RTOG® Highlights Biomarker-Driven Science

Radiation oncology studies continue to move the science forward.RTOG highlights

Eight RTOG®-sponsored studies were recently recognized at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting as significant to the field of radiation oncology.

Of these recognized studies, RTOG investigators participated in three oral abstract presentations, one of which reported long-term findings related to the primary aims of a phase-III brain cancer trial, as well as a session outlining how biomarker classification models can assist in classification of glioblastoma tumors. In addition, an RTOG abstract comparing treatments for noninvasive breast cancer received the additional distinction of being featured in a program highlighting cutting-edge science from the ASCO meeting. Underlying these three RTOG clinical studies is the attempt to further characterize specific subcategories of cancer types, especially on a molecular level, and according to the way they respond to various treatment modalities. Such efforts are aimed at enhancing opportunities for the personalization of cancer therapy.

Looking at the Genes

Results show chromosomal abnormality is a strong indicator for addressing oligodendroglioma.

RTOG 9402: Phase-III Intergroup Randomized Comparison of Radiation Alone vs. Pre-Radiation Chemotherapy for Pure and Mixed Anaplastic Oligodendrogliomas was undertaken to evaluate whether the addition of chemotherapy to radiation therapy (RT) would prolong overall survival for patients with malignant oligodendroglioma brain tumors in which both chromosomes 1p and 19q were deleted. The phase-III trial randomized 291 patients with pure and mixed anaplastic oligodendrogliomas to treatment with procarbazine, CCNU [lomustine], and vincristine (PCV) chemotherapy and RT or to treatment with RT alone. After a median follow-up RTOG 1of 11.3 years, the current analysis demonstrated that for the 126 patients with1p and 19q co-deletion, those in the PCV and RT arm had a much longer median survival time (MST) than those in the RT-alone arm (14.7 years versus 7.3 years, respectively).

Study investigators concluded that the presence of this chromosomal abnormality has definitive prognostic and predictive value for managing the treatment of adult patients with these relatively rare brain tumors.

Four other NCI-supported cooperative groups participated in the intergroup trial, which was led by J. Gregory Cairncross, MD, professor and head of the Department of Clinical Neurosciences at the University of Calgary in Alberta, Canada. According to Cairncross, “The profound association between improved outcome for patients who lack the 1p and 19q chromosomes and were treated with PCV chemotherapy and radiation therapy has significant implications for patients with anaplastic oligodendrogliomas. We now have evidence that the chromosomal structure of 1p and 19q co-deletion can be used as a marker to determine which patients will benefit from combined chemotherapy and radiation therapy.”

Walter J. Curran Jr., MD, FACR, RTOG group chair, executive director of the Winship Cancer Institute of Emory University in Atlanta, characterizes the trial results as “exciting and practicechanging.” He also notes that “the close collaboration of many groups and centers is required to reach this achievement.”

Modeling Class

Biomarker profiles added to the glioblastoma analysis model may result in more relevant prognostic classes.

RTOG 0525, a phase-III trial comparing RT plus conventional adjuvant temozolomide (TMZ) with RT plus dose-intensive TMZ in patients with newly diagnosed glioblastoma, included a secondary aim related to molecular analysis of tumor tissue. Additional molecular variables specifically related to glioblastoma treated with temozolomide were identified to update the former recursive partitioning analysis (RPA) model that relied on clinical variables to classify this tumor type into relevant prognostic categories. Profiling of key signaling molecules in tissues collected from 162 trial participants demonstrated a significant association of pAKT, c-met, and MGMT protein with adverse outcome on multivariate analysis.

Investigators combined the molecular biomarkers with such clinical variables as age, performance status, and extent of resection. They based their investigation on the former RPA model — developed by Curran — as well as the genetic variables used in the monocyte chemoattractant protein model that was more recently developed by Kenneth D. Aldape, MD, the RTOG 0525 co-chair of RTOG 2neuropathology and correlative biology. As a result, the investigators were able to generate a more discriminatory RTOG RPA model with more definitive prognostic groups ). The researchers concluded that, although further validation is needed, the RPA model holds promise for patients with glioblastoma who are treated with RT and TMZ.

“Since 1993 [when the original RPA model was developed], much has been learned about the molecular makeup of malignant gliomas. With this trial, we’ve taken a step toward updating the classification system to include molecular factors.” says Arnab Chakravarti, MD, chair of the College of Medicine at Ohio State University in Columbus, and an RTOG 0525 co-hair. “These data will be useful in prognostic classification of glioblastoma tumors, which could be used to direct patients to clinical trials aiming to develop targeted treatments based upon a tumor’s molecular profile.”

Optimal Observation

Important study of the role of radiation therapy in “good-risk” DCIS featured in the “Best of ASCO” meetings.

The increasingly common diagnosis of noninvasive ductal carcinoma in situ (DCIS), an early and curable form of breast cancer (approximately 20 percent of all breast cancer diagnoses), which has been the result of the growing acceptance of mammography as a screening tool, has heightened interest in optimizing treatment strategies. Building upon the experience of previous retrospective studies that suggest small DCIS lesions with a low-grade pathology classification, also known as “good risk” lesions, can be effectively treated with RT or managed with observation, RTOG 9804 investigators sought to evaluate the efficacy of observation alone in such a subset of patients diagnosed with DCIS.

From December 1999 to July 2006, 636 women with DCIS detected by mammography, with low or intermediate nuclear grades, tumor sizes of less than 2.5 centimeters, and surgical margins of greater than 3 millimeters were randomized to receive RT (50 Gray) or undergo observation. Participants were stratified by age, margin width, grade, primary tumor size, and tamoxifen use, which was allowed but not required for inclusion in the trial.

Initial data analysis from this phase-III trial demonstrated reduced rates of local failure associated with whole-breast radiation versus observation alone. Although the overall number of women experiencing a recurrence in either invasive or in situ breast cancer was small, the addition of RT showed a statistically significant reduction in such recurrence — 0.4 percent for the RT arm and 3.2 percent for the observation arm at five years. The rates of disease-free survival and overall survival were considered excellent. The rate of grade 1–2 toxicities was 76 percent in the RT arm versus 30 percent in the observation arm. However, higher grade toxicities occurred at similar rates (4 percent) in both arms.

“The low number of study participants who had a recurrence of their breast cancer strongly suggests that we have successfully identified criteria that distinguish good-risk DCIS lesions, which is important for evaluating treatment options for this patient population,” says RTOG Principal Investigator Beryl McCormick, MD, FACR, chief of External Beam Radiotherapy Service at Memorial Sloan-Kettering Cancer Center in New York. RTOG researchers plan continued follow-up with the trial participants to assess long-term outcomes.

The RTOG 9804 ASCO abstract presentation was selected to be included in three domestic and 15 international meetings, commemorating the best presentations of the ASCO annual meeting. Confirming the potential for RTOG 9804 findings to impact treatment decision making, Julia R. White, MD, chair of the RTOG Breast Cancer Working Group and director of breast radiation oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus, Ohio, states, “These results can serve as one more piece of information for clinicians to consider in counseling patients with DCIS to determine if radiation is an appropriate option.”

As these three studies and related research continues, the radiation oncology community will continue to gain new tools and techniques to improve the way disease is diagnosed and treated. For more information about RTOG, visit www.rtog.org.

By Nancy Fredericks, MBA, and Julie Catagnus, MPH, ELS
Nancy Fredericks, MBA (This email address is being protected from spambots. You need JavaScript enabled to view it.), is communications director, ACR Clinical Research Center. Julie Catagnus, MPH, ELS, is a freelance writer.

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