Just In... Meeting News
Key news updates from recent oncology and hematology meetings.
Tuesday, September 30, 2014
BY SARAH DIGIULIO
SAN FRANCISCO—Survivors of non-small-cell lung cancer who had never smoked or who were former smokers at the time of diagnosis were found to have a lower risk of developing secondary primary lung cancer compared with patients who were current smokers when diagnosed, according to new data presented here at the American Society for Radiation Oncology Annual Meeting (Abstract 170).
Previous research has linked tobacco use to an increased risk of lung cancer in such patients, but this is the first large study using a rigorous statistical analysis accounting for other variables that may affect outcomes, the researchers noted.
“We showed for the first time that cumulative smoking history was the primary driver of secondary lung cancer among survivors of non-small-cell lung cancer,” the study’s lead author, John Michael Boyle, MD, a radiation oncology resident at Duke Cancer Institute, said during a news briefing at the meeting. “And interestingly we found that never-smokers have a very low risk of second primary lung cancer—and we also found that smoking history exposes patients with lung cancer to a greater risk of death.”
JOHN MICHAEL BOYLE, MD
The study included 1,484 patients (372 current smokers, 1,014 former smokers, and 98 never smokers) who had undergone surgery—with or without chemotherapy or radiation therapy—for stages I-IIIA non-small-cell lung cancer at Duke University Medical Center between 1995 and 2008. The data showed that five years after initial diagnosis, current smokers were more likely to develop a second primary lung cancer than the other patients in the study.
The five-year incidence of a second primary lung cancer was: 13 percent for current smokers; seven percent for former smokers; and zero percent for patients who had never smoked.
In this study, second primary lung cancer was defined as a new lung cancer unrelated to the initial tumor based on histology and location in the lung.
Other findings from the data were:
One patient who had never smoked developed a second primary lung cancer seven years after surgery for the first cancer;
When restricting the analysis to continuing and former smokers with pack-years as a continuous variable, the risk of second primary lung cancer increased with the number of years of tobacco exposure—an eight percent increased risk per 10 pack-years;
For all patients there was no difference in local control or distant metastases based on smoking status; and
All former smokers, regardless of when they quit, as well as never smokers, had increased survival compared with current smokers.
“Smoking cessation efforts are an important part of care for our lung cancer patients,” Boyle noted. “This study adds more evidence that smoking has subsequent implications—and the results provide a powerful tool as we counsel our patients.”
In an email after the meeting, Boyle said that going ahead it will also be important to understand how smoking behavior following a lung cancer diagnosis affects outcomes—including the incidence of second cancers and overall survival. “The challenge is that you would likely need a very large study population. And while smoking history is often detailed at initial diagnosis and consultation, history (i.e., smoking status, packs per day, etc.) is not often included in follow-up documentation following treatment.”
Implications for Radiation Oncologists
Also commenting via email after the meeting, the session’s moderator, Benjamin Movsas, MD, FASTRO, Chair of the Radiation Oncology Department at Henry Ford Health System, said: “This is one of the largest analyses of this particular issue. Radiation oncologists are treating more and more patients with lung cancer, particularly early-stage lung cancers, with stereotactic body radiation therapy, which has led to promising long-term tumor control and survival rates. Radiation oncologists thus need to be fully aware of these important findings in order to counsel and refer patients for smoking cessation and properly follow their patients in this regard.”
BENJAMIN MOVSAS, MD, FASTRO
Movsas, who was also Vice-Chair of the Annual Meeting Scientific Committee, said that next step of this research will be determining the most effective strategies to help these patients quit smoking—“which can be very challenging.”
Sunday, September 28, 2014
BY ED SUSMAN
SAN FRANCISCO -- Oh, honey… You just don’t have what it takes--at least when it comes to reducing radiation-induced esophagitis, researchers reported here at the American Society for Radiation Oncology Annual Meeting.
Compared with best supportive care, neither Manuka honey liquid nor Manuka honey lozenges provided relief for treatment-related esophagitis other than what doctors now often use to control that pain at individual centers, said Lawrence Berk, MD, PhD, Chief of Radiation Oncology at the University of South Florida.
“The problem with doing studies with natural products is that they are natural products and there is no uniformity of the product. Each batch of these products may be different, and there are an infinite number of products, which is particularly true with honey.”
The researchers were hoping to give doctors guidance on how to treat esophagitis – an area where no standard of care exists: “We chose Manuka honey—honey derived from the Manuka tree in New Zealand--because it has been studied; it is a medical honey,” he explained. “It has been used for wound healing. It is regulated by an association that both tests it and oversees its production. They test for its antibacterial activity, not its inflammatory ability. It is commercially available.”
Berk noted that small studies have been published about the use of various honey products in head and neck cancer patients, showing mixed results from Egypt, Iran, Malaysia, and Nepal. Further scrutiny of these trials might find a product that could prove itself in another trial, he said.
For the study he reported, the researchers enrolled patients who were receiving once-daily concurrent chemotherapy – presumed to be platinum based – plus radiation therapy with a total dose of 60 Gy for treatment of lung cancer. The patients were assigned to receive standard supportive care; 100 cc of liquid Manuka honey four times a day during the concurrent chemotherapy and radiation treatments; or10 cc equivalent Manuka honey in lozenge form four times a day during radiation and chemotherapy treatments.
The honey was donated to the trial by one of the Manuka honey distributors in New Zealand, Berk noted.
Patients kept a pain diary that helped determine swallowing pain as assessed on an 11-point scale at four weeks of radiation therapy – the primary endpoint of the study. That endpoint, though, he noted, was entirely arbitrary, and the researchers also tested a wide variety of secondary endpoints.
Standard of Care Is Individualized
Asked for his perspective for this article, Kenneth Roberts, MD, Professor of Therapeutic Radiology at Yale School of Medicine, said, “Standard of care for managing esophagitis is all individualized. We use a combination of local anesthetic agents, viscous lidocaine-containing mixtures, narcotic pain medicines, agents that reduce acid reflux, and agents that also coat the mucosa.
“But one of the major things we can do to reduce the risk of esophagitis is how we plan out the radiotherapy and being attentive to how much radiation goes to that organ, and then getting to patients to use these therapies to make patients more comfortable. If this particular type of honey had panned out, we would have had a very simple, non-toxic thing to use,” he said.
Berk explained that although the trial had been foreseen as relatively straightforward, the project became subject to almost all the ills that can befall mankind, including an earthquake that shut down production of the product. The trial opened to accrual on February 28, 2012, and accrual was reached by October 15, 2013, despite being suspended twice.
A total of 53 patients were assigned to standard of care, 53 to receive liquid honey, and 54 to lozenge honey. Eventually, the researchers were able to evaluate the effects in 40 patients receiving best supportive care; 41 receiving liquid honey and 38 receiving lozenge honey.
The outcome: There were no differences between standard of care and liquid honey in numerical pain score, nor between the effects of lozenge honey and standard of care at four weeks.
In reviewing the multiple prespecified secondary endpoints, the researchers were able to observe one positive finding: Patients who were taking the lozenge reported a benefit in their numerical pain scores at 12 weeks.
“In the Radiation Trial Oncology Group, we are looking for ways to ameliorate the side effects of the treatments so we could reduce the dose of radiation,” Berk said. “One area that is underexplored is radiation esophagitis. The other area of interest was natural products -- the things that patients are interested in but generally aren’t commonly investigated within the cooperative group trials.”
He said that the trial might have had a different outcome if a different product had been selected to test. “We were dealing with natural products and I picked one, and it might have been the wrong product. Perhaps the product I selected did not have the appropriate active compound.”
Roberts added that natural products are very difficult to study: “They are not standardized, and there are a lot of claims out there for all sort of different products. This was an attempt to pick one to see if it helped. It’s a very benign agent to use, but it didn’t show any benefit over standard of care.”
Sunday, September 28, 2014
BY ED SUSMAN
SAN FRANCISCO – A three-pronged anti-prostate cancer attack for men at high-risk for recurrence after surgery appears to extend the time of freedom from disease progression, researchers reported here at the American Society for Radiation Oncology Annual Meeting.
In the preliminary Radiation Therapy Oncology Group 0621 trial, 73 percent of patients survived the critical three-year post-prostatectomy period without evidence of cancer progression, fulfilling the study’s primary endpoint, said Mark Hurwitz, MD, Professor of Radiation Oncology at Thomas Jefferson University in Philadelphia.
“In light of these very favorable findings, Phase III trials assessing the use of androgen-deprivation therapy and chemotherapy with radiation in this high-risk population are clearly warranted,” he said in his oral presentation.
The goal of the single-arm study was to determine if the addition of androgen-deprivation therapy plus docetaxel chemotherapy to the standard adjuvant radiation therapy would improve the historical freedom from progression rate from 50 percent of these at-risk patients to at least 70 percent at three years.
“The study endpoint was met,” Hurwitz said.
“Prostatectomy benefits many but certainly not all patients,” he continued, explaining that the researchers sought to find ways to improve outcomes following prostatectomy for men who were clearly at higher risk of recurrence--particularly to determine if systemic therapy would improve outcomes.
“Failure within three years of prostatectomy is associated with increased risk of prostate cancer specific mortality,” Hurwitz said. “While adjuvant radiation will benefit most patients, there clearly are subgroups at high risk of failure despite surgery and radiation.”
For the study, Dr. Hurwitz and colleagues recruited 80 patients of whom 74 met all the eligibility criteria. The patients were enrolled from 2008 through 2010.
To be eligible for the study, post-prostatectomy nadir prostate specific antigen (PSA) had to be greater than 0.2 ng/ml, and the tumor Gleason score had to have been 7 or greater. Men were also eligible if their nadir PSA was 0.2 ng/ml or less and they were diagnosed with Gleason 8 or greater prostate cancer and the patients also were diagnosed with Stage pT3a or greater--meaning extracapsular extension of the cancer.
Hurwitz said that the eligibility was based on previous cooperative group studies that identified men most likely to have disease progression within three years of surgery.
At the three-year time point, 20 events had occurred among the men, which translated to a freedom from progression rate of 73 percent. Failure was defined as a PSA value of at least 0.4 ng/ml, the use of non-protocol hormones, clinical failure, or death within three years.
After a median follow-up of 4.4 years, 26 events were recorded: “Not surprisingly, the initial failure was biochemical in nature,” Hurwitz said. Of the 26 events, 24 were defined as biochemical failure; two first events were the emergence of distant metastases.
“With less than five years of follow-up, 11 of our patients experienced distant metastasis and there were two prostate cancer specific deaths,” he said. One other patient died from non-prostate cancer causes. The researchers did not observe any cases of local-regional progression.
In a multivariate analysis, PSA nadir was associated with freedom from progression, and both PSA nadir and Gleason score were associated with biochemical failure.
Cost in Adverse Events
The systemic treatments did come with a cost in adverse events, Hurwitz reported. More than 50 of the 74 patients in the trial experienced Grade 3 or 4 neutropenia and leukopenia. However, he said, “most of these adverse events were anticipated and were manageable without long-term sequelae. These were laboratory and not clinically-based toxicities. Rates of febrile neutropenia and infection were low.
“There did not seem to be long-term toxicity with the addition of docetaxel and androgen-deprivation therapy,” he said. He noted that the use of docetaxel in the study was based on Phase III trials that indicated the effectiveness of the taxane in treatment of metastatic prostate cancer.
In commenting on the study, Kenneth Roberts, MD, Professor of Radiation Oncology at Yale University School of Medicine, said in an interview: “This trial is hypothesis generating, suggesting that the addition of docetaxel to high-risk individuals after prostatectomy for prostate cancer who would otherwise be getting adjuvant radiation seems to improve survival.
“This needs to be moved forward into a randomized trial,” he added. “These results are compared with historical controls and there are lots of pitfalls with those comparisons.”
In the trial, all patients received six months of androgen deprivation followed eight weeks later with the start of radiation treatment. The radiation dose was 66.6 Gy delivered in fractions of 1.8 Gy. “Three to six weeks later, the initiation of docetaxel for a total of six cycles was begun, using the regimen for metastatic disease,” he said.
In the RTOG 0621 study he was reporting, patients were treated with docetaxel dosed at 75 mg/m2 on day 1 of a 21-day cycle.
The patients in the study had a median age of 62; 61 of the patients had Gleason scores of 8 to10, and 41 men or 55 percent of the total in the trial were diagnosed with a Gleason score of 9; 40 men were diagnosed with Stage pT3b, and 58 percent had positive margins following surgery.
“The take-away message is that the patients in this study had, by and large, more significant risk factors than those in other series,” Hurwitz said. He noted that in a previous SWOG study, about 12 percent of men had Gleason scores of 8 or greater compared with 82 percent in this study. In addition, 47 percent of the men had a nadir PSA higher than 0.2 ng/ml.
The study was supported by grants from the National Cancer Institute and sanofi-aventis.
Sunday, September 28, 2014
BY ED SUSMAN
SAN FRANCISCO – For patients diagnosed with inoperable esophageal cancers, the addition of the monoclonal antibody cetuximab to the standard chemotherapy regimen did not improve outcomes, researchers reported here at the American Society for Radiation Oncology Annual Meeting.
The hope had been to build on outcomes in previous trials that indicated that the monoclonal antibody that targets the epidermal growth factor receptor – often overexpressed in esophageal cancers -- in combination with standard treatments could move the needle forward in these patients.
But, as Mohan Suntharalingam, MD, Professor of Radiation Oncology at the University of Maryland School of Medicine, reported, the trial was unable to show that the addition of cetuximab was significantly different than that of standard of care.
In presenting the results of the Radiation Therapy Oncology Group 0436 trial, he noted that when assessing overall survival at two years – the primary endpoint of the trial – 45 percent of the patients on the cetuximab arm of the trial were alive compared with 42.4 percent of those being treated without the targeted biologic agent.
The trial design anticipated that the addition of cetuximab would improve two-year overall survival rates from 41 to 53 percent, but the outcomes fell short of that goal.
Local failure occurred in 49 percent of the patients treated with chemotherapy and radiation after two years compared with not quite 45 percent of patients also treated with cetuximab, also a non-significant finding, Suntharalingam said in his oral report in the highlighted clinical trials symposium at the meeting.
Trial Stopped Early Because of the Disappointing Results
He noted that the study was stopped early after interim analyses suggested futility. The researchers had planned to recruit 420 patients, but recruitment was halted in 2013 after 344 patients had been accrued.
In explaining the rationale for the trial, Suntharalingam described the history of treatment for the disease that led to this trial: “Standard of care for non-operative esophageal cancer was established a long time ago in RTOG 85-01. That trial utilized fluorouracil, cisplatin, and daily radiotherapy and resulted in five-year overall survival of 26 percent, and local regional control of approximately 55 percent. When you think that the trial results were published in the New England Journal of Medicine in 1991, clearly from that time we have struggled to advance the outcomes among patients being treated without surgical intervention.”
Among the attempts to improve overall outcomes were the use of dose escalation in radiotherapy and new induction agents but, “we really haven’t moved beyond what was achieved in RTOG 85-01,” he said. Attempts were also made to reduce toxicity by treating patients with taxanes and other platinum combinations.
With the arrival of biologic agents that target the EGFR, the researchers thought they had a combination that would improve outcomes. “The enthusiasm to study these agents in esophageal cancer is fueled by data that have shown us that overexpression of EGFR is seen in 60 to 80 percent of patients who have both adenocarcinoma and squamous cell carcinomas of the esophagus,” he said.
“Then we had trials that showed us it was feasible to combine cetuximab and carboplatin, paclitaxel and radiotherapy. These results were encouraging and helped serve as the backdrop for the design of RTOG 0436.”
The definite results of RTOG 0436, he said, show that cetuximab plus cisplatin/paclitaxel/radiation therapy did not improve local control or overall survival at two years in esophageal cancer.”
‘Disappointing, but Negative Trials Are Part of Clinical Research’
Commenting on the trial results in an interview, Kenneth Roberts, MD, Professor of Radiation Oncology at Yale University School of Medicine, explained: “Since the study using cetuximab in treatment of patients with head and neck cancer had been positive, there has always been a hope that cetuximab could be added to chemotherapy with radiotherapy. But we have not as yet been able to find a place where that turns out to be true.
“I think we have to develop better predictive tools to determine who might benefit from the addition of cetuximab to our current treatment regimens for esophageal cancer. This trial was a disappointment, but negative trials are part of clinical research.”
In RTOG 0436, all patients enrolled in the trial were treated with a radiation dose of 50.40 Gy in 1.80 daily fractions. The chemotherapy regimen consisted of paclitaxel at 50 mg/m2 and cisplatin at 25 mg/m2 administered weekly for six weeks. The trialists treated 169 patients with that regimen. In another group of 159 patients, cetuximab was added in a regimen that included a 400 mg/m2 loading dose followed by 1,250 mg/m2 weekly for weeks 2-6.
The trial opened in June 2009, and the last of the patients were accrued through January 2013. The median age of the patients was about 64; more than 80 percent of the participants were men; about 20 percent presented with T1/T2 disease; the rest of the patients were diagnosed with T3/T4 esophageal cancer. About 15 percent of the patients were in Stage M1a. More than 60 percent of the patients had adenocarcinoma.
Suntharalingam said that according to the design of the trial, patients were stratified on the basis of disease histology, cancer lesion size, and the presence or absence of disease in the celiac nodes. He said the only factors favoring a longer overall survival was a better Zubrod Performance Status, the cancer lesion size, and the T-Stage at presentation. The treatment regimen did not appear to influence outcomes, he said.
“Toxicities were evenly matched in both arms. It might not surprise this group to see that really the only differences seen were in dermatologic and skin toxicities associated with the experimental arm.” About 10 percent of the patients in the cetuximab arm experienced Grade 3 dermatologic toxicities compared with less than one percent of patients in the standard-treatment arm.
The Phase III, Intergroup randomized trial was government funded, but also received some support from Bristol-Myers Squibb.
Friday, September 26, 2014
BY ED SUSMAN
SAN FRANCISCO – Patients who are diagnosed with extensive-stage small-cell lung cancer who respond to platinum-based chemotherapy appear to have improved outcomes if they are subsequently treated with thoracic radiotherapy in addition to prophylactic cranial irradiation, researchers reported here at the American Society for Radiation Oncology Annual Meeting.
“Thoracic radiotherapy should be offered in addition to prophylactic cranial irradiation to patients with a response after initial chemotherapy,” said Ben Slotman, MD, PhD, Professor and Chairman of the Department of Radiology at Vrije Universiteit Medical Center in the Netherlands, in presenting his oral clinical trials study.
He reported that 13 percent of these patients survived for at least 24 months if they received thoracic radiation compared with three percent of patients who treated with only prophylactic radiation to the head to prevent occurrence of brain metastases, a difference that reached statistical significance (p=0.004). Overall survival was the primary endpoint of the study, he said.
In addition, the relative risk of disease progression among those patients treated with both chest and brain radiation was decreased 27 percent.
Intrathoracic progression occurred in about 44 percent of the patients treated with radiation to the chest and the head versus almost 80 percent of patients who received brain irradiation only, he said.
“Thoracic radiotherapy in extensive-stage small-cell lung cancer improves overall survival, progression-free survival, and intrathoracic control of the cancer. I think this study shows that even though these patients have metastatic disease we cannot not treat them. There can be a difference in outcomes.”
‘Clearly Will Change Clinical Practice’
In commenting on the trial in an interview, session moderator Benjamin Movsas, MD, Chairman of Radiation Oncology at Henry Ford Hospital, said, “Clearly this study potentially will change clinical practice in extensive-stage small-cell lung cancer. This randomized study showed that the addition of a short course of radiation therapy not only improved the local control which we might have anticipated but even the survival of those patients, which is huge.
“These are patients who may not have typically been treated with radiation,” he continued. I think this really speaks to the fact that radiation therapy – even though it is a local treatment – may often have a much broader and greater effect to help our patients. Second of all, it shows the importance of now having a multidisciplinary approach. So even though these patients have metastatic disease, they are not only managed by medical oncologists but also in collaboration with radiation oncologists.”
Slotman noted that in designing the trial, he and his international research team realized that although in previous studies prophylactic cranial irradiation improved overall survival and reduced the risk of brain metastases but failed to control intrathoracic disease progression. In those trials, persistent intrathoracic disease following chemotherapy was observed in 76 percent of patients and intrathoracic progression occurred in 89 percent.
Hence, he and his colleagues considered that treating these patients with thoracic radiation with an eye to controlling intrathoracic progression might make a difference in outcomes.
The study--named CREST for Chest Radiotherapy Extensive Stage Trial—enrolled 498 patients diagnosed with extensive-stage small-cell lung cancer. The patients were treated with four to six cycles of platinum-based chemotherapy and were eligible for the study if the chemotherapy resulted in a response (complete, partial, or what was determined as a “good response”).
Patients had to be free of brain, leptomeningeal, and lung metastases and could not have received prior radiation to the brain or thorax. Patients were then treated with radiation two to seven weeks after completing chemotherapy.
Enrollment, which was from January 2009 through December 2012, included patients from 42 centers in the Netherlands, United Kingdom, Norway, and Belgium. “Patient accrual was accomplished faster than we anticipated,” Slotman said.
The researchers randomly assigned 249 patients to receive standard of care – i.e., prophylactic cranial irradiation -- and 249 patients to both cranial and thoracic radiation. The dose to the chest was set at 30 Gray, delivered in 10 fractions. He said that further studies using thoracic radiation in extensive stage small cell lung cancer might include increasing the radiation dose.
In the intention-to-treat analysis, the research team analyzed the outcomes of 247 patients who received thoracic and cranial radiation and 248 patients treated with cranial radiation alone. The demographics and medical conditions of the patients were not statistically different in the two arms of the trial. Patients were about 63 years old, about 55 percent were men, and most had a WHO performance status of 1-2.
Following chemotherapy, 25 patients had a complete response, 350 had partial responses, and 120 had good responses—defined, Slotman explained, as showing improvement in their tumor size, but not reaching the criteria for a partial response.
‘Very Well Tolerated’
Treatment was considered to be very well tolerated, he said. Grade 3 adverse events were similar for both groups of patients, although four patients receiving thoracic radiation developed Grade 3 esophagitis, which was not observed among the patients receiving only radiation to the head.
The only Grade 4 adverse event in the trial was a case of fatigue in one patient receiving cranial irradiation alone.
There were 11 cases of Grade 3 fatigue among the patients receiving radiation to both sites, and eight cases of Grade 3 fatigue occurred among the individuals receiving prophylactic cranial irradiation alone.
Slotman said that when overall survival was analyzed on the basis of subgroups, there did not appear to be differences on the basis of sex, age, or performance status. There appeared to be a trend in favor of improved survival if a patient achieved a complete response to chemotherapy, but that difference did not achieve statistical significance.