Proton Therapy for Lung Cancer at Loma Linda University Medical Center (LLUMC), Locally Advanced Disease
Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 13, 2009
Presenter: D. Bush Presenter's Affiliation: Loma Linda, USA Type of Session: Scientific
Despite aggressive treatment with chemoradiation, outcomes in patients with locally advanced NSCLC remain poor, with a median survival of approximately 18 months.
There have been several advancements that have been made over time that have improved outcomes compared with standard fractionated radiation therapy:
Numerous prior studies have demonstrated that adjuvant systemic chemotherapy improves metastasis free- and overall survival when combined with radiation (Dillman, NEJM 1990; Sause, Chest 2000).
There are also now numerous studies which have found that the concurrent use of radiation with chemotherapy improves both local control and overall survival (Curran, ASCO 2003).
There are some data to suggest that higher doses of radiation result in better local control, including data in early stage disease from LLUMC.
There are data to suggest that accelerated fractionation can result in improved outcomes based on the CHART study.
The combined use of all of the above techniques could be more effective, however, it could also be extremely toxic. This group investigated the feasibility of using proton therapy to reduce toxicity, allowing all of the above mentioned techniques to be used together.
The following study was a phase II study examining the use of proton therapy in the treatment on patients with locally advanced (IIIA/B) non-small cell lung cancer (NSCLC).
Materials and Methods
Patients with stage IIIA or IIIB disease were enrolled on this phase II trial.
Staging workup included CT, PET, Bone Scan, and MRI of the brain.
Carboplatin AUC 6
Paclitaxel 200 mg/m2
Concurrent Chemotherapy (weekly)
Carboplatin AUC 2
Paclitaxel 50 mg/m2
Clinical Target Volume (CTV): All patients had mediastinal and hilar nodes treated. Mediastinal nodes that were covered in all patients included: paratracheal, precarinal, AP window, and subcarinal. The CTV was treated to 46 CGE in 23 fractions.
Gross Tumor Volume (GTV): was defined as the lung tumor and any clinically or pathologically positive nodes. The GTV was treated to an additional 30 CGE. This was done by starting bid dosing during the last three weeks of treatment. Hence, the final tumor dose was 76 CGE given over the course of five weeks.
A total of 22 patients with stage IIIA/B NSCLC were enrolled, and the median follow up is 36 months.
Specifics regarding dose constraints were not presented, however, the authors did note that the lung, esophagus and cord doses were generally well within tolerance.
There were three case of clinically evident pneumonitis. One of the three patients required hospitalization for treatment but did recover.
There were no cases of esophagitis which required intervention, such as IV fluids or feeding tube placement. There were no treatment breaks related to esophagitis.
One patient had hematologic toxicity which resulted in a treatment break, however, the majority of hematological toxicity was grade 0-2. The authors looked at one patient’s spine dose and found that the dose to the spine was much lower with the proton planned used as compared to a 3D conformal plan which was run later. These findings suggest that there is decreased marrow dose with proton therapy.
The authors found that the survival appears to compare favorably with historical data on a Kaplan Meier curve. However, they emphasize that with only 22 patients it is not appropriate to draw meaningful conclusions regarding survival from this study.
Tumor motion remains a problem with proton therapy and gating, 4D CT and breath holding may be used in the future to limit tumor motion
Designing compensators can be complex and time consuming, however, there are several groups investigating ways to improve on compensator design.
Changes in tissue density affect proton range. Specifically, effusions and atelectasis have a greater effect on proton dosimetry compared with photon dosimetry and should be accounted for in the future.
There is a rationale for the use of proton therapy in the treatment of locally advanced NSCLC.
The results of this study suggest that proton therapy with higher doses using a bid technique with concurrent chemotherapy is tolerable.
Trials are ongoing at LLUMC.
As more centers develop proton facilities, it will become important to organize larger cooperative trials to study the use of proton therapy in locally advanced NSCLC in greater detail.
Patients with stage III NSCLC continue to have poor outcomes despite aggressive treatment. Improvements in treatment are essential to improve outcomes in this patient group. Decreasing radiation related toxicity with protons may allow the use of higher radiation doses or, potentially, the use of higher doses of chemotherapy with radiation. It is also possible that if there is less toxicity associated with chemoradiation, surgery may be added later with less toxicity. This study, along with prior studies by MD Anderson, suggest that the concurrent use of chemoradiation using protons results in less toxicity and may make combined modality treatment more tolerable.
In addition to the studies at LLUMC, ongoing studies at MD Anderson and Harvard are comparing the use of photon based therapy with proton therapy in the treatment of NSCLC with concurrent chemoradiation using higher doses.
As the authors have noted, there is great potential for proton therapy in advanced NSCLC and greater cooperation between the upcoming facilities is needed to explore how best to use protons in NSCLC
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