Exploring proton therapy's effectiveness on the most common form of lung cancer

Proton therapy can deliver a higher radiation dose to lung tumors and a lower dose to healthy tissue compared to standard radiation therapy. However, the effectiveness of proton therapy has not yet been documented in clinical trials for patients with non–small cell lung cancer (NSCLC), the most common type of lung cancer. Two ongoing trials of proton therapy aim to demonstrate its effectiveness and may change the standard of care for NSCLC.

Since 2004, the standard treatment for locally advanced (stage II or III), inoperable NSCLC has been concurrent platinum-based chemotherapy and photon-based intensity-modulated radiation therapy (IMRT), usually with a total radiation dose of at least 60 Gy. However, because photons are transmitted via high-energy waves that pass through the tumor, adjacent healthy tissues often are affected, exposing patients to cardiac and pulmonary toxicity.

The radiation dose to healthy lung and heart tissue in NSCLC patients can be reduced by using proton therapy. Unlike photon therapy, proton therapy uses high-energy particles to target tumors; the particles stop at the tumor site and release most of their energy, sparing healthy tissues.

“NSCLC often occurs in smokers who have poor cardiopulmonary reserve, so reducing the total dose of radiation to the lung tissue and heart is critical,” said Quynh-Nhu Nguyen, M.D., an associate professor of Radiation Oncology at MD Anderson.

Nguyen, along with Zhongxing Liao, M.D., professor of Radiation Oncology, and other colleagues, recently conducted a retrospective study of 134 patients with inoperable stage II or III NSCLC treated with concurrent proton therapy and chemotherapy at MD Anderson. Patients with stage II NSCLC had a median overall survival of 40.4 months, and those with stage III NSCLC had a median overall survival of 30.4 months. Only six of the 134 patients experienced grade 3 toxic effects, and one patient experienced a grade 4 toxic effect.

These promising findings illustrated the need for prospective clinical trials to compare photon and proton therapies head to head. “Results from randomized trials are needed to show that proton therapy is effective for patients with NSCLC,” Nguyen said. Two such trials — one comparing photon therapy to proton therapy and another evaluating the effectiveness of a simultaneous integrated boost to increase the treatment dose in both photon and proton therapy — are underway at MD Anderson.

Randomized head-to-head trial

Nguyen and Liao currently are enrolling previously untreated patients with inoperable stage II or III NSCLC in a randomized phase III trial (RTOG 1308) comparing the overall survival durations of patients treated with chemotherapy and concurrent photon therapy to those of patients treated with chemotherapy and concurrent proton therapy.

Nguyen is the institutional principal investigator and Liao is the national principal investigator for this multicenter trial.

Patients in the trial are randomly assigned to receive either IMRT or passively scattered proton therapy at a total dose of 70 Gy given in daily fractions five days per week for seven weeks (35 fractions); the total dose can be reduced to 60 Gy if treatment planning for the higher dose level does not meet the dose constraints for healthy tissue.

“This could be a practice-changing trial,” Liao said. “Our results may provide level I evidence of the benefits of proton therapy and shape clinical guidelines.”

Simultaneous integrated boost

Liao is also the principal investigator for a nonrandomized phase I/II trial (2011-1058) in which patients with stage II or III NSCLC receive chemotherapy with IMRT or scanning beam intensity modulated proton therapy (IMPT). Unlike the randomized phase III trial, both the photon and proton radiation therapy in this trial will include a simultaneous integrated boost to deliver more radiation to the tumor than to the surrounding tissue.

“Traditionally, the radiation treatment volume for both photon and proton therapy includes a margin of 1.3–1.5 cm around the tumor, which is a huge amount of potentially healthy lung tissue,” Liao said. “Our goal is to use the simultaneous integrated boost to maintain the standard dose to the margin and maximize the dose to the tumor.”

Previous efforts to increase the dose to the tumor by adding extra treatment fractions have led to increased toxicity to nearby tissue.

In IMPT, the simultaneous integrated boost is delivered using pencil beam scanning. The radiation oncologist “paints” protons in multiple layers in both the tumor and the margin. Each layer of protons delivered to the tumor has a higher dose than that delivered to the margin. For IMRT, the simultaneous integrated boost technique is more like film exposure, with the tumor being exposed to photon radiation longer than the margin is.

In the trial, IMRT and IMPT with simultaneous integrated boost are delivered five days per week for 7 weeks (30 fractions). The phase I portion of the trial determined the total doses for the phase II portion: 60 Gy for healthy tissue in the tumor margin and up to 78 Gy for tumor tissue.

The phase II portion of the trial is still accruing patients. The goals of this portion are to assess local tumor control and toxic effects in patients treated with the new simultaneous integrated boost and to determine whether simultaneous integrated boost with IMPT or IMRT more effectively controls the tumor.

Candidates for this trial include patients with stage II or III NSCLC whose tumors are difficult to excise (such as pulmonary sulcus tumors), those for whom induction chemotherapy failed, or those who underwent surgery but experienced tumor recurrence.

This story originally appeared in the June issue of OncoLog.