Module 5: Clinical Outcomes by Disease Site - The Use of Proton Therapy in the Treatment of Cancers of the Lung

Eric Shinohara MD, MSCI
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

Lung-cancer is the most common malignancy seen in men and women in the United States. Lung cancer is responsible for more cancer deaths in the United States than any other cancer and an estimated 161,840 people will die of lung cancer in 2008. This is higher than the mortality associated with prostate, breast, rectal and pancreatic cancer combined. This number averages to one patient dying every three minutes of lung cancer. The 5 year overall survival for patients with lung cancer is estimated to be 15%. A significant percentage of lung cancer patients are treated with radiation therapy at some point during the course of their disease. Currently, the local control is less than 50% using current radiation techniques and changes are needed to improve on this number. Since many of these patients have poor lung function due to years of smoking tobacco, preservation of functioning lung tissue is paramount. The destruction of lung tissue by conventional radiation techniques limits the delivery of potentially curative doses of radiation therapy.

Proton therapy may improve the therapeutic ratio in lung cancer, which may allow dose escalation. The spread out Bragg peak seen with protons may allow dose escalation while sparing normal tissues due to decreased exit dose compared with photons. Proton therapy can be delivered in two ways, either with a passive scatter technique or a spot scanning beam, which allows the use of Intensity Modulated Proton Therapy (IMPT). However, organ motion presents a major problem in the treatment of lung cancer with proton therapy. There are data that demonstrate improvements in normal tissue sparing when IMRT and 3D conformal radiation therapy plans are compared. Prior studies have found a 10-20% improvement in V5 and V10 dose in both stage I and stage III lung cancers when they were planned with Intensity Modulated Radiation Therapy (IMRT) versus 3D conformal radiation therapy. Studies have also shown that when passive scatter proton plans were compared with IMRT plans there was even greater normal tissue sparing even when a higher total tumor dose was used. IMRT plans have also been compared with IMPT plans in patients with stage III non-small cell lung cancer. Results demonstrated a 13-22% improvement in V5 and V10 dose with the IMPT plans compared with the IMRT plans. IMPT plans have also been compared with passive scatter proton plans and results demonstrated a 5-10% improvement in V5 and V10 dose with IMPT versus passive scatter.  There are also concerns regarding changes in the patient’s anatomy during treatment due to weight loss as well as changes to the tumor during proton therapy.  Changes in the size and density of the tumor can cause a greater dose to be delivered to normal tissues distal to the tumor.  A recent study performed at M.D. Anderson suggests that if a CTV based on a 4D CT to account for organ motion is used at the start of treatment, for the majority of patients, the initial CTV will be adequate (Hui Z. et al., Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1385-95.).  However, in a select number of patients replanning will be needed and studies examining anatomical changes and proton therapy are ongoing.

Early results using proton therapy or a combination of proton therapy with photon based therapy have been promising.  A study from Loma Linda examined outcomes in patients with clinical stage I to IIIA non-small cell lung cancer treated to a total dose of 73.8 CGE (Bush DA et al., Chest 116 (1999), pp. 1313–1319.).  Rates of toxicity and outcomes (local disease control of 87% at 2 years) appeared to compare favorably with photon based therapy.  A study from Japan examined proton therapy in patients with stage I-IV and recurrent disease (Y. Shioyama et al., Int J Radiat Oncol Biol Phys 56 (2003), pp. 7–13.).  Median fraction size was 3.0 Gy and median dose was 76 Gy.  The five year overall survival rate was 29% for all patients.  Patients with Stage IA and IB disease had 5 year overall survivals of 70% and 16%, respectively.  Toxicity was limited, and these results suggested that hypofractionated proton therapy was safe and appeared to be effective in patients with very early stage lung cancer.    

Loma Linda has also run a Phase II study examining the use of proton therapy in stage I non-small cell lung cancer (D.A. Bush et al., Chest 126 (2004), pp. 1198–1203.).  Patients with stage I non-small cell lung cancer who were medically inoperable or who refused surgery were included in this study.  Patients were treated with doses from 51-60 CGE in 10 fractions.  Three year local control and disease free survival rates were 74% and 72%, respectively.  There was minimal toxicity in this study and it suggested that hypofractionated proton therapy was safe and effective in stage I lung cancer.      

Based on past studies, with XRT alone, survival in non-small cell lung cancer is about 10 months, sequential chemoradiation results in a median survival of 13 months and concurrent chemoradiation therapy is 17 months.  Some studies have shown that dose escalation to 74 Gy with concurrent chemotherapy can result in median survivals of up to 24 months. M.D. Anderson has run a study investigating whether proton therapy could reduce toxicity when used concurrently with chemotherapy compared with either 3D conformal radiation or IMRT, despite going to higher doses.  In this study, protons were delivered using a synchrotron delivering protons of between 160-225 MeV.  Tumor motion was accounted for using an ITV derived from 4D CT simulation.  Patients were treated with 2 CGE fractions with a concurrent platinum-based doublet.  All patients had inoperable lung cancer.  Patients were enrolled from May 2006 to June of 2008 and were compared to historical controls treated with 3D conformal radiation and IMRT.  Patients in each group made up approximately one third of the study population.  Patients treated with 3D conformal or IMRT received a median dose of 63 Gy where as patients treated with protons received a median dose of 74 CGE.  Grade 3 esophagitis (requiring placement of a PEG tube) was seen in 16%, 40%, and 6% of patients treated with 3D conformal, IMRT, and protons, respectively.  Grade 3 pneumonitis (some of which was lethal) was seen in 32%, 9% and 0% of patients treated with 3D conformal, IMRT, and protons, respectively.  Results from this study suggest that it is possible to go to higher doses with proton therapy with concurrent chemotherapy without increasing esophageal or pulmonary toxicities.  This has spawned a randomized trial of protons versus photons in the treatment of stage II/III non-small cell lung cancer.  Patients are to be randomized to either 74 Gy of IMRT or 74 CGE of protons both delivered in 2 Gy/CGE fractions.  However, if the dose constraints can not be met, the patient on study will not be treated.  Randomization is to be adapted using a Bayesian analysis, where based on prior results the randomization will change to favor the better arm.  The primary outcome will be local control and grade three or greater pneumonitis and esophagitis.  The study is to be run jointly by MD Anderson and Harvard.  

Links to reviews of recent abstracts and presentations regarding proton therapy for lung cancer:

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