Skip to content

Technology Evaluation
Center (TEC)


Proton Beam Therapy for Non-Small-Cell Lung Cancer

EXECUTIVE SUMMARY

Radiotherapeutic modalities such as stereotactic body radiotherapy (SBRT) have been developed to minimize damage to normal tissues and maximize radiation dose delivered to sites of malignancy.   The focus of this TEC Assessment is proton beam therapy (PBT) which is intended to deliver better dose distributions to tumors than those produced with photons (ionizing radiation therapies).  This Assessment evaluates the health outcomes following PBT compared to SBRT for management of non-small-cell lung cancer.

Objective:  This Assessment evaluates the health outcomes following PBT compared to SBRT for management of non-small-cell lung cancer.

The key question is how health outcomes (overall survival, disease-specific survival, local control, disease-free survival, and adverse events) with PBT compare with outcomes observed with SBRT.  This Assessment will specifically address the following 4 key questions:

  1. In patients with stage I non-small-cell lung cancer who are not surgical candidates what are the comparative effects of PBT and SBRT for survival and tumor control outcomes?
  2.  In patients with more advanced non-small-cell lung cancer (Stages II, III or IV), or patients with recurrent disease who are not surgical candidates, what are the comparative effects of PBT and SBRT for survival and tumor control outcomes?
  3.  In patients with stage I non-small-cell lung cancer who are not surgical candidates, what are the comparative effects of PBT and SBRT for adverse events?
  4.  In patients with more advanced non-small-cell lung cancer (Stages II, III or IV), or patients with recurrent disease who are not surgical candidates what are the comparative effects of PBT and SBRT for adverse events?

Ideally, in order to directly compare effectiveness of PBT with SBRT, randomized controlled studies comparing these modalities would be conducted with sufficient long-term follow-to assess long-term survival and adverse event endpoints.

Search strategy:  MEDLINE® was searched (via PubMed) using the following disease terms: “lung neoplasms” or “lung” and either “cancer” or “carcinoma.”  These terms were cross-referenced with the term “proton.”  The search was performed for the time period from January 1980 through June 2010 and was limited to English-language articles on human subjects, yielding 345 citations.  Electronic searches were supplemented with a review of bibliographies from recent review articles and clinical studies.  A technical brief commissioned by the Agency for Healthcare Research and Quality also provided citations.  An additional search of studies on radiotherapy and lung cancer was also conducted, focusing on systematic reviews, meta-analyses, decision analyses and cost-effectiveness analyses. 

Selection criteria:  Studies were selected for inclusion in the Assessment if they were full-length, peer-reviewed articles published in an English-language journal and studied non-small-cell lung cancer treated with PBT in a comparative study of any size or single-arm study of at least 10 patients.  Evidence for SBRT and intensity modulated radiotherapy was sought from recent systematic reviews and meta-analyses.

Main results:  Eight PBT case series were identified that included a total of 340 patients.  No comparative studies, randomized or nonrandomized, have appeared.  The main focus here is on stage I, which comprised 88.5% of all patients; only 39 patients were in other stages or had recurrent disease.  Among 7 studies reporting 2-year overall survival, probabilities ranged between 39% and 98%.  At 5 years, the range across 5 studies was 25% to 78%.  It is unclear if the heterogeneity of results can be explained by differences in patient and treatment characteristics. 

A recent indirect meta-analysis found a nonsignificant difference of 9 percentage points between pooled 2-year overall survival estimates favoring SBRT over PBT.  The nonsignificant difference of 2.4 percentage points at 5 years also favored SBRT over PBT.  Based on separate groups of single-arm studies on SBRT and PBT, it is unclear if this indirect meta-analysis adequately addressed the possible influence of confounding on the comparison of SBRT and PBT. 

Author’s conclusions and comments:  Overall, evidence is insufficient to permit conclusions about the results of PBT for any stage of non-small-cell lung cancer.  All PBT studies are case series; there are no studies directly comparing PBT and SBRT.  Among study quality concerns, no study mentioned using an independent assessor of patient reported adverse events, adverse events were generally poorly reported and details were lacking on several aspects of PBT treatment regimens.  The PBT studies were similar in age, but there was great variability in percent within stage Ia, sex ratio and percent medically inoperable.  There is a high degree of treatment heterogeneity among the PBT studies, particularly with respect to planning volume, total dose, number of fractions and number of beams.  Survival results are highly variable.  It is unclear if the heterogeneity of results can be explained by differences in patient and treatment characteristics.  Indirect comparisons between PBT and SBRT, comparing separate sets of single-arm studies on PBT and SBRT, may be distorted by confounding.  In the absence of randomized controlled trials, the comparative effectiveness of PBT and SBRT is uncertain.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether PBT for non-small-cell lung cancer meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.

1.         The technology must have final approval from the appropriate government regulatory bodies.

There are 510(k) clearances for devices used for delivery of PBT, and devices considered to be accessory to treatment delivery systems such as the Proton Therapy Multileaf Collimator.  This accessory device can be mounted on a PBT system and is designed to shape the treatment field perimeter (510K marketing approval awarded in December 2009.  Between 2001 and 2010, 12 devices classified as medical charged-particle radiation therapy systems received 510K marketing approval).

2.         The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

Eight PBT case series were identified that included a total of 340 patients with non-small-cell lung cancer.  No comparative studies, randomized or nonrandomized, have appeared.  The main focus here is on stage I, which comprised 88.5% of all patients; only 39 patients were in other stages or had recurrent disease.  Among study quality concerns, no study mentioned using an independent assessor of patient reported adverse events, adverse events were generally poorly reported and details were lacking on several aspects of PBT treatment regimens.  These studies were similar in age, but there was great variability in percent within stage Ia, sex ratio and percent medically inoperable.  There is a high degree of treatment heterogeneity among the PBT studies, particularly with respect to planning volume, total dose, number of fractions and number of beams.  Among 7 studies reporting 2-year overall survival, probabilities ranged between 39% and 98%.  At 5 years, the range across 5 studies was 25% to 78%.  It is unclear if the heterogeneity of results can be explained by differences in patient and treatment characteristics. 

Adverse events reported after PBT generally fall into these categories: rib fracture, cardiac, esophageal, pulmonary, skin and soft tissue.  Adverse events data in PBT studies are difficult to interpret due to lack of consistent reporting across studies, lack of detail about observation periods and lack of information about rating criteria and grades.

3.         The technology must improve the net health outcome

Overall, evidence is insufficient to permit conclusions about the results of PBT for any outcome among patients with any stage of non-small-cell lung cancer.  Survival results are highly variable and there is considerable heterogeneity in patient and treatment characteristics.  There is even less clarity about adverse events evidence.  Thus, it is unclear if benefits of PBT outweigh harms.

4.         The technology must be as beneficial as any established alternatives.

A recent indirect meta-analysis found a nonsignificant difference of 9 percentage points between pooled 2-year overall survival estimates favoring SBRT over PBT.  The nonsignificant difference of 2.4 percentage points at 5 years also favored SBRT over PBT.  Based on separate groups of single-arm studies on SBRT and PBT, it is unclear if this indirect meta-analysis adequately addressed the possible influence of confounding on the comparison of SBRT and PBT.  Randomized controlled trials would be better able than indirect meta-analyses to control for potential imbalances of patient characteristics between treatment groups.

5.         The improvement must be attainable outside the investigational settings.

Whether PBT for non-small-cell lung cancer improves outcomes in any setting has not yet been established.

Proton beam radiotherapy for treatment of non-small-cell lung cancer at any stage or for recurrent non-small-cell lung cancer does not meet the TEC criteria.

 _____________________________________________________________________

NOTICE OF PURPOSE:  TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.