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Wednesday, December 18, 2013
BY RAMASWAMY GOVINDAN, MD
Clinical Advisory Editor, Oncology Times;
Co-Director, Section of Medical Oncology
Professor of Medicine, Division of Oncology
Washington University School of Medicine
This year’s World Conference on Lung Cancer (WCLC), held in Sydney, Australia, had the theme of Next-Generation Lung Cancer Care, reflecting, as the organizers said, “the need for collaboration and cooperation in producing the best possible outcomes in the treatment of lung cancer.”
The presentations are available online.
This brief review focuses on a few select presentations covering immunotherapy with checkpoint inhibitors, epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors, and thoracic radiation.
Immunotherapy with Checkpoint Blockade
Immunotherapy with checkpoint blockade has attracted considerable attention over the past few years. Updated results of the Phase I study using nivolumab (anti-PD-1) in patients with non-small cell lung cancer (NSCLC) were presented at this meeting.
The fully human IgG4 PD-1 immune checkpoint inhibitor antibody nivolumab restores anti-tumor T cell activity by preventing interaction with its ligands PD-L1 and PD-L2. In this study, the overall response rate in 129 patients treated at three different dose levels was 17 percent, with an estimated median duration of response of 74 weeks. The median overall survival was 9.9 months in this heavily pre-treated population.
More importantly, durable responses were observed, with responses ongoing in nearly half of responders. Nearly 50 percent of responders demonstrated benefit within eight weeks of starting therapy. Of the seven responders who discontinued therapy for reasons other than disease progression, six continue to have no evidence of disease progression despite not receiving therapy.
This phenomenon of durable response even in patients who discontinue checkpoint blockade is being observed repeatedly with other agents that inhibit PD-1 or PD-L1. Nivolumab is associated with immune-related side effects affecting the skin, gastrointestinal tract, lung, liver, and kidneys, but all appear to be mostly manageable.
Randomized controlled trials are now under way to define the role of niovlumab in patients with NSCLC.
Activating Mutations in EGFR Receptor
Activating mutations in the EGFR are typically associated with dramatic and at times durable response to EGFR TK inhibitors such as gefitinib, erlotinib, and afatinib. Exon 19 deletions and L858R mutations are the two most common EGFR mutations known to be sensitive to EGFR TK inhibitors in patients with metastatic non-small-cell lung cancer (NSCLC).
With the advent of next-generation sequencing, several uncommon mutations in the EGFR TK domain are being reported. It is unclear whether EGFR TK inhibitors are active in patients with “uncommon” EGFR TK mutations. At the meeting, Ping Yang and colleagues presented data from three trials regarding the efficacy of afatinib in this group of patients. Seventy-five patients from three prospective studies (LUX-Lung 2, 23 patients; LUX-Lung 3, 26 patients; and LUX-Lung 6, 26 patients) who had uncommon EGFR mutations received afatinib either as frontline therapy (62 patients) or after chemotherapy (13 patients).
Patients were divided into three subgroups (a) T790M group, 14 patients; Exon 20 insertions (23 patients); and the larger “other” group that included various mutations including L861Q, G719X, G719X+S768I, and G719X+L861Q (38 patients). The response rates (71%) and median duration of response (11.1 months with 95% CI 1.3-35+ months) with afatinib in the “other” group is similar to what has been reported historically with EGFR TK inhibitors in patients with exon 19 deletion and L858R.
The response rate was low in patients with de novo EGFR T790M mutations and exon 20 insertions, though some patients have had durable responses even lasting up to 13.8 months. Afatinib was recently approved for use in the treatment of EGFR-mutant NSCLC in the United States. Hopefully, we will learn a lot more about specific mutations and responses to targeted therapies through prospective clinical trials and registries (www.mycancergenome.org).
Despite having impressive responses, though, most patients with EGFR TK mutation eventually die from relapsed NSCLC. A common mechanism of resistance is the emergence of the T790M mutation. There are no effective therapies for patients with acquired resistance to EGFR TK inhibitors including those with EGFR T790M NSCLC.
At the meeting, Jean Charles Soria and colleagues reported the results of an ongoing first-in-human dose finding study of CO-1686 in patients with EGFR-mutant NSCLC who have had progressive disease following EGFR TK inhibitors.
CO-1686 is a novel and selective inhibitor of cells harboring key EGFR-activating and T790M-resistance mutant cells. At the time of presentation, 56 patients (93% of whom had either exon 19 deletion or L858R) had been enrolled, receiving a dose of 150 mg once a day to 900 mg twice daily. Among these 56 patients, 39 (70%) of tumors were positive for T790M and 12 were negative (21%). The investigators reported a response rate of 67 percent in evaluable T790M-mutant patients treated at 900 mg bid.
The majority of these patients had progressed on EGFR TKI immediately preceding treatment with CO-1686, suggesting clinical benefit perhaps from directly inhibiting the growth of T790M mutant cells. In keeping with the selectivity of this compound for EGFR mutants, skin rash was not seen in this study. Adverse events attributed to the study drug included nausea, vomiting, fatigue, diarrhea, and decreased appetite.
Studies are ongoing with an improved oral formulation. These results, though preliminary, are indeed very promising.
AZD9291 is an irreversible, potent, and selective TK inhibitor of activating and resistance (T790M) mutations in patients with advanced NSCLC. Promising response rates were reported from an ongoing Phase I study. Of 35 patients with EGFR-mutant NSCLC, 15 had a partial response and nine of 18 patients with EGFR T790M NSCLC had a partial response.
Although these results have to be confirmed, these two compounds show considerable promise in the treatment of patients with EGFR T790M NSCLC.
Several retrospective studies and some Phase I and II studies had reported promising results with 74 Gy of thoracic radiation in patients with locally advanced NSCLC. Results of the Radiation Therapy Oncology Group (RTOG) 0324 trial showed a two-year survival rate of 49 percent in patients with stage III NSCLC with the addition of cetuximab to chemoradiation in patients with locally advanced NSCLC.
RTOG 0617 is an intergroup Phase III study comparing standard dose (60 Gy) with high-dose (74 Gy) chemoradiotherapy with or without cetuximab in patients with stage III NSCLC. This study randomized patients in a 2 x 2 factorial design. Patients received paclitaxel and carboplatin chemotherapy regimen.
When a planned interim analysis revealed no benefit with high-dose radiation, enrollment was discontinued. The presentation at the conference focused on the efficacy of cetuximab in this setting, since the results with regard to high-dose versus standard-dose radiation were presented at this year’s ASCO Annual Meeting. Of 465 patients evaluated, 237 received cetuximab.
There was no difference in overall survival (primary objective) or progression-free survival. The 18-month overall survival rates were 67.1 percent (95% CI: 56.8-75.5) and 67.9 percent (95% CI: 57.6-76.2), respectively, in the standard-dose arm with or without cetuximab. The 18-month overall survival rates were 58 percent (95% CI: 47.6-67.1) and 52.3 percent (95% CI: 41.5-62.0), respectively, in the high-dose arm with or without cetuximab.
The addition of cetuximab to chemoradiation increased overall grade 3-5 toxicities. There was a suggestion that cetuximab may have a more beneficial effect in patients with high EGFR expression than in patients with low EGFR expression. However, this issue needs to be studied more carefully. Currently there is no role for cetuximab or high-dose (74 Gy) radiation in patients with locally advanced NSCLC.
In summary, I am very optimistic that outcomes for patients with lung cancer will continue to improve in the coming years, perhaps more dramatically for some. There is considerable promise that immune checkpoint inhibitors and EGFR inhibitors targeting specifically T790M will alter the clinical practice in the very near future.
Our understanding of the altered genomic landscape of lung cancer continues to evolve. The new genre of large early-phase studies targeting specific molecular subsets is quite promising.
Monday, December 16, 2013
Todd Buchanan/ASH 2013
BY MARK FUERST
NEW ORLEANS – Three and a half years after demonstrating the first successful use of genetically engineered T cells to fight leukemia, a research team from the University of Pennsylvania and Children’s Hospital of Philadelphia have now reported that these modified T cells produce longer-term responses and persist in patients’ bodies with vaccine-like activity for more than three years, according to presentations here at the American Society of Hematology Annual Meeting.
“Modified T cells can do the work of normal T cells. They target, trigger, kill, expand, and contract. This is the Holy Grail of adoptive T-cell therapy,” Michael Kalos, PhD, Adjunct Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania Perelman School of Medicine, said in an interview.
“Infused adoptive T cells are ‘serial killers.’ Each infused cell or its progeny kills on average more than 1,000 leukemia cells. These cells are poised to replace bone marrow transplantation with a therapy that is less expensive, more widely available, and less toxic than current allogeneic stem cell transplantation therapy.”
The investigational treatment pioneered by the Penn team begins by removing patients' T cells via an apheresis process, then reprogramming them with a gene-transfer technique using a lentivirus vector. The newly built T cells target tumor cells using an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to the CD19 protein -- which is found on the surface of cancerous B cells associated with both chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).
The modified cells are then infused back into the patient's body following lympho-depleting chemotherapy. These “hunter” T cells both multiply and attack, Kalos said, and a signaling domain built into the CAR promotes rapid growth of these cells. Cells that do not express CD19 are left untouched by the modified T cells, which limits the prolonged, systemic side effects typically experienced during traditional cancer therapies.
Reports on Three Groups of Patients
At the ASH meeting, the research team reported findings from three different groups of patients:
- Nineteen of 22 children (86%) with ALL had complete responses (Abstract 67). Two-thirds of these patients, for whom all other treatments had failed, have ongoing complete responses at more than three months. Five patients have relapsed, including one whose tests revealed new tumor cells that do not express the CD19 protein.
- In that same study, all five adult ALL patients treated so far experienced complete responses, the longest of which continues for six months after treatment. One patient subsequently underwent a bone marrow transplant and remains in remission. One patient relapsed after three months with disease that also tested negative for CD19.
- Fifteen of 32 (47 percent) adult patients with CLL responded to the therapy, with seven experiencing a complete response (Abstract 4162). In a recently completed pilot study of 14 CLL patients, four patients (29%) have achieved a complete response at more than 10 months. And, three of the first 18 CLL patients (17%) in a Phase II, dose-optimization trial have achieved complete responses (Abstract 873).
“These new and expanded data provide significant proof that T cells engineered to express cancer-targeting CARs not only work, but work dramatically and in a sustained manner in patients with relapsed, treatment-resistant leukemia, and further demonstrate the potential of this approach to help these patients achieve complete response,” Kalos said.
“Further, our results show that we can potentially measure and track the activity of these engineered cells in the body as a way to monitor treatment -- an exciting finding considering that this treatment is often the last hope for these patients.”
How Adoptive T Cells Work
At a news conference at the meeting on “Pioneering Precision Medicine Approaches for Hard-to-Treat Blood Disorders” that featured the studies, Kalos said the essential elements of successful adoptive T-cell therapy are a large number of potent antigen-specific T cells, expansion in vivo in response to antigen encounter, potent anti-tumor activity, contraction and long-term persistence, and the ability to respond to challenge.
Patients with the greatest expansion of T cells (above 5% of the total of all of their T cells) were very likely to achieve complete responses, Kalos said. Those with less robust, but still detectable, cell expansion were partial responders, and those who had no detectable T-cell expansion did not respond to treatment.
For those in complete response, the engineered T cells were usually detectable many months after the infusion and continued to show functional activity.
“We see long-term persistence of the adoptive T cells and ongoing B-cell aplasia in patients who achieve complete response,” Kalos said, noting that in all cases, no further therapeutic treatment intervention is needed after infusion. These patients show massive expansion of T cells, almost all of it within the first month of therapy.
The therapy does induce some side effects. In the trials for both CLL and ALL, all responding patients experienced a cytokine release syndrome (CRS), which marks the process of the engineered cells multiplying and attacking tumor cells.
Patients typically have varying degrees of flu-like symptoms, with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. About one-quarter of patients require a hospital stay and having breathing difficulties, which are relieved by treatment. The researchers said they have also seen neurological deficits, including delirium, confusion, and aphasia, that disappear in a few days.
Kalos said they have learned how to manage the CRS reaction, if necessary, using the immunosuppressant monoclonal antibody tocilizumab, which tamps down elevated levels of the inflammatory cytokine interleukin-6 (IL-6). IL-6 spikes during the most robust phase of the engineered cells’ expansion in the body, he noted. Patients with B-cell aplasia have been managed with replacement therapy.
At his oral presentation later in the meeting, Kalos said that engineered T cells may be the first example of successful “synthetic biology.”
“T cells can be engineered to express antibody fragments that persist and express antibody for at least three years in patients with leukemia,” he summed up. “Complete and durable clinical responses are associated with robust expansion and long-term persistence of the adoptive T cells, and in patients with heavy tumor burden, delayed tumor lysis syndrome and CRS.”
“T cells expand, contract, and persist in responders,” he told OT. “We don’t know why some patients respond and others do not. Some robust expansion is part of the efficacy of the treatment.”
He noted that some adoptive T cells transfer to the central nervous system in ALL patients, and responses are associated with deep molecular remission.
‘Extremely Active’ Therapy
“The key point is that these adoptive T cells are extremely active,” the lead author of the ALL study, Stephan A. Grupp, MD, PhD, Director of Translational Research at the Center for Childhood Cancer Research at Children's Hospital of Philadelphia and Professor of Pediatrics at the University of Pennsylvania, said in an interview.
“Gene transfer technology is used to stably express CARs on T cells, conferring novel antigen specificity. The T cells can be directed against any tumor cell that expresses the CD19 surface antigen. This therapy takes advantage of the cytotoxic potential of T cells, thereby killing tumor cells in an antigen-dependent manner. Persistent adoptive T cells consist of both effector – cytotoxic -- and central memory T cells.”
At his oral presentation, Grupp said that taking all 27 ALL patients together, 24 patients (89%) have achieved complete remission in a median of 145 days, with six relapses. “The follow-up is short, only 3.4 months. We need more time for long-term results,” he said. “We do see persistence out to 18 months in responding patients. In some of these patients, half of the circulating white blood cells are engineered T cells.”
He added, "Our results demonstrate the potential of this treatment for patients who truly have no other therapeutic option. In the relatively short time that we've observed these patients, we have reason to believe that this treatment could become a viable therapy for their relapsed, treatment-resistant disease.”
He called the therapy a "game changer" for controlling the toxicity seen with these engineered T cells, and noted that there has been no graft-vs.-host disease seen.
Kalos said the Penn team’s next big effort is to define why the treatment works in some patients and not others: “Is it the patient, T cells, the disease, or something else that will improve responses?
“The response rates so far are incredible,” he said. “The goal is to move the therapy as early as possible in these diseases.”
The Penn researchers have licensed the technologies involved in these trials to Novartis.
The moderator of the news conference, Laurence Cooper, MD, Professor of Pediatrics at the University of Texas MD Anderson Cancer Center, said in an interview, “T cells extracted from leukemia patients’ blood latch onto tumor cells and destroy them. Importantly, this works for a sustained period of time.
“These patients are quite sick, but the CRS is manageable, with expected complications. That the patients do not succumb to their illness is a testament to the skill of these practitioners. These data are encouraging. How the therapy plays out in the marketplace is unknown. It needs time to evolve.”
The limitation of the therapy is no longer genetic modification, Cooper noted. “It’s antigen identification. We know it’s safe to use these targeted T cells. Can we design trials that capture the adoptive response? Or perhaps we need to sequence therapies, first with CAR T cells and then programmed cell death 1 ligand. Then we can infuse regular T cells. There is the potential ability to turn the cells off with high-dose steroids and blunt the immune response.”
At MD Anderson, Cooper said, researchers are thinking about targeting two receptors at the same time -- perhaps CD 19 plus either CD 22 or CD 20. “Most of these leukemia patients are too advanced for transplantation. But once they are in remission after receiving CAR T cells, they potentially are able to receive a transplant.”
At Memorial Sloan-Kettering Cancer Center, he continued, many CAR T-cell-treated patients go on to transplant. “At MD Anderson, we give these patients, mostly those with ALL, some with CLL, CAR T cells and then send them on to transplant.”
Cooper has a simple message about adoptive T-cell therapy for practicing oncologists: “If you have refractory leukemia patients, they deserve this therapy now. This could possibly be offered instead of transplant in leukemia patients. Genetically marked cells in patients have been seen decades later. There is good reason to believe these genetically modified T cells may persist a long time.”
Monday, December 16, 2013
BY ROBERT H. CARLSON
ATLANTA -- A randomized controlled trial comparing external-beam radiotherapy and high-dose rate brachytherapy vs. chemo-radiotherapy for patients with stage IIIB squamous cell carcinoma of the cervix found a small but statistically significant survival benefit with the addition of cisplatin. Importantly, though, as reported here at the American Society for Radiation Oncology Annual Meeting (Abstract 8), the regimen was associated with acceptable toxicity.
Adding chemotherapy to radiotherapy is known to improve outcomes in early-stage cervical cancer, but until now trials have not demonstrated benefit for patients with later stages, said Antonio C. Zuliani, MD, a radiation oncologist at Campinas State University in Brazil, who presented the data.
He said the best evidence for disease-free and overall survival of women with stage IIIB cervical cancer undergoing chemo-radiotherapy vs. radiotherapy has been from a meta-analysis of 18 trials (Cervical Cancer Meta-analysis Collaboration, 2010) – which showed a decrease in benefit from 10 percent for patients with stages IB-IIA disease to three percent for those with stage III-IVA.
In this new randomized, controlled trial, women with stage IIIB squamous cervical cancer received external-beam radiotherapy and high-dose rate brachytherapy with or without cisplatin. The study endpoints were disease-free and overall survival. All patients received external-beam radiation (45 Gy) to the pelvic region in 25 fractions, a 14.4 Gy boost to compromised parametria, and high-dose rate brachytherapy in four weekly fractions of 7 Gy prescribed to point A (the crossing of the uterine artery and the ureter). The chemo-radiotherapy group also received weekly cisplatin (40 mg/m2) during the pelvic brachytherapy.
Between September 2003 and July 2010, 147 patients were accrued -- 72 patients receiving chemo-radiotherapy and 75 radiotherapy alone. The mean follow-up was 54.9 months.
Women with a Karnofsky performance scores of less than 90 had a significantly worse disease-free survival, with a relative risk of 2.52, Zuliani reported. The same was true for women with bilateral wall invasion (relative risk of 2.93), and baseline hemoglobin under 10 mg/dL (relative risk of 2.22).
On the other hand, disease-free survival was significantly better in women assigned to chemo-radiotherapy (relative risk of 0.52). Overall survival was also negatively associated with a Karnofsky score of under 90 (relative risk of 2.75), and with baseline hemoglobin under 10 mg/dL (relative risk of 2.22).
Again, patients in the chemo-radiotherapy group had a better overall survival rate, but this was not statistically significant (relative risk of 0.67), he said.
Grade 1/2 acute toxicity was 37.5 percent for patients receiving chemo-radiotherapy, and 28 percent for those receiving radiotherapy along. Grade 3/4 late toxicity was 9.7 percent for chemo-radiotherapy and three percent for radiotherapy.
“In testing the new approach of chemotherapy with traditional external-beam radiation therapy and high-dose rate brachytherapy, we were extremely cautious about possible toxicity, and we were pleased by an increase in local control and the very low toxicity rates,” Zuliani said. “We believe these results demonstrate that this combined treatment protocol is safe to offer to patients and provides some beneficial improvements in disease-free survival and toxicity levels.”
Other Patient Groups
In a news conference during the meeting, the moderator, Beth A. Erickson, MD, Professor of Radiation Oncology at Medical College of Wisconsin, said the regimen could be useful in patients with advanced cervix cancer who are at high risk for dying of disease outside of the radiation field -- especially those with bulky tumors and a high risk of para-aortic lymph node involvement.
Another group who could potentially benefit are frail patients and those with comorbidities, many of whom are socioeconomically deprived, she noted. “They haven’t been screened for other diseases -- that’s why they have stage III cervix cancer, because of delayed diagnosis -- and those are other compounding factors that impact survival,” she added.
Erickson mentioned an ongoing clinical trial that will address this population, the Outback Trial, using cisplatin and radiation therapy with or without carboplatin and paclitaxel to treat patients with locally advanced cervical cancer. “This is giving advanced cervical cancer patients chemotherapy after chemo-radiation to try to reduce this risk of distant metastases, and therefore also improve survival,” she said.
Risk of Second Breast Cancers and Cardiac Mortality Not Increased with RT
The author of another study reported at the meeting noted that while breast-conservation treatment incorporating lumpectomy and radiotherapy appears to be equivalent to mastectomy in overall survival and breast-cancer specific survival, the potential adverse late effects of radiotherapy to the chest area have been a concern. New data, however, show that those risks may not be as significant as believed – i.e., there was no measurable increase in the risk of cardiac mortality, breast cancer mortality, or secondary cancer mortality in the chest area in patients with best-prognosis breast cancer treated with external-beam radiotherapy.
Jason C. Ye, MD, a third-year resident at New York Presbyterian Hospital/Weill Cornell Medical College, described the retrospective review of SEER data, which he said supports the continued use of breast-conserving therapy in patients with early-stage breast cancer.
The study identified 5,385 women who had breast-conserving surgery or mastectomy for stage T1aN0 breast malignancy in 1990 to1997. The incidence of mortality was compared between the radiotherapy and no-radiotherapy groups to assess overall survival, breast cancer survival, second tumor specific survival, and cardiac cause specific survival.
The median age of the 2,397 patients who received radiotherapy after breast cancer surgery was 55, and 59 for the 2,988 patients in the no-radiotherapy group. Median follow-up was 169 and 171 months, respectively.
Ye reported a 10-year overall survival of 91.6 percent for patients in the radiotherapy group versus 87.0 percent for those in the no-radiotherapy group; 10-year breast cancer survival was 97.0 percent for radiotherapy vs. 95.7 percent for the no-radiotherapy group; 10-year cardiac cause specific survival was 96.7 percent vs. 92.7 percent; and lung cancer mortality was 1.9 percent vs. 1.6 percent.
“To our surprise, the cardiac cause-specific survival was better in the radiation arm,” he said. “Also, in the radiotherapy group, having left-sided breast cancer did not increase the incidence of cardiac mortality compared with right sided breast cancer.”
There were no statistically significant incidences in mortality due to subsequent lung, esophageal, or soft tissue cancers, lymphoma, or leukemia cancers, Ye said. The cancers causing the most common second cancer mortality were lung (2%), lymphoma (0.4%), leukemia (0.4%), soft tissue including heart (0.06%), and esophageal (0.04%.
Ye said a limitation of the study is that the results cannot be applied to younger patients when making decision about breast conservation or radiation, since fewer than five percent of the patients in the study were under age 40. Also, the cardiac outcomes may have been influenced by selection bias if physicians treating at the time based their decision to use radiation or not on the patient’s health status. In addition, the study could not control for smoking and comorbidities.
Future research, he said, should include longer follow-up and examination of possible reductions in toxicity due to evolving radiotherapy technologies such as 3D conformal radiation therapy, intensity-modulated radiation therapy, and hypofractionated radiation therapy.
The abstracts for both studies can be accessed via http://online.myiwf.com/astro2013/Abstract.aspx
Sunday, December 15, 2013
BY DANIEL FERRARO, MD, PHD, Chief Resident, Department of Radiation Oncology, Washington University School of Medicine and The Alvin J. Siteman Cancer Center, St. Louis, Missouri; and JEFFREY BRADLEY, MD, Professor of Radiation Oncology, Washington University School of Medicine and The Alvin J. Siteman Cancer Center, St. Louis, Missouri.
ATLANTA -- At the 2013 American Society for Radiation Oncology Annual Meeting, the topic of stereotactic body radiotherapy (SBRT) for patients with early-stage non-small-cell lung cancer (NSCLC) was addressed in multiple presentations. As this modality becomes more widely used in clinics across the country, we believe these reports are of interest to the larger oncology community. Summarized below are some reports of particular importance.
· Videtic and colleagues reported one-year results of RTOG 0915, a phase 2 study comparing two different SBRT fractionation schedules in medically inoperable patients with stage I peripherally located (greater than 2cm from bronchial tree) NSCLC (Abstract 6). From September 2009 through March of 2011, 94 patients with T1-2N0M0 disease were randomized to receive 34Gy in a single fraction vs. 48Gy total over four consecutive, once-daily 12Gy fractions. The primary endpoint of this study was grade 3 or higher toxicities at one year, with plans to select the most favorable regimen for a phase 3 study comparing the three-fraction regimen defined by RTOG 0236. Grade 3+ toxicity at one year for the single-fraction regimen was 9.8 percent and 13.3 percent for the four-fraction regimen. Overall survival, a secondary endpoint, was not significantly different between the two regimens. Though the follow-up is too short to change practice, these data suggest that a single fraction of SBRT for NSCLC may be equally as safe and effective as four fractions. Plans for a Phase III trial comparing one versus three fractions of SBRT for this population await longer follow up to confirm the safety and efficacy of single-fraction SBRT.
· Onishi and colleagues from Japan reported results of a large multi-institutional retrospective analysis of 2226 patients who received SBRT for stage I NSCLC (Abstract 21). A wide range of doses (32-70 Gy), as well as number of fractions (3-12), was used in this cohort. The overall survival rate was 72 percent, and disease-specific survival was 85 percent at three years. Grade 3+ NCI-CTC pulmonary complications occurred in 2.9 percent of patients. Subgroups that demonstrated better three-year overall survival included females (83% vs. 68%, p<0.01), patients who received doses with a biologically equivalent dose (BED) of 100Gy or higher (75% vs. 63%, p<0.01), and medically operable patients (78% vs. 68%, p<0.01). Patients with pulmonary interstitial changes and/or emphysema had poorer overall survival.
· Hymas and colleagues from William Beaumont Cancer Institute reported results of a matched-pair analysis of patients with stage I NSCLC who received SBRT, lobectomy, or wedge resection (Abstract 23). A total of 286 patients treated between 2003 and 2010 were selected for matched-pair analysis. In head-to-head comparison, local recurrence at two and five years did not differ significantly between lobectomy and SBRT; however, local recurrence after wedge resection was significantly higher when compared with lobectomy. With respect to overall survival at two and give years, lobectomy did significantly better than both wedge resection and SBRT. Regional and distant failure rates, as well as cause-specific survival did not differ significantly between the three groups. These data suggest that SBRT is a reasonable alternative to wedge resection, while lobectomy remains the standard of care in operable patients. Additionally, these results suggest that SBRT may have similar rates of overall survival compared with lobectomy in a prospective randomized trial where patient selection bias can be minimized.
· Aneese and colleagues, also from William Beaumont, reviewed their SBRT experience in patients with tumors located centrally (less than 2 cm from the proximal bronchial tree) and compared toxicities in patients treated for peripheral tumors during the same time period (Abstract 80). Doses ranged from 48 to 60 Gy in four to five fractions (biologically equivalent dose = 106-132 Gy). In a matched-pair analysis, toxicity between peripheral and central tumors was similar and severe toxicity was less than one percent. These results increase the anticipation for results of the RTOG 0813 phase I/II multi-institutional trial. This trial used a five fraction scheme to determine the maximum tolerable dose and local control with the use of SBRT in the treatment of proximally located early-stage NSCLC. Patients were treated to doses ranging from 10 Gy x 5 fractions to 12 Gy x 5 fractions. The trial recently closed to accrual in September 2013, with early results anticipated in one year.
· Finally, Shah and colleagues presented an analysis of the cost effectiveness of SBRT compared with surgical resection (either lobectomy or wedge resection) for stage I NSCLC (Abstract 98). Patients over 65 years old were assumed in the model, with both clearly operable and marginally operable scenarios investigated. The model takes into account disease, treatment, and toxicity data for SBRT, wedge resection, and lobectomy, and cost was calculated in 2012 dollars as well as quality-of-life adjusted years. Lobectomy was found to be the most cost effective option for clearly operable elderly patients, while SBRT was the most cost effective option for marginally operable patients over 65. With the National Lung Screening Trial showing a survival benefit for CT screening of high-risk patients, the number of early-stage NSCLC is likely to increase. Given this reality, further cost-effectiveness investigations comparing lung surgery with SBRT are likely.
All the abstracts can be accessed via this link: http://online.myiwf.com/astro2013/Abstract.aspx
Friday, December 13, 2013
BY ROBERT H. CARLSON
ATLANTA -- Cancer patients age 35 to 50 with brain metastasis had increased overall survival when treated with stereotactic radiosurgery alone, compared with stereotactic radiosurgery plus whole brain radiotherapy, in an individual-patient-data meta-analysis of three published randomized controlled trials. As reported here at the ASTRO Annual Meeting (Abstract LBA3—accessible via http://online.myiwf.com/astro2013/Abstract.aspx), the results showed that beyond age 50 there was no difference in the two arms of the meta-analysis.
The three randomized trials -- EORTC 22952-26001, JRSOG99-1, and MDACC NCT00460395 – included newly diagnosed patients who had one to four brain metastases, treated with either stereotactic radiosurgery alone or stereotactic radiosurgery plus whole brain radiotherapy.
Those trials by themselves, however, were each under-powered for overall survival comparisons, said the first author of the new meta-analysis, Arjun Sahgal, MD, Associate Professor in the Department of Radiation Oncology at the University of Toronto and Deputy Chief of Radiation Oncology at Odette Cancer Center, also in Toronto.
Analyzing the raw patient data in this new meta-analysis allowed the researchers to formulate conclusions that could not be done through an aggregate meta-analysis previously performed earlier by the same group, he explained. “What we see now is that overall survival is significantly increased with radiosurgery alone in patients age 35 to 50 years, relative to an age-matched cohort treated with whole brain radiation plus radiosurgery.”
In the new meta-analysis, the risk of distant brain failure was significantly higher with radiosurgery alone, but only for patients 55 and older. The risk of new metastasis was also greater in patients with more than one metastasis.
Sahgal noted that previous research by his group showed that the addition of whole-brain radiation to radiosurgery improves distant brain control and local control but makes no difference on overall survival
(Tsao et al: Cancer 2012; 118: 2486-2493).Therefore, he said, radiosurgery alone is a reasonable option because it spares the patient the adverse effects of whole brain radiation. In addition, the new meta-analysis expands on the results by age.
Patient Data Detailed
Sahgal reported a median time to death of 10 months for use of stereotactic radiosurgery vs. 8.2 months for radiosurgery plus whole brain irradiation; local failure was 6.6 vs. 7.4 months, respectively; and distant brain failure was 4.5 vs. 6.5 months, respectively.
The only significant treatment effect modifier was age.
Patients with a single metastasis also had significantly longer overall survival than those with two to four metastases. Those with more than one brain metastasis had a significantly greater risk of distant brain failure. Distant brain control and local control significantly favored the addition of whole brain irradiation, but multivariable analysis showed significant increases in distant brain failures in the radiosurgery-alone cohort only in patients older than 50.
“Therefore, based on our individual patient data of randomized controlled trials from three continents, we conclude that stereotactic radiosurgery alone is the preferred treatment for patients presenting with one to four brain metastases, recursive partitioning analysis score class 1 or 2, Karnofsky performance score of 70 or above, and age 50 years or younger,” Sahgal said.
“This conclusion allows radiosurgery alone to be offered and the patient potentially spared the adverse effects of whole brain radiation.”
Patient inclusion was limited to those with a recursive partitioning analysis score of 1 or 2, and Karnofsky performance score of 70 or above. The meta-analysis was based on one-stage time-to-event individual patient data.
Among 364 patients from the three randomized controlled trials who met the inclusion criteria, 51 percent had been treated with stereotactic radiosurgery alone; 19 percent were age 50 or younger; 41 percent were recursive partitioning analysis class 1; and 60 percent had a single brain metastasis.
In total, 21 percent of patients had a local failure, 44 percent had distant brain failure, and 86 percent died during follow-up.
Sahgal said the survival advantage with radiosurgery alone in younger patients may be explained by the lack of benefit in those receiving whole brain radiation in reducing the risk of brain metastases, while still exposing patients to the toxicities of worse memory function and harming quality of life, which ultimately translated into shorter survival.
Moving Away from Whole Brain Irradiation
The moderator of a news briefing at the meeting, Daphne Haas-Kogan, MD, Professor of Radiation Oncology and Neurologic Surgery and Program Director of the Department of Radiation Oncology at the University of California, San Francisco, said the strength of the study is that it identified a cohort of patients in which the risk of distant brain metastases is not great, and that those patients might not need whole brain radiotherapy on top of stereotactic radiosurgery.
“The study provides us with results we would not otherwise have had if we had examined the individual studies separately,” she said. “These survival results have the potential to change practice as our field moves away from whole brain radiation.”
She added that it is not understood why the younger age group has less risk of dying. Her first thought on reading the abstract, she said, was that there were perhaps more breast cancer patients in the younger age group since they tend to have less risk for distant brain metastases. But in fact, more patients had lung cancer than breast cancer.
“We’re going deeper into the data to understand it better,” Sahgal said, noting that the majority of the patients were treated before the era of molecular tests, and molecular predictors such as EGFR status is not known, “but the data are there and we can make some strong inferences.”
WBI still has a role to play, however--the majority of patients will be offered whole brain irradiation because most present with a large number of brain metastases.”