For patients with advanced, inoperable stage 3 lung cancer, concurrent chemotherapy and the specialised radiation treatment, proton therapy, offers improved survival compared to historical data for standard of care, according to a study from The University of Texas MD Anderson Cancer Centre.
The research reported an overall survival (OS) of 26.5 months. In contrast, the historical OS rate with standard of care concurrent chemotherapy and traditional radiation was 16 months at the time when the study was designed.
The findings are the final results of the single institution, Phase II study and represent the longest follow-up to date of stage 3 lung cancer patients who have received proton therapy, said Dr Joe Y Chang, professor, radiation oncology and the study’s corresponding author.
Lung cancer is the leading cause of cancer death in both men and women in the US. According to the American Cancer Society, more than 222,500 people will be diagnosed and 155,870 will die from the disease in 2017, with the majority of patients still being diagnosed when the disease is in an advanced stage.
“Advanced lung cancer patients with inoperable disease traditionally have been treated with concurrent chemotherapy and conventional photon radiation therapy. However, the therapy can be very difficult for patients due to associated toxicities and because many patients are also dealing with comorbidities,” explained Chang.
Proton therapy is an advanced type of radiation treatment that uses a beam of protons to deliver radiation directly to the tumour, destroying cancer cells while sparing healthy tissues. Protons enter the body with a low radiation dose and stop at the tumor, matching its shape and volume or depth. They deposit the bulk of their cancer-fighting energy right at the tumour, thereby reducing the dose to cardiopulmonary structures, which impacts the toxicity, functional status, quality of life and even survival for patients, explained Chang.
“With our study, we hypothesized that proton therapy would offer a survival benefit to patients and reduce treatment-associated toxicities, which can be very serious,” he said.
The study opened at MD Anderson in 2006; in this research, Chang and his colleague report on the study’s five-year results.
For the prospective Phase II trial, 64 patients with inoperable, Stage III non-small-cell lung cancer were enrolled. The study’s primary endpoint was OS. The researchers hypothesised that the median OS would increase from historical data of 16 months on standard therapy to 24 months. Secondary endpoints included distant metastasis and local and regional recurrence rates. Toxic effects of treatment in both the acute and late settings also were analysed.
Median follow up was 27.3 months for all patients, and 79.6 months for alive patients. At five years, the median OS was 26.5 months, and the corresponding five-year OS was 29%. Median progression-free survival was 12.9 months, with a five-year progression-free survival of 22%.
In sum, 39 patients experienced a relapse, with distant sites representing 62% of all recurrences. Local and regional recurrence rates were low, 16% and 14%, respectively.
Among the acute and late toxic effects diagnosed in patients were: esophagitis, pneumonitis and cardiac arrhythmia. Of note, said Chang, no patients developed the most severe, or grade five, toxicities, as seen in patients who receive standard of care.
Chang noted his study is not without limitations. Of greatest significance: the study was designed more than a decade ago. While the study’s survival, recurrence rates and toxic effects are still favorable when compared to rates associated with the most advanced traditional photon radiation therapy, intensity modulated radiation therapy (IMRT), technology to diagnose and stage the disease, as well all treatment modalities have significantly improved.
“When the study opened, PET imaging had just been approved for lung cancer staging. The image quality was poor and didn’t include a CT component in most facilities across the country,” said Chang. “Obviously, the technology has improved dramatically over the last decade and has made a significant impact on diagnosis and staging. Also, delivery of both the conventional intensity-modulated radiation therapy (IMRT) and proton therapy (IMPT), have improved, thereby reducing side effects for both treatment modalities.”
For example, MD Anderson proton therapy patients with advanced lung cancer now can receive IMPT. The technique uses an intricate network of magnets to aim a narrow proton beam at a tumor and “paint” the radiation dose onto it layer by layer. Healthy tissue surrounding the tumor is spared, and side effects are even more reduced than earlier proton delivery, said Chang.
A Phase II trial studying IMPT and concurrent chemotherapy is underway.
Chang also noted the advancements in cancer biology and immunotherapy and that both are important areas of research focus in combination with proton therapy.
Importance: Proton beam radiotherapy (PBT) has the potential to reduce toxic effects in the definitive management of locally advanced non–small-cell lung cancer (NSCLC), but long-term prospective data are lacking.
Objective: To report the final (5-year) results of a prospective study evaluating concurrent chemotherapy and high-dose PBT to treat unresectable stage III NSCLC.
Design, Setting, and Participants :In this open-label, single-group assignment study, with median follow-up of 27.3 months for all patients and 79.6 months for survivors, 64 patients were enrolled and analyzed; inclusion criteria were unresectable IIIA/IIIB histologically confirmed NSCLC, Karnofsky performance status 70 to 100, and
and 6-month prediagnosis weight loss of no more than 10%. Staging used positron emission tomography and/or computed tomography. Induction chemotherapy was allowed.
Interventions: Concurrent chemotherapy (carboplatin-paclitaxel) and passively scattered PBT (74-Gy relative biological effectiveness) in all patients.
Main Outcomes and Measures: Kaplan-Meier analysis of overall survival (OS), progression-free survival (PFS), actuarial distant metastasis, and locoregional recurrence. Patterns of treatment failure were categorized as local/regional or distant. Acute and late toxic effects were prospectively assigned using Common Terminology Criteria for Adverse Events, v3.0.
Results: Of 64 patients (22 [34%] female; median [range] age, 70 [37-78] years; stage IIIA, 30 [47%]; IIIB, 34 [53%]), 17 (27%) were alive at last follow-up. Median OS was 26.5 months (5-year OS, 29%; 95% CI, 18%-41%). Five-year PFS was 22% (95% CI, 12%-32%); 5-year actuarial distant metastasis and locoregional recurrence were 54% (n = 36) and 28% (n = 22), respectively. Treatment failures were largely (31 [48%] patients) distant, with low rates of crude local (10 [16%]) and regional (9 [14%]) recurrences. Rates of grade 2 and 3 acute esophagitis were 18 (28%) and 5 (8%), respectively. Acute grade 2 pneumonitis occurred in 1 (2%) patient. Late toxic effects were uncommon: 1 (2%) patient developed an esophageal stricture (grade 2) and 1 (2%) grade 4 esophagitis. Late grades 2 and 3 pneumonitis occurred in 10 (16%) and 8 (12%), respectively. Two (3%) patients developed a bronchial stricture (grade 2), and 1 (2%) a grade 4 bronchial fistula. There were no acute or late grade 5 toxic effects.
Conclusions and Relevance: Concurrent chemotherapy and PBT to treat unresectable NSCLC afford promising clinical outcomes and rates of toxic effects compared with historical photon therapy data. Further optimization of proton therapy, particularly intensity-modulated proton therapy, is still needed.
Joe Y Chang, Vivek Verma, Ming Li, Wencheng Zhang, Ritsuko Komaki, Charles Lu, Pamela K Allen, Zhongxing Liao, James Welsh, Steven H Lin, Daniel Gomez, Melenda Jeter, Michael O’Reilly, Ronald X Zhu, Xiaodong Zhang, Heng Li, Radhe Mohan, John V Heymach, Ara A Vaporciyan, Stephen Hahn, James D Cox