Treating Lung Cancer With Adaptive Radiotherapy

Trial explores adaptive radiotherapy's effect on locally advanced non-small-cell lung cancer.treating lung cancer

The recently launched RTOG 1106/ACRIN 6697 clinical trial is evaluating if, during the course of radiotherapy (RT) treatment, information gained from an FDG-PET/CT scan can facilitate individualized adaptive therapy in patients with inoperable stage-III non-small-cell lung cancer (NSCLC).

"For more than three decades, RT for NSCLC has been based on a one-size-fits-all theory that the tumor never changes with patients receiving a uniform dose for six to eight weeks, with no change in treatment plans or fields, regardless of patient size, tumor size, or location of the tumor," states University of Michigan researcher and the study's Principal Investigator, Feng-Min "Spring" Kong, M.D., Ph.D.

Kong and her colleagues began an adaptive RT treatment regimen in a single arm phase-II study in 2008 and treated approximately 24 patients — witnessing significant reduction in tumor volume or activity each week during RT (70 percent by PET and 40 percent by CT). Kong's team was able to deliver a higher RT dose to the resistant active tumor while maintaining the same level of toxicity to normal tissue, with promising results in tumor control and survival by CT at four weeks.

Homing In on Cancer Treatment

The primary objective of RTOG 1106/ACRIN 6697 is to determine whether tumor dose can be escalated to improve the "freedom from local-regional progression" rate after two years of treatment using FDG-PET/CT scans to individualize adaptive RT plans. All participants will undergo a baseline FDG-PET/CT scan as part of their treatment planning. Participants in both arms will receive RT once a day, five days a week, for six weeks. After four weeks of treatment, participants in both arms will undergo a second FDG-PET/CT scan. Participants in the experimental arm will have the RT planning modified to provide as high a dose as possible to the residual metabolically active tumor while keeping doses to normal lung tissue constant (mean lung dose of 20 Gy) and doses to other adjacent organs within safe limits, whereas participants in the control arm will complete the initial treatment as planned.

Kong says, "We will also individualize treatment to every tumor within the same participant, such as a primary tumor and smaller lymph nodes. We hope to achieve a 20-percent increase in local control with an increase in survival as well." The trial will also compare the rates of severe radiation-induced lung toxicity and other adverse events in both arms. "I find it satisfying to educate patients and family members about how modern technology, including 3-D-conformal and image-guided RT methods, now allows very precise delivery of a high dose to the tumor while not exceeding safe levels to normal tissue," she adds.

"We will also individualize treatment to every tumor within the same participant, such as a primary tumor and smaller lymph nodes. We hope to achieve a 20-percent increase in local control with an increase in survival as well." — Feng-Min Kong, M.D., Ph.D.

Sites conducting this trial are required to have credentials in image-guided RT, 4-D RT, motion control, adaptive RT planning, image registration, and tumor contouring. "This trial is revolutionary for RTOG, which has traditionally used 2-D and 3-D RT techniques in its clinical trials," notes Kong. She expects investigators to find participating in this research rewarding. "For a physician, it's satisfying to see a patient's tumor shrinking during treatment and to have the option of adjusting the dose toward a more precise target," she adds. "Providing feedback to the study participant about the PET-confirmed tumor volume reduction is also inspiring to the participant."

The ultimate goal according to Kong is to validate adaptive RT planning in a phase-III multicenter study. However, she anticipates that clinicians who hope to help this patient population could put adaptive RT planning into practice even before the study is complete. As Kong clarifies, "The practice of using adaptive RT planning to shrink large tumors is already happening in some centers. However, testing the expanded use of adaptive radiotherapy is a larger, multicenter trial is necessary to ensure that it will benefit a majority of patients."

Imaging Aspects

The trial also measures how effective imaging is in predicting disease location and in identifying where to focus efforts for local control of the tumor. Co-principal investigator of the trial's imaging component, Daniel Pryma, M.D., from the Hospital of the University of Pennsylvania in Philadelphia, elaborates, "We want to know if treating only the area of active disease as shown in the imaging scans will effectively kill all remaining tumor cells."

The trial's imaging aim is to determine if FDG-PET/CT scans — at baseline and then at four weeks during treatment — will show how well a patient's cancer responds to treatment based on various imaging parameters such as tumor intensity and size. "The mid-treatment scan is significant," clarifies Pryma, "because it can identify changes in tumor function before those changes appear anatomically and when treatment plans can be adjusted and personalized."

"The idea behind this research — personalizing care for patients with NSCLC and not subjecting them to futile treatment — is powerful." — Daniel Pryma, M.D.

In a subset of the study's participants, 18F-fluoromisonidazole (FMISO)-PET/CT will be conducted at baseline to identify the presence of hypoxia, which inhibits the production of oxygen-free radicals that cause radiation to damage DNA and to kill tumor cells. "It has been a long-standing idea to use imaging to identify hypoxic areas and target those areas with higher levels of radiation and to use that information to predict which tumors won't respond to radiation," says Pryma. "This trial is ideal to test this notion because some participants will receive higher radiation levels, while others will receive standard levels. The important question is whether areas of hypoxia identified at baseline will contain residual disease at mid-treatment stage, since it's the slowest to die off."

The short time intervals between scanning and adjusting treatment require close collaboration between radiation oncology and nuclear medicine site investigators. "We need to ensure that the scans are timed in such a way that they can be used for treatment planning," says Pryma. "Imaging investigators expend significant effort to differentiate changes due to disease from those due to treatment." Participating sites also will need to qualify their PET/CT scanner for participation in the study.

Kong, who is excited about the opportunity to work closely with nuclear medicine physicians to move this innovative trial forward, states, "this is the first time that PET-based adaptive RT treatment is being done with any cancer anywhere in a multicenter setting. I hope the results will enable future individualized and adaptive lung cancer treatment." Pryma agrees: "The idea behind this research — personalizing care for patients with NSCLC and not subjecting them to futile treatment — is powerful," he says. "Most centers preparing to conduct the trial have successfully established necessary communication between radiation oncology and nuclear medicine departments."

By Nancy Fredericks, M.B.A., and Julie Catagnus, M.P.H., E.L.S.
Nancy Fredericks, M.B.A. (This email address is being protected from spambots. You need JavaScript enabled to view it.), is communications director, ACR Clinical Research Center.
Julie Catagnus, M.S.W., E.L.S., is a freelance writer.

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