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Lung Cancer: Radiation Advances, New Agents, Featured in Thoracic Oncology Meeting

Carlson, Robert H.

doi: 10.1097/01.COT.0000422174.29285.3d

Although advances in radiation therapy, surgery, and chemotherapy have improved outcomes in lung cancer, response and survival rates remain low. Some encouraging news was heard last month at the Multidisciplinary Symposium in Thoracic Oncology.

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Cranial Irradiation Reduces Brain Mets

An updated analysis of the Radiation Therapy Oncology Group 0214 study confirmed the effectiveness of prophylactic cranial irradiation (PCI) for prevention of brain failures in patients with non-small-cell lung cancer (NSCLC), but showed no improvement in overall survival or disease-free survival.

“Brain metastases have a profound impact on patients with lung cancer in terms of quality of life,” said lead author Elizabeth M. Gore, MD, Professor of Radiation Oncology at Medical College of Wisconsin and Associate Director of Radiation Oncology at Zablocki VA Medical Center in Milwaukee. The Phase III comparison of PCI versus observation found that in 340 evaluable patients with Stage III locally advanced NSCLC without progression of disease after therapy, PCI decreased the five-year rate of brain metastasis, which was about 17 percent for patients receiving the irradiation vs. about 27 percent for the observation-only group.



Five-year survival rates, however, did not differ significantly: Overall survival was about 26 percent for the PCI group vs. about 25 percent for the observation group; and five-year disease-free survival was 18.5 percent vs. about 15 percent, respectively.

“Unfortunately, this study was very difficult to enroll patients on and ultimately did not accrue enough patients to answer the primary question” on overall survival, she said at a telephone news briefing, one of two held before the meeting.

Prophylactic cranial irradiation was delivered to reach 30 Gy in 15 fractions. Median follow-up time was 24.2 months for all patients and 58.6 months for living patients.

Of the patients for whom the treatment failed, 10 percent of patients on the PCI arm and 23 percent of those on the observation arm experienced failure in the brain initially. Brain metastases were the only component of first failure in 9.1 percent of the patients with PCI and 21.5 percent of patients without PCI.

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Crizotinib Effective in ALK-Positive NSCLC

Another study selected for discussion at a news briefing also included data on responses in the brain, as brain metastases were found to respond to the oral ALK inhibitor crizotinib.

In a subset of the global Phase II “PROFILE” 1005 study with crizotinib in advanced anaplastic lymphoma receptor tyrosine kinase (ALK)-positive NSCLC, patients with previously untreated brain metastases had a response rate in the brain of 22 percent and 67 percent had stable disease there, said lead author Gregory J. Riely, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center.

The primary finding of the trial was that crizotinib demonstrated a high response rate and progression-free survival, and a favorable tolerability profile. The study confirms that crizotinib is the standard of care for patients with ALK-positive lung cancer, he said.

Study patients had all had disease progression after one or more courses of chemotherapy for recurrent/advanced/metastatic disease. Among 260 patients evaluable for tumor response, after a median treatment duration of 25 weeks, the overall response rate was 60 percent (2% had complete responses, and 58% had partial responses); the median duration of response was 43 weeks, and median progression-free survival was 8.0 months.

Among 439 patients evaluable for safety, the most frequent treatment-related adverse events were visual effects (50%), nausea (46%), vomiting (39%), and diarrhea (35%), mostly grades 1–2.

“The activity in brain metastases is especially encouraging as there has been concern that crizotinib might not be active in the brain,” said the moderator of the news briefing, Heather Wakelee, MD, Assistant Professor at Stanford Clinical Cancer Center.

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Bavituximab Well Tolerated, May Extend Survival

In a double-blind, randomized, placebo-controlled, multicenter Phase II study in previously treated patients with Stages IIIB and IV non-squamous NSCLC, bavituximab given at 1 or 3 mg/kg in combination with docetaxel was well tolerated and demonstrated a trend toward superiority in overall and progression-free survival compared with docetaxel-placebo.

Although median overall survival has not yet been reached in either bavituximab-containing cohort, “there is a clear and persistent separation of the survival curves warranting further development of bavituximab,” said lead author David Gerber, MD, Assistant Professor of Internal Medicine at Simmons Cancer Center of the University of Texas Southwestern Medical Center.

He noted that bavituximab has a novel mechanism of action, localizing selectively to tumor vasculature causing vascular shutdown in tumors and reactivating innate and adaptive tumor immunity.

Among 117 evaluable patients, the overall response rates for patients receiving docetaxel with bavituximab at 1 mg/kg and docetaxel with bavituximab at 3 mg/kg bavituximab were about 15 and 18 percent, respectively, versus about eight percent for the docetaxel-placebo arm.

Median progression-free survival times were 4.2 and 4.5 months for the two bavituximab arms, respectively, and 3.0 months for the control arm. And median overall survival was 11.1 months for patients receiving the 1 mg/kg dose, 13.1 months for the 3 mg/kg dose, and 5.6 months for the control group.

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Pemetrexed: Survival Not Superior vs. Paclitaxel

In another study reported at a news briefing, results from the randomized, open-label, Phase III “Point-Break” trial showed that the use of pemetrexed instead of paclitaxel in treatment of advanced-stage non-squamous NSCLC (NS-NSCLC) did not improve survival rates.

The regimen of pemetrexed plus carboplatin-bevacizumab followed by maintenance with pemetrexed-bevacizumab was not superior in overall survival compared with the standard paclitaxel-carboplatin-bevacizumab regimen followed by maintenance bevacizumab in patients with Stages IIIb or IV NS-NSCLC.

“The fact that there was no improvement in survival with the experimental regimen was disappointing, but these findings are important as we continue to navigate ways to improve survival for this devastating disease,” said the lead author, Jyoti Patel, MD, Associate Professor of Medicine-Hematology/Oncology at the Feinberg School of Medicine of Northwestern University.

Patients included had no prior systemic therapy, but those with previously treated brain metastases were allowed to be enrolled. They were randomly assigned to receive the pemetrexed regimen (472 patients) or the paclitaxel regimen (467) every three weeks for up to four cycles. Those continuing without progressive disease received maintenance.

Median overall survival was 12.6 months for the pemetrexed arm vs. 13.4 months for the paclitaxel arm; median progression-free survival was 6.0 vs. 5.6 months, respectively; and the overall response rates were 34.1 vs. 33.0 percent.

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Different Toxicity Profile

She said that one reason pemetrexed has garnered attention is because its toxicity profile differs from that of paclitaxel: While both were well tolerated in the trial, the pemetrexed arm had significantly more study drug-related Grade 3/4 anemia—14.5 vs. 2.7 percent; thrombocytopenia, 23.3 vs. 5.6 percent; and fatigue, 10.9 vs. 5.0 percent. The paclitaxel arm of the study had significantly more grade 3/4 neutropenia—40.6 vs. 25.8 percent; febrile neutropenia, 4.1 vs. 1.4 percent; sensory neuropathy, 4.1 vs. 0 percent; and complete alopecia, 21.4 vs. 1.1 percent.

Study drug-related discontinuations due to serious side effects were 2.7 percent for pemetrexed vs. 3.6 percent for paclitaxel; adverse events of 10.4 vs. 9.0 percent, respectively; and study drug-related deaths due to adverse events of 1.8 vs. 2.3 percent.

Wakelee commented that while the much anticipated results from that study were disappointing, the ongoing ECOG E5508 trial will answer some of the remaining questions about maintenance therapy with the backbone regimen of paclitaxel-carboplatin-bevacizumab.

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Marital Status May Be Surrogate for Supportive Care in NSCLC

A study from the University of Maryland's Greenebaum Cancer Center showed that married men with NSCLC had a three-year overall survival rate of 25 percent, vs. only three percent for single men. In addition, married patients had triple the rate of overall survival at three years compared with single patients—33 vs. 11 percent.

“These results confirm the positive impact of spousal support on patient survival,” said lead author Elizabeth Nichols, MD, a resident in the Department of Radiation Oncology. The hypothesis, she said, is that caregivers provide not only daily care for patients, but also logistical support to help manage the treatment plan, compliance, and more accurate reporting of patient symptoms.

The results are consistent with similar studies of other site-specific cancers, including head and neck and prostate cancers, she noted.

In the new study, conducted between 2000 and 2010, a total of 168 patients with Stage III NSCLC were treated with curative intent, with a median radiation dose of 66.6Gy; 89 percent of patients received concurrent chemotherapy, mainly carboplatin/paclitaxel, followed by systemic or consolidative chemotherapy.

For all 168 patients, with a median follow-up of 1.3 years, median survival was 13 months, with three- and five-year estimates of overall survival rates at 21 and 12 percent, respectively.

Marital status made a huge difference: overall survival for married patients with Stage III NSCLC was 33 percent at three years, vs. 11 percent for single patients. And at five years, overall survival for married patients was 23 percent, with none of the single patients surviving.

Gender and marital status stacked up against single men, with a three-year overall survival rate of only three percent, compared with 46 percent for married women. Single females and married men had three-year survival rates of 25 percent. When stratified by race, married white patients had a three-year survival rate of 40 percent, followed by 26 percent for married black patients and 11 percent for single patients of either race.

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Longer Survival for Foreign-Born Hispanics

Another study highlighted in a news briefing showed that foreign-born Hispanics with NSCLC have a decreased risk of disease-specific mortality compared with U.S.-born Hispanics and non-Hispanic white patients, despite lower income, education, and access to medical care among the foreign-born Hispanics.

Social factors may help explain this survival advantage, said the lead author, Manali Patel, MD, a post-doctoral fellow in the Hematology/Oncology Department at Stanford University. “Social and neighborhood factors, in addition to a patient being foreign-born, appear to be positive contributing factors to incidence and survival that need further study.”

Analysis of 14,829 Hispanic NSCLC patient records in the California Cancer Registry database from 1988 to 2008 showed that foreign-born Hispanics had a 13 percent decreased risk for disease-specific death compared with that for U.S.-born Hispanic patients.

The data also indicate that foreign-born Hispanics who lived in the least U.S.-assimilated neighborhoods had the better overall survival, she said. “Enclave plays an important, perhaps protective role for foreign-born Hispanics with non-small cell lung cancer.”

Enclave may serve as a proxy for social capital, she explained. “The study confirms the ‘Hispanic paradox’ of improved survival rates for Hispanic/Latino non-small cell lung cancer patients compared with non-Hispanic white patients, despite lower socioeconomic status.”

© 2012 Lippincott Williams & Wilkins, Inc.
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