May 19; 108(9).

16. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small cell lung cancer. J Clin Oncol. 2004 Dec 1; 22(23):4837-4845. Erratum in J Clin Oncol. 2005 Jan 1; 23(1):248.

17. Gore EM, Bae K, Wong S, et al. A phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer: Initial analysis of Radiation Therapy Oncology Group 0214. J Clin Oncol. 27(15S); 2009 May 20 (suppl; abstr 7506).

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38. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006 Oct 20, 24(30): 4833-4839.

39. Turrisi AT, Kim K, Blum R, et al. Twice daily compared to once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28; 340(4): 265-271.

40. Wang S, Liao Z, Wei X, et al. Analysis of clinical and dosimetric factors associated with treatment related pneumonitis (TRP) in patients with non-small cell lung cancer (NSCLC) treated with concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). Int J Radiat Oncol Biol Phys. 2006 Dec 1; 66(5):1399-1407.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*