Proton Therapy With Concurrent Chemotherapy for Non–Small-Cell Lung Cancer: Technique and Early Results

doi:10.1016/j.cllc.2011.11.008

Clinical Lung Cancer

Volume 13, Issue 5, September 2012, Pages 352-358

Presented at the Chicago Multidisciplanary Symposium in Thoracic Oncology, December 2010

https://doi.org/10.1016/j.cllc.2011.11.008 Get rights and content

Abstract

Background

Proton therapy can deliver a more conformal dose distribution than photon radiation and may allow safe dose escalation in stage III lung cancer. Early outcomes are presented here for patients who received proton therapy with concurrent chemotherapy for non–small-cell lung cancer (NSCLC).

Materials and Methods

Nineteen patients with regionally advanced NSCLC were treated with concurrent chemotherapy (carboplatin and paclitaxel [n = 18]) and proton therapy from August 2008 to April 2010 either with (n = 7) or without (n = 12) induction chemotherapy. Eighteen patients had stage III NSCLC, and 1 patient had stage IIB disease. The median proton therapy dose was 74 cobalt gray equivalent (CGE) in 2 CGE fractions with 18 patients who received ≥70 CGE. Twelve patients also received selective nodal proton therapy to the adjacent uninvolved nodal regions, with a median dose of 40 CGE (range, 40-46 CGE). The patients were routinely evaluated for treatment-related toxicity and disease progression every 3 months, with a history, physical, and computed tomography or positron emission tomography–computed tomography.

Results

The median follow-ups for living patients were 15 and 16 months (range, 7-26 months), respectively. Nonhematologic and hematologic acute grade 3+ toxicity (<90 days) developed in 1 and 4 patients, respectively. Two of 16 patients assessable for late toxicity (≥90 days) developed a significant grade 3+ nonhematologic late toxicity, whereas 1 patient developed a grade 3+ hematologic late toxicity. Local progression was the site of first relapse in one patient.

Conclusion

Mediastinal proton therapy with concomitant chemotherapy was associated with acceptable toxicity. Although encouraging, longer follow-up with more patients is needed to confirm the long-term efficacy of this treatment.

Introduction

Thirty-five percent of all newly diagnosed lung cancer is regionally advanced, with a median survival of approximately 15 to 18 months and a 5-year survival rate of 15% with standard therapy, including concurrent chemoradiation.1, 2, 3 This poor survival rate is due to both local and distant relapses. Radiation doses have traditionally been low, at 60 Gy, due to the risks of radiation injury to critical normal structures, which results in pneumonitis, esophagitis, and myelitis.4, 5, 6 Three-dimensional (3-D) conformal and intensity-modulated radiotherapy (IMRT) techniques have reduced normal tissue exposure, which allows for dose escalation to 74 Gy and improvements in local control.7, 8 Another promising technology that may facilitate radiation dose escalation beyond what can be achieved with 3-D conformal and IMRT is proton therapy.

The potential improvement with proton therapy is related to its finite range of penetration in tissue. Whereas, the advantage of 3-D conformal and IMRT techniques come from redistribution or “spreading” of the dose to nontargeted normal tissues, the advantage of proton therapy comes from reduction of the dose to nontargeted tissues. Several dosimetric studies have already shown more-precise targeting and reduced dose to normal tissues with protons over photon radiation in advanced lung cancer.9, 10, 11 Early clinical studies in stage I non–small-cell lung cancer (NSCLC) treated with proton therapy have reported lower rates of adverse effects compared with photon radiotherapy.12, 13, 14, 15 Currently, there are few clinical data that describe the outcomes of patients with locally advanced lung cancer with proton therapy.16, 17, 18, 19, 20, 21, 22, 23

Due to the development of new proton therapy centers and their anticipated increasing use in lung cancer, the present study set out to describe the University of Florida Proton Therapy Institute (UFPTI) early experience of treating patients who have regionally advanced lung cancer with proton therapy and provides a detailed description of our current treatment planning strategy.

Section snippets

Materials and Methods

From August 2008 through June 2010, at the UFPTI, 19 consecutive patients were evaluated for NSCLC and were treated with concurrent chemotherapy and proton therapy, either with (n = 7) or without (n = 12) induction chemotherapy. Pretreatment characteristics are listed in Table 1. These patients consented and were enrolled on either a prospective outcomes-tracking protocol or a stage III NSCLC treatment protocol. The present study was approved by the University of Florida Institutional Review

Results

The median follow-up for all patients was 15 months and for living patients was 16 months from proton therapy (range, 7-26 months). The median progression-free survival and median OS were 14 and 18 months, respectively. Seven patients are currently alive without evidence of disease, and 7 other patients died from disease progression, including 6 with distant metastases as their first site of relapse and 1 with local progression as their first site of relapse. Two patients developed metastatic

Discussion

The present study is one of the first to report the early outcomes of patients treated with concurrent chemotherapy and mediastinal proton therapy for lung cancer. The study defines the current method for proton treatment planning for lung cancer at UFPTI and demonstrates the feasibility of this treatment approach with acceptable toxicity and good local control.

Only 1 (6%) patient developed grade 3 or higher acute nonhematologic toxicities. This rate is lower than that reported by the

Conclusion

Proton therapy for stage III lung cancer is a promising treatment approach. The early experience reported here indicates that toxicities from the treatment are acceptable. Larger prospective studies are needed to confirm these findings, define the critical dosimetric points that may be unique to proton therapy, and investigate the potential of proton therapy to facilitate radiation dose escalation and/or combined modality therapy.

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

The authors thank Jessica Kirwan of the University of Florida Department of Radiation Oncology, for her help with editing the manuscript, and Keri Hopper and Katrina Sullivan for their care and follow-up with patients involved in this study.

References (31)

A. Jemal et al.
Cancer statistics, 2010
CA: Cancer J Clin
(2010)
A. Auperin et al.
Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer
J Clin Oncol
(2010)
K. Furuse et al.
Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer
J Clin Oncol
(1999)
M.V. Graham et al.
Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)
Int J Radiat Oncol Biol Phys
(1999)
F.R. Macbeth et al.
Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancerThe Medical Research Council Lung Cancer Working Party
Clin Oncol
(1996)
Z.C. Zhang et al.
Clinical and dosimetric risk factors of acute esophagitis in patients treated with 3-dimensional conformal radiotherapy for non-small-cell lung cancer
Am J Clin Oncol
(2010)
J.G. Rosenman et al.
High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial
Int J Radiat Oncol Biol Phys
(2002)
R. Rengan et al.
Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
(2004)
T. Auberger et al.
Photons or protons: precision radiotherapy of lung cancer
Strahlenther Onkol
(2007)
R.C. Nichols et al.
Proton radiation therapy offers reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage III non-small-cell lung cancer: a dosimetric study
Clin Lung Cancer
(2011)

J.Y. Chang et al.

Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in stage I or stage III non-small-cell lung cancer

Int J Radiat Oncol Biol Phys

(2006)

J.P. Grutters et al.

Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis

Radiother Oncol

(2010)

H. Nakayama et al.

Proton beam therapy for patients with medically inoperable stage I non-small-cell lung cancer at the University of Tsukuba

Int J Radiat Oncol Biol Phys

(2010)

H. Iwata et al.

High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer

Cancer

(2010)

D.A. Bush et al.

Hypofractionated proton beam radiotherapy for stage I lung cancer

Chest

(2004)

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There is no consensus about an ideal robust optimization (RO) strategy for proton therapy of targets with large intrafractional motion. We investigated the plan robustness of 3D and different 4D RO strategies.
For eight non-small cell lung cancer patients with clinical target volume (CTV) motion >5 mm, different RO approaches were investigated: 3DRO considering the average CT (AvgCT) with a target density override, 4DRO considering three/all 4DCT phases, and 4DRO considering the AvgCT and three/all 4DCT phases. Robustness against setup/range errors, interplay effects based on breathing and machine log file data for deliveries with/without rescanning, and interfractional anatomical changes were analyzed for target coverage and OAR sparing.
All nominal plans fulfilled the clinical requirements with individual CTV coverage differences <2pp; 4DRO without AvgCT generated the most conformal dose distributions. Robustness against setup/range errors was best for 4DRO with AvgCT (18% more passed error scenarios than 3DRO). Interplay effects caused fraction-wise median CTV coverage loss of 3pp and missed maximum dose constraints for heart and esophagus in 18% of scenarios. CTV coverage and OAR sparing fulfilled requirements in all cases when accumulating four interplay scenarios. Interfractional changes caused less target misses for RO with AvgCT compared to 4DRO without AvgCT (≤42%/33% vs. ≥56%/44% failed single/accumulated scenarios).
All RO strategies provided acceptable plans with equally low robustness against interplay effects demanding other mitigation than rescanning to ensure fraction-wise target coverage. 4DRO considering three phases and the AvgCT provided best compromise on planning effort and robustness.
High-Risk Non-Small Cell Lung Cancer Treated With Active Scanning Proton Beam Radiation Therapy and Immunotherapy
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Citation Excerpt :
Proton beam therapy (PBT) has shown the ability to reduce cardiopulmonary radiation exposure compared with IMRT in numerous dosimetric studies.7-12 Clinical results have been reported by multiple institutional series and have explored oncologic and toxicity outcomes of concurrent PBT chemoradiation for locally advanced NSCLC.13-17 However, the majority of publications to date have used passive scatter PBT as opposed to pencil beam scanning (PBS) systems, and to our knowledge none have reported treatment planning using Monte Carlo algorithms exclusively.
Non-small cell lung cancer (NSCLC) is a deadly malignancy that is frequently diagnosed in patients with significant medical comorbidities. When delivering local and regional therapy, an exceedingly narrow therapeutic window is encountered, which often precludes patients from receiving aggressive curative therapy. Radiation therapy advances including particle therapy have been employed in an effort to expand this therapeutic window. Here we report outcomes with the use of proton therapy with curative intent and immunotherapy to treat patients diagnosed with high-risk NSCLC.
Patients were determined to be high risk if they had severe underlying cardiopulmonary dysfunction, history of prior thoracic radiation therapy, and/or large volume or unfavorable location of disease (eg, bilateral hilar involvement, supraclavicular involvement). As such, patients were determined to be ineligible for conventional x-ray–based radiation therapy and were treated with pencil beam scanning proton beam therapy (PBS-PBT). Patients who demonstrated excess respiratory motion (ie, greater than 1 cm in any dimension noted on the 4-dimensional computed tomography simulation scan) were deemed to be ineligible for PBT. Toxicity was reported using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Overall survival and progression-free survival were calculated using the Kaplan-Meier method.
A total of 29 patients with high-risk NSCLC diagnoses were treated with PBS-PBT. The majority (55%) of patients were defined as high risk due to severe cardiopulmonary dysfunction. Most commonly, patients were treated definitively to a total dose of 6000 cGy (relative biological effectiveness) in 30 fractions with concurrent chemotherapy. Overall, there were a total of 6 acute grade 3 toxicities observed in our cohort. Acute high-grade toxicities included esophagitis (n = 4, 14%), dyspnea (n = 1, 3.5%), and cough (n = 1, 3.5%). No patients developed grade 4 or higher toxicity. The majority of patients went on to receive immunotherapy, and high-grade pneumonitis was rare. Two-year progression-free and overall survival was estimated to be 51% and 67%, respectively. COVID-19 was confirmed or suspected to be responsible for 2 patient deaths during the follow-up period.
Radical PBS-PBT treatment delivered in a cohort of patients with high-risk lung cancer with immunotherapy is feasible with careful multidisciplinary evaluation and rigorous follow-up.
Chemoradiation with Hypofractionated Proton Therapy in Stage II-III Non-Small Cell Lung Cancer: A Proton Collaborative Group Phase 2 Trial
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Patient eligibility criteria were the following: at least 18 years of age; a stage II or III diagnosis, per the American Joint Committee on Cancer 7th edition, of NSCLC within the prior 3 months and staged with a positron emission tomography (PET)/computed tomography (CT) scan and brain magnetic resonance imaging (MRI) (or CT when not eligible for MRI) with contrast; deemed medically or surgically inoperable; and Eastern Cooperative Oncology Group performance status of 0 or 1. The previously published phase 1 study used a 5 + 2 design wherein 5 patients were treated on each succeeding dose arm, unless a serious adverse event occurred, in which case an additional 2 patients were treated on that dose arm.10 The occurrence of 2 or more serious adverse events would result in the closure of that arm.
Hypofractionated radiation therapy has been safely implemented in the treatment of early-stage non-small cell lung cancer (NSCLC) but not locally advanced NSCLC owing to prohibitive toxicities with photon therapy. Proton therapy, however, may allow for safe delivery of hypofractionated radiation therapy. We sought to determine whether hypofractionated proton therapy with concurrent chemotherapy improves overall survival.
The Proton Collaborative Group conducted a phase 1/2 single-arm nonrandomized prospective multicenter trial from 2013 through 2018. We received consent from 32 patients, of whom 28 were eligible for on-study treatment. Patients had stage II or III unresectable NSCLC (based on the 7th edition of the American Joint Committee on Cancer's staging manual) and received hypofractionated proton therapy at 2.5 to 4 Gy per fraction to a total 60 Gy with concurrent platin-based doublet chemotherapy. The primary outcome was 1-year overall survival comparable to the 62% reported for the Radiation Therapy Oncology Group (RTOG) 9410 trial.
The trial closed early owing to slow accrual, in part, from a competing trial, RTOG 1308. Median patient age was 70 years (range, 50-86 years). Patients were predominantly male (n = 20), White (n = 23), and prior smokers (n = 27). Most had stage III NSCLC (n = 22), 50% of whom had adenocarcinoma. After a median follow-up of 31 months, the 1- and 3-year overall survival rates were 89% and 49%, respectively, and progression-free survival rates were 58% and 32%, respectively. No acute grade ≥3 esophagitis occurred. Only 14% developed a grade ≥3 radiation-related pulmonary toxic effect.
Hypofractionated proton therapy delivered at 2.5 to 3.53 Gy per fraction to a total 60 Gy with concurrent chemotherapy provides promising survival, and additional examination through larger studies may be warranted.
Hypofractionated Proton Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial from the University of Florida and Proton Collaborative Group
2020, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Radiation was delivered using passive-scatter, uniform-scanning, or pencil-beam techniques. Proton treatment planning followed those previously described.14,15 The dosimetric constraints are shown in Table E2 and were more conservative at a higher dose per fraction to the brachial plexus, spinal cord, and heart.
We report the safety data from the first multicenter phase 1 trial investigating the use of hypofractionated proton therapy with concurrent chemotherapy for patients with stage II or III non-small cell lung cancer.
From 2013 through 2018, patients with newly diagnosed stage II or III non-small cell lung cancer were enrolled in a multicenter phase 1 clinical trial evaluating concurrent chemotherapy with increasing dose-per-fraction proton therapy. This was a stepwise 5 + 2 dose-intensification protocol with the following dose arms: (1) 2.5 GyRBE per fraction to 60 GyRBE; (2) 3.0 GyRBE per fraction to 60 GyRBE; (3) 3.53 GyRBE per fraction to 60.01 GyRBE; and (4) 4.0 GyRBE per fraction to 60 GyRBE. A dose arm was considered tolerable if no radiation therapy–attributable severe adverse event (SAE) occurred within 90 days of treatment among 5 patients enrolled on the arm or if 1 SAE occurred among 7 patients enrolled. Dose constraints to the heart, brachial plexus, and spinal cord were more conservative at higher doses per fraction.
The study closed early because of slow accrual and competing enrollment in NRG 1308 before accrual was met, with no maximum tolerated dose identified. Eighteen patients were treated, including 5 patients on arms 1 and 2, 7 patients on arm 3, and 1 patient on arm 4. Two SAEs occurred among 7 patients treated at 3.53 GyRBE per fraction; however, per outside expert review, both were attributed to chemotherapy and unrelated to radiation therapy.
Hypofractionated proton therapy delivered at 2.5 to 3.53 GyRBE per fraction to a dose of 60 GyRBE with concurrent chemotherapy has an acceptable toxicity profile. Further exploration of this regimen is warranted on a phase 2 clinical trial.
Photons, protons or carbon ions for stage I non-small cell lung cancer – Results of the multicentric ROCOCO in silico study
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To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial.
For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions.
The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ.
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Original studyProton Therapy With Concurrent Chemotherapy for Non–Small-Cell Lung Cancer: Technique and Early Results

Abstract

Background

Materials and Methods

Results

Conclusion

Introduction

Section snippets

Materials and Methods

Results

Discussion

Conclusion

Disclosure

Acknowledgments

Cancer statistics, 2010

CA: Cancer J Clin

Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer

J Clin Oncol

Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer

J Clin Oncol

Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)

Int J Radiat Oncol Biol Phys

Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancerThe Medical Research Council Lung Cancer Working Party

Clin Oncol

Clinical and dosimetric risk factors of acute esophagitis in patients treated with 3-dimensional conformal radiotherapy for non-small-cell lung cancer

Am J Clin Oncol

High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial

Int J Radiat Oncol Biol Phys

Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer

Int J Radiat Oncol Biol Phys

Photons or protons: precision radiotherapy of lung cancer

Strahlenther Onkol

Proton radiation therapy offers reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage III non-small-cell lung cancer: a dosimetric study

Clin Lung Cancer

Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in stage I or stage III non-small-cell lung cancer

Int J Radiat Oncol Biol Phys

Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis

Radiother Oncol

Proton beam therapy for patients with medically inoperable stage I non-small-cell lung cancer at the University of Tsukuba

Int J Radiat Oncol Biol Phys

High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer

Cancer

Hypofractionated proton beam radiotherapy for stage I lung cancer

Chest

Original study
Proton Therapy With Concurrent Chemotherapy for Non–Small-Cell Lung Cancer: Technique and Early Results