MAJOR ADVANCES IN CANCER IN 2011

The annual Clinical Cancer Advances 2011 report from the American Society of Clinical Oncology (ASCO), now in its seventh year, highlights 12 major advances made in 2011 and 42 advances that it considers "notable."
The report was compiled by 18 prominent oncologists, and covers the period from October 2010 to September 2011. The research highlighted in this report is considered by the experts to have had a significant impact on the way a cancer is understood or to have had a direct effect on patient care. Most of the advances were covered by Medscape Medical News.
Major Clinical Advances
Lung cancer deaths reduced by low-dose computed tomography (CT) scanning of people at high risk. These results come from the landmark National Lung Screening Trial, which was halted early because of benefit. The study followed 53,454 people at high risk for lung cancer (they had smoked the equivalent of a pack of cigarettes a day for 30 years), and showed that anannual CT scan reduced the risk of dying from lung cancer by 20%, compared with an annual chest x-ray, over the course of 3 years (N Engl J Med. 2011:365:395-409). "This was the first randomized trial to find a definitive reduction in lung cancer deaths with screening," according to the report.
Crizotinib (Xalkori) approved for rare type of lung cancer in August 2011 by the US Food and Drug Administration (FDA). This drug, indicated for use in patients with advanced nonsmall-cell lung cancer who harbor a specific type of alternation in the anaplastic lymphoma kinase (ALK) gene, is "one of the latest examples of a successful personalized medicine approach," says the report.
Exemestane (Aromasin) reduced risk for breast cancer in high-risk postmenopausal women in the MAP.3 (Mammary Prevention Trial). The trial followed 4560 women 60 years and or older who were at high risk for breast cancer, and 3-year results showed that exemestane reduced the risk for invasive breast cancer by 65% (N Engl J Med. 2011:364:2381-2391). "This is the first conclusive evidence that an aromatase inhibitor reduced the risk of a first breast cancer," the report notes, adding that exemestane now offers an alternative to tamoxifen and raloxifene, which are approved for chemoprevention but not widely used because of concerns about toxicity.
In early breast cancer, adding regional nodal irradiation decreases recurrences. In women with early-stage breast cancer who have 1 to 3 positive lymph nodes or who are node-negative but at high risk, the addition of regional nodal irradiation reduces the risk for both local recurrence and distant metastases. These results should encourage radiation oncologists to discuss with their patients a more extended radiotherapy field to reduce the risk for recurrences, the report notes.
Vemurafenib (Zelboraf) improves survival in advanced melanoma in patients with BRAFmutations, compared with standard chemotherapy (New Engl J Med. 2011;364:2507-2516).The drug was approved by the FDA in August, and the report notes that it is "a new standard treatment" for patients with melanoma and BRAF mutations (about half of all patients with melanoma).
First-line ipilimumab (Yervoy) plus chemotherapy improves survival in metastatic melanoma in a phase 3 study (N Engl J Med. 2011;364:2517-2526). The new drug is an immunotherapeutic that activates T cells, and was approved by the FDA in March. "This is the first study showing the benefit in prolonging life by combining chemotherapy and immunotherapy in patients with advanced melanoma," the report notes.
Bevacizumab (Avastin) has been shown to delay progression in both recurrent and newly diagnosed ovarian cancer in 2 separate phase 3 trials. The report considers this to be 2 separate major clinical advances. The data in recurrent ovarian cancer come from the phase 3 OCEANS trial, and show a 52% reduction in the risk for disease progression when bevacizumab is added to chemotherapy, compared with chemotherapy alone. The other study, known as ICON 7, found an improvement in overall survival in some women with newly diagnosed ovarian cancer. The report notes that researchers are waiting for longer-term data from both of these trials.
A new high-dose chemotherapy regimen improves survival in neuroblastoma. In children with high-risk metastatic neuroblastoma, an intense dosing with busulphan plus melphalan improved the event-free survival rate to 49% at 3 years, compared with 33% with the standard regimen of carboplatin, etoposide, and melphalan. These findings establish a new standard of care, the report notes.
A new chemotherapy regimen boosts event-free survival in acute lymphoblastic leukemia (ALL). The results from a phase 3 study of nearly 2500 children and young adults showed that giving methotrexate in large consistent doses, rather than gradually increasing the dose (as happens in the standard regimen) is more effective at preventing relapses and extended survival. These findings set a new standard of care and push cure rates for pediatric patients with ALL up to more than 80%, the report notes, adding that "this disease was once considered one of the most deadly pediatric cancers, but today is seen as one of the most curable."
Imatanib (Gleevec) for 3 years improves survival in patients with high-risk gastrointestinal stromal tumors. After surgery, patients who took imatanib for 3 years had significantlyimproved overall and recurrence-free survival, compared with those who took the drug for 1 year.
Abiraterone acetate (Zytiga) was approved for prostate cancer in April by the FDA. The drug is used in combination with prednisolone in patients with metastatic prostate cancer who have previously been treated with docetaxel. According to the report, it offers a much-needed new option for these patients.
Notable Advances
Brentuximab vedotin (Adcetris) shows tumor shrinkage in lymphomas. This novel antibody–drug combination was granted accelerated approval by the FDA in August for use in refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma. This is the first drug for Hodgkin's lymphoma to be approved by the FDA in more than 30 years, the report notes.
Ruxolitinib (Jakafi) used for high-risk myelofibrosis. The drug showed increased response rates, decreased spleen size, and improved symptoms such as fatigue, night sweats, weight loss, and bone pain in the COMFORT I and II studies (2011 ASCO annual meeting, abstract 6500 andabstract LBA6501). These are the first-ever randomized trials conducted in patients with myelofibrosis, and the findings promise to change the standard of care, the report notes. Ruxolitinib, a JAK inhibitor, was recently approved by the FDA for myelofibrosis.
Treating HER2 breast cancer with drug combinations is more effective than treating with single agents. Although trastuzumab (Herceptin) is effective in treating HER2-positive breast cancer, a significant number of tumors do not respond or become resistant. Two studies have shown that adding another agent improves or extends treatment response — trastuzumab was used with lapatinib (Tykerb) in the CHER-LOB study (2011 ASCO annual meeting, abstract 507) and with docetaxel and pertuzumab (Omnitarg) in the NeoSphere study (2010 San Antonio Breast Cancer Symposium, abstract S3-2). The report notes that larger, longer-term trials (ALTTO and Neo-ALTTO) are currently evaluating whether this approach ultimately extends survival.
PARP inhibitor did not improve survival in metastatic triple-negative breast cancer. The investigational drug iniparib, which acts as an inhibitor of the PARP enzyme that is involved in tumor cell DNA repair, showed promising activity in a randomized phase 2 study (n = 123) when it was added to gemcitabine and carboplatin, increasing overall survival from 8 to 12 months. However, a larger phase 3 study (n = 519) with the same drug combination failed to show any improvement in survival (2011 ASCO annual meeting, abstract 1007). The contrasting results underscore the need to conduct carefully controlled, adequately powered studies to clarify promising results in a preliminary study, the report noted.
Gene biomarkers linked to glioblastoma survival. Analysis of data collected during a phase 3 trial of temozolomide with radiation in patients with newly diagnosed glioblastoma showed that patients with tumors that carried the "silenced" gene for methyl guanine methyltransferase (MGMT) had better overall survival. Further study revealed several more biomarkers or groups of biomarkers that could predict clinical outcome (2011 ASCO annual meeting, abstract LBA2000).
Gene deletion linked to poor glioblastoma survival. Previous studies have shown that nearly all glioblastomas have alterations in the epidermal growth-factor receptor (EGFR) gene, but drugs targeting this pathway have not been effective. One study has shown that the deletion ofNFKBIA, a gene that inhibits the EGFR signaling pathway, affects tumor formation, increases chemotherapy resistance, and worsens survival. It might provide a new target for treatment (N Engl J Med 2011; 364:627-637).
New mutation patterns were found in medulloblastoma. Researchers characterized the most common genetic alterations in medulloblastoma, making it the first pediatric solid tumor to be genetically sequenced (Science 2011;331:435-439). This might allow for better molecular classification of the disease and better prognosis, and might lead to the identification of new drug targets, the report notes.
Trastuzumab was approved for HER2-positive gastric cancer by the FDA in late 2010. The drug is indicated for use in patients with metastatic gastric cancer with tumors that express high levels of HER2 (about 15% to 18% of patients). Adding trastuzumab to chemotherapy (cisplatin and either capecitabine or 5-fluorouracil) was shown to improve survival in the ToGA trial(Lancet 2010;376:687-697). This trial was the first to show a median survival of more than 1 year in this patient population, the report notes.
Sunitinib (Sutent) and everolimus (Afinitor) were approved for pancreatic neuroendocrine tumors in patients with unresectable or metastatic disease. Both drugs were shown to more than double the time it took for the cancer to progress, compared with placebo, the report notes, and they offer new options for the treatment of this cancer, which previously was treated with interferon and chemotherapy. The indication for pancreatic neuroendocrine tumors was approved for sunitinib and everolimus within weeks of each another in May 2010.
Cabozantinib shows benefit in advanced prostate cancer in a phase 2 trial. This investigational drug showed impressive activity in a phase 2 trial in patients with progressive metastatic hormone-refractory prostate cancer (2011 ASCO annual meeting, abstract 4516). Results from 100 evaluable patients showed tumor shrinkage in 84% and disease control in 71% of patients. In addition, the researchers reported that 56 of 65 patients (86%) with bone metastases experienced either partial or complete disappearance of the bone metastases on scans, often with a drop in blood biomarkers that are indicative of bone damage, leading to significant pain relief.
Cabozantinib shows significant effect in melanoma and other cancers. The same investigational agent showed impressive activity in another phase 2 trial — this time in patients with a variety of advanced solid tumors (including liver, ovarian, and prostate cancer) and in melanoma (2011 ASCO annual meeting, abstract 3010). Cabozantinib, which also showed suppression of bone metastases, is a novel multitargeted agent, with activity against MET, VEGFR2, RET, KIT — protein kinases that are involved in the development and progression of many cancers, the report notes.
Axitinib (Inlyta) used as second-line therapy for advanced kidney cancer. Results from the phase 3 AXIS trial of 723 patients with metastatic renal cell carcinoma in whom previous treatment had failed showed that axitinib improved progression-free survival to 7 months, compared with 5 months with sorafenib (Nexavar) (2011 ASCO annual meeting, abstract 4503). Axitinib is not marketed yet, but an FDA Oncologic Drugs Advisory Committee recently voted unanimously to recommend its approval for second-line treatment in renal cell carcinoma.
Denosumab (Xgeva) prevents skeletal-related events in metastatic cancer patients. This novel bone drug, a monoclonal antibody that targets a protein (RANK ligand) involved in cancer-related bone destruction, was approved by the FDA in November 2010 for preventing skeletal-related events in cancer patients with solid tumors and bone metastases. In 2 clinical trials, denosumab was significantly better at reducing skeletal-related events in patients with advanced breast and prostate cancer than the bisphosphonate zoledronic acid (Zometa).
The Cancer Genome Atlas provides details on ovarian cancer and points to potential drug targets. The first comprehensive effort to map the genome of ovarian cancer focused on serous ovarian adenocarcinoma (which accounts for about 70% of deaths), and found several molecular features: TP53 mutations in 96% of cases, BRCA mutations in 22%, and defects that interfere with DNA repair (which could be susceptible to PARP inhibitors) in about 50% of tumors (Nature. 2011;474:609-615). These findings reinforce the promise of ongoing research on PARP inhibitors, which are being evaluated in late-stage clinical trials in ovarian cancer, the report notes.
PARP inhibitors and maintenance therapy used in ovarian cancer. A phase 2 study of 265 women with relapsed high-grade serous ovarian cancer showed that the investigational PARP inhibitor olaparib used after standard chemotherapy improved progression-free survival to 8 months, compared with 5 months for placebo (2011 ASCO annual meeting, abstract 5003). If these results are confirmed in larger trials, which are underway, olaparib could become an important treatment for women with advanced or high-risk ovarian cancer, the report notes.
The Lung Cancer Mutation Consortium matched tumor mutation to drug selection. Aprospective study identified at least 1 of 10 recognized "driver" mutations in tumors of nearly two thirds of patients with adenocarcinoma, many of which are targeted with drugs that are already marketed or in clinical trials. As a result of this program, "multiplex testing" for many tumor mutations at the same time is now routine at some of the 14 American centers that took part, and is also applicable to other cancers, the report notes.
Maintenance pemetrexed extends survival in advanced lung cancer. The phase 3 PARAMOUNT study showed that after initial treatment with pemetrexed and cisplatin, patients who continued on maintenance pemetrexed had a longer progression-free survival than those who did not (4 vs 3 months). This is the first trial to show that longer-term maintenance with one of the drugs used in the initial treatment can improve outcomes, the report notes. Pemetrexed maintenance was recently approved in Europe and has been approved in the United States since 2009, after a previous trial showed benefit.
Combination of investigational oral therapies used in melanoma. A phase 1/2 trial showed that a combination of 2 oral targeted therapies — the MEK inhibitor GSK1120212 and the BRAF inhibitor GSK2118436 — appears to have substantial antitumor activity in advanced melanoma. The results suggested promising synergistic anticancer activity (2011 ASCO annual meeting,abstract CRA8503).
Pazopanib (Votrient) and brivanib show benefit in advanced sarcoma. Pazopanib is already marketed for advanced kidney cancer, but has also shown benefit in patients with metastatic soft-tissue sarcoma in the phase 3 PALETTE trial. Second-line pazopanib improved progression-free survival, compared with placebo (5 vs 2 months) (2011 ASCO annual meeting,abstract LBA10002). The investigational drug brivanib, which blocks both vascular endothelial growth factor and the fibroblast growth factor, significantly improved progression-free survival, compared with placebo, in a phase 2 discontinuation study (2011 ASCO annual meeting,abstract 10000).
Other Notable Advances
Other notable advances covered in the report are related to strides that have been made in advanced cancer care, in patient and survivor care, and in prevention and screening.

CHEMOTHERAPY ALONE FOR HODGKIN LYMPHOMA?

 New long-term data have shifted the debate over the best treatment for patients with limited-stage Hodgkin's disease in favor of chemotherapy alone, and have highlighted the risk for late complications from radiotherapy.
The new long-term data, from a 12-year follow-up of the Hodgkin's Disease 6 trial (HD6), were presented here at the American Society of Hematology (ASH) 53rd Annual Meeting and published simultaneously online December 11 in the New England Journal of Medicine.
Chemotherapy alone was associated with a higher overall survival when compared with radiation with or without chemotherapy (94% vs 87% of patients were still alive at 12 years; hazard ratio, 0.50; 95% confidence interval, 0.25 - 0.99; P = .04). The main reason was fewer deaths from causes other than Hodgkin's lymphoma, including secondary cancers and cardiovascular events, said lead investigator Ralph Meyer, MD, from Queen's University, Kingston, Ontario, Canada.
Commenting on the study for Medscape Medical News, ASH President J. Evan Sadler, MD, PhD, professor of medicine in the Division of Hematology at Washington University in St. Louis, Missouri, said: "I interpret this study as evidence that the long-term complications of radiotherapy are not necessarily worth the short-term efficacy".
In the shorter term, the results from radiotherapy in combination with chemotherapy do look better, he said. "Now, looking at the very long-term data, the morbidity and mortality associated with late complications from radiotherapy may well trump this short-term effectiveness," he added.
Long-term survival is the most important treatment outcome, and "this is the first trial that used late survival as the primary end point," noted David Strauss, MD from the lymphoma service at the Memorial Sloan-Kettering Cancer Center, New York City, in an editorial accompanying the New England Journal of Medicine article.
Patients treated with radiation developed more secondary cancers and cardiovascular events, he noted, adding that deaths from these causes increase dramatically after 10 years, and so it could be expected that the rate of survival in these patients may decrease even further in the future.
Long Wait for Results 
The HD6 trialists have been very patient, waiting for 17 years for assessment of the primary end-point, and "the results have been well worth the wait," the editorialist comments.
When the study began in 1994, the standard of care for these patients with early-stage Hodgkin's lymphoma was radiotherapy, which in the trial was delivered as extended field subtotal nodal radiation (up to 35 Gy in 20 daily fractions). "This is no longer practiced today," Dr. Meyer commented at a press briefing, "and it would now be considered excessive."
How the results from this radiotherapy compare with modern radiotherapy approaches used now is one of the "core issues" with these data, and is discussed at length in both the published paper and the editorial, he noted.
The experimental group in the trial was chemotherapy alone, in which patients were given up to 4 or 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients assigned to radiotherapy who had an unfavorable risk profile (139/203 patients) also received chemotherapy, given as 2 cycles of ABVD.
At 12 years' follow-up, there were significantly fewer deaths in the group treated with chemotherapy alone compared with those treated with radiotherapy (12 vs 24).
The difference was primarily a result of death from causes other than Hodgkin's lymphoma, Dr. Meyers noted. There were 6 deaths from Hodgkin's lymphoma or an early-treatment complication of treatment in the chemotherapy-alone group, and 4 such deaths in the radiotherapy group, but there were only 6 deaths from other causes (4 from secondary cancers and 2 from cardiac events) in the chemotherapy-alone group compared with 20 such deaths in the radiotherapy groups (of which 10 were caused by secondary cancers and 2 by cardiac events).
When considering all patients, and not just those who died, secondary cancers were more common among those treated with radiotherapy (23 patients vs 10 receiving chemotherapy alone), as were cardiac events (26 vs 16).
Better Disease Control 
Patients treated with radiotherapy showed a benefit over those treated with chemotherapy alone in one aspect: they had better disease control. The rate of freedom from disease progression was significantly lower (12-year estimates, 87% vs 92%; hazard ratio for disease progression, 1.91; 95% confidence interval, 0.99 - 3.69; P = .05) among patients who had received radiotherapy.
However, these results challenge the notion that "keeping the disease away will keep patients living for longer," commented Dr. Myers, and these 12-year data show that this is not the case. Hodgkin's lymphoma is a "highly curable disease," and the mean age of patients is around 35 years. Thus, these new data "emphasize the importance of frontline treatment that is provided," he commented.
"The results of our study suggest that in the long term, patients with limited-stage Hodgkin's lymphoma may be better served by a treatment approach that uses chemotherapy without radiation, as this method seems to be associated with fewer deaths from other causes," Dr. Meyer concluded.
Debate Continues, but Practice Will Shift 
The debate over whether to use radiation as well as chemotherapy has raged fiercely for some years now, as previously reported by Medscape Medical News.
At present there is a split worldwide in how clinicians treat these patients, Dr. Meyers commented at the press briefing, with some using radiotherapy and others not. Although the old-fashioned radiotherapy used in this trial will fuel further debate over how these results apply to modern radiotherapy, and whether the long-term complications would be similar, Dr. Myers predicted that these new results will have an effect on clinical practice. He predicted that the proportion of physicians opting for each of the 2 approaches will change, and that clinicians more will now opt to use chemotherapy alone.
ASH Secretary Charles Abrams, MD, who was coordinator of the abstracts review and is associate chief of the Division of Hematology/Oncology at the University of Pennsylvania in Philadelphia, commented that this was a very well-designed study with very long-term follow-up. In answer to the question of whether this is a final answer, he said: "I doubt that there will be another trial like this."
The HD-6 trial was supported by a grant from the Canadian Cancer Society Research Institute. Dr. Myers reports receiving honoraria from Lilly and Cologne, and other coauthors also report relationships with industry, as detailed in the article. 
American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 590. Presented December 12, 2011.

TOP ONCOLOGY ADVANCES IN 2011

Counting Down: Game Changers 10 Through 6

In 2011, great progress was made in the science and management of a variety of cancers. Our Medscape commentators selected and ranked the top 10 game changers in oncology for 2011. Here are their selections.

10. New Regimen Improves Outcomes in Neuroblastoma

A provocative European study^[1] showed improved outcomes in high-risk neuroblastoma using a high-dose myeloablative regimen. Until now, the best outcome in neuroblastoma has hovered around the 50% survival threshold, but the new regimen tested has pushed this up to 60%. European investigators say this regimen should be the new standard of care. "This is an incredible success and a great achievement for pediatric oncology," said Julie Park, MD, from Seattle Children's Hospital in Washington, who acted as discussant for the study.
The results are important for patients with this extremely difficult-to-treat disease," said principal investigator Ruth Ladenstein, MD, MBA, Associate Professor of Pediatrics at the University of Vienna, Austria.
Treatment for neuroblastoma comprises several steps. It begins with intense upfront chemotherapy to induce remission (induction) and is followed by surgery and radiation, myeloablative therapy with stem cell transplantation, and then consolidation therapy with 13-cis-retinoic acid and immunotherapy, if available.
The European trial used an induction regimen known as rapid COJEC, which consists of both cisplatin and carboplatin, and then compared a high-dose myeloablative regimen known as BuMel (busulphan plus melphalan) with carboplatin, etoposide, and melphalan (control group).
The BuMel group led to significantly improved survival at 3 years compared with the control group (60% vs 48%). "The superiority was based on a lower relapse rate," noted Dr. Ladenstein.
Read the complete Medscape News article on this trial, which was presented during the plenary sessions of the 2011 American Society for Clinical Oncology (ASCO®) annual meeting.

9. A Shooting Gallery of Targets in Lung Cancer

The treatment of non-small cell lung cancer (NSCLC) is undergoing a revolution driven by a greater understanding of the genetic factors fueling this disease. In personalized therapy, drugs are chosen according to the mutations found in the patient's tumor rather than chemotherapy chosen for the organ where the tumor is located.
Contributing to the growing knowledge of genetic targets is a landmark study by the Lung Cancer Mutation Consortium (LCMC),^[2] which involves 14 centers across the United States. The LCMC conducted a prospective study in which lung cancer tissue was assessed using a multiplex assay that identified 10 known driver mutations. In addition to EGFR and ALK, they are testing for KRAS,HER2, BRAF, PIK3CA, AKTI, MEKI, NRAS, and MET. Many of these mutations have targeted agents under development or, in the case of HER2, have targeted drugs already on the market (trastuzumab and lapatinib, which are used in breast cancer). The results so far show that 54% of the tested tumor samples have single-driver mutations. This information is now being used to select patients for first-line therapy with erlotinib or to place these patients into clinical trials with experimental targeted therapies specifically directed at their tumor mutation.
"Although an individual driver mutation may have a single-digit percentage incidence, when you look at all of the possible mutations that exist in lung cancer, you are likely to find a mutation," said Mark G. Kris, MD, lead author and Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York City, in a Medscape commentary. "Even in individuals who did not have a mutation that would suggest a certain clinical trial, we knew what treatments not to give those patients." This study, Dr. Kris added, "brings us one step closer to our goal of personalized medicine."
View the complete commentary by Mark G. Kris, MD, and read the original Medscape News storyon this trial, which was reported at the 2011 ASCO® annual meeting.

8. Strongest Data Ever for ER-Positive Breast Cancer

The combination of everolimus plus exemestane produced "the strongest data ever seen in estrogen receptor [ER]-positive breast cancer," principal investigator José Baselga, MD, from the Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News. The pivotal phase 3 study, known as BOLERO-2,^[3] was stopped early because of the benefit observed. Results were unveiled at the 2011 European Multidisciplinary Cancer Congress (EMCC).
"Everolimus is the most important advance in breast cancer since trastuzumab," said Fabrice André, MD, PhD, from the Institut Gustave Roussy, Paris, France, who acted as discussant. "The data are robust and are clinically relevant," he said, adding that "the efficacy is in the range of the most important recent advances in the field of medical oncology."
Everolimus is an mTOR inhibitor that has already been approved in the United States for the treatment of progressive neuroendocrine tumors of pancreatic origin and advanced renal cell carcinoma in certain patients. Exemestane is an aromatase inhibitor that is already widely used as adjuvant therapy for ER-positive breast cancer. Both drugs are taken orally.
Read the complete Medscape News story on this trial.

7. Extended Adjuvant Treatment Improves Survival in GIST

Extended adjuvant treatment with imatinib improves survival in patients with high-risk gastrointestinal stromal tumors (GIST). Imatinib administered for 3 years improved both relapse-free survival and overall survival in patients after surgery, compared with 1 year of adjuvant treatment.^[4]
Previous data showed that initiating adjuvant imatinib therapy reduces the risk for GIST recurrence compared with placebo. "But the effect of imatinib on overall survival is not known," said lead author Heikki Joensuu, MD, Professor of Oncology at Helsinki University Central Hospital in Finland, who presented the findings during the plenary session here at the ASCO® 2011 annual meeting.
The 5-year relapse-free survival in patients was higher in those who received 3 years of treatment than in those who received 1 year (65.6% vs 47.9%; hazard ratio [HR], 0.46; P < .0001). The 5-year overall survival was also better in patients who received 3 years of therapy (92.0% vs 81.7%; HR. 0.45; P = .019).
Kathy Miller, MD, Chair of the scientific program for the 2011 ASCO® annual meeting, said in a Medscape commentary, "There had been a lot of debate in the GIST community that perhaps the drug was so effective in people with metastatic disease that you didn't really need to give adjuvant therapy for a longer time or maybe you didn't need to give it at all. You could just catch up and treat these folks when they recurred, and that was definitely not true. A longer duration of therapy, 3 years instead of 1, improved survival."
"We are looking at 92% in the 3-year group, and that is very high," said Dr. Joensuu. "We are making substantial improvement here."
View the complete commentary by Kathy D. Miller, MD, and read the original Medscape News story on this trial.

6. New Hope for Patients With Refractory Lymphoma

The experimental agent brentuximab vedotin, which has shown strong responses in patients with resistant and refractory Hodgkin lymphoma, was the first drug approved for lymphoma in 30 years. The results were reported at the 52nd annual meeting of the American Society of Hematology by Robert Chen, MD, Assistant Professor at the City of Hope National Medical Center in Duarte, California.^[5] The data come from a single-group multicenter study of 102 patients, all of whom had failed autologous stem cell transplantation and a median of 4 chemotherapy regimens (range, 1-13). The median age of patients was 31 years (range, 15-77 years).
Brentuximab 1.8 mg/kg was administered as a 30-minute outpatient intravenous infusion once every 3 weeks for up to 16 cycles of therapy (median, 9 cycles).
Responses were "dramatic," Dr. Chen said. The objective response rate was 75%, and tumor reduction was demonstrated in 94 patients (96%). Around one third of patients (34%) achieved complete remission.
In August, the US Food and Drug Administration (FDA) granted accelerated approval of brentuximab vedotin infusion for the treatment of relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, as reported at the time by Medscape.
"Why are we so excited about this?" asked Bruce D. Cheson, MD, Professor of Medicine, Georgetown University, Washington, DC, in a Medscape commentary. "Not only is this a great drug, it is also a proof of concept. We now have demonstrated that you can take an antibody and link it strongly to a poison. It will get in the cells and kill them, without doing much damage to the rest of the body. This will be one of many to follow in its footsteps."

5. Improved Survival in Metastatic Pancreatic Cancer

A chemotherapy combination provided the best survival time ever reported in metastatic pancreatic cancer, according to a study from French researchers, but the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) was considerably more toxic than gemcitabine. Data from the study, which were first presented at the 2010 annual meeting of ASCO® and reported by Medscape Medical News at that time, were published in May in The New England Journal of Medicine.^[6] Although the data are largely the same, the published paper includes new information on quality-of-life measures, said lead author Thierry Conroy, MD, from the Centre Alexis Vautrin, Vandoeurve les Nancy, France.
Gemcitabine, used alone or in combination with other agents, has been the "reference regimen" for advanced pancreatic cancer treatment for an extended period of time, according to Dr. Conroy and colleagues from 48 centers in France. However, the study authors propose that FOLFIRINOX is now a first-line option for patients with metastatic pancreatic cancer "who are younger than 76 years, and who have a good performance status (Eastern Cooperative Oncology Group score [ECOG] 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels."
"This is the first study to show substantial improvements in survival in advanced pancreatic cancer," said Alok A. Khorana, MD, Associate Professor and Vice-Chief of Hematology-Oncology at the University of Rochester, Rochester, New York, in a Medscape viewpoint. "It is unfortunate, however, that this gain occurs with an aggressive multichemotherapy regimen rather than with the addition of targeted therapy as many had hoped for. Although the efficacy of the regimen is clear and substantial, concerns about toxicity and tolerability are ongoing."

4. New Standard of Care for High-Risk ALL

A regimen of high-dose methotrexate was found to be superior to the standard protocol of escalating methotrexate in children and young adults with high-risk B-precursor acute lymphoblastic leukemia. The results of a phase 3 trial,^[7] which were presented at the 2011 ASCO® annual meeting, established a new standard of treatment for this population.
In a planned interim analysis, 5-year event-free survival for patients who received the high-dose regimen was 82% compared with 75% for those receiving the escalation protocol.
"We feel that it is the standard of care to receive high-dose methotrexate in this population," said lead author Eric C. Larsen, MD, Director of the Maine Children's Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children's Hospital at Maine Medical Center in Portland, adding that "high-dose methotrexate will be incorporated in current and future Children's Oncology Group trials for children and young adults."

3. Increased Survival in Metastatic HER2-Positive Breast Cancer

The first randomized trial to compare the novel agent trastuzumab emtansine (T-DM1) with standard therapy shows that it significantly increased progression-free survival in women with metastatic breast cancer.^[8] The study was presented at the 2011 EMCC in Stockholm, Sweden.
"First-line treatment with T-DM1 was associated with a statistically significant improvement in progression-free survival and was also associated with a reduction in the risk for toxicity," said lead author Sara Hurvitz, MD, Director of the Breast Oncology Program, Division of Hematology/Oncology, University of California, Los Angeles.
Median progression-free survival was 14.2 months for women who received T-DM1 and 9.2 months for those who received standard therapy with trastuzumab plus docetaxel. The hazard ratio was 0.59, indicating that treatment with T-DM1 reduced the probability of disease progression or death by 41% compared with standard therapy, noted Dr. Hurvitz.
"These results validate the hypothesis that the unique targeted delivery of chemotherapy through T-DM1 may lead to an improved therapeutic index," she said.
Fabrice André, MD, PhD, Associate Professor at the Institut Gustave Roussy, Villejuif, France, as reported in a Medscape commentary, finds T-DM1 interesting for 3 distinct reasons. "The first is conceptual -- This is the first time that an immunoconjugate (a combination of a monoclonal antibody and a cytotoxic agent) has shown efficacy in cancer. It's a new concept, and we have the proof of concept. The second reason is the finding that immunoconjugate is safer compared with conventional chemotherapy. We had the presentation today, during which we heard that the frequency of grade 3 adverse events was lower in patients treated with T-DM1. The third reason it is so important is that these drugs can be delivered for a long time. Because of this prolongation of the treatment, we had a better progression-free survival, specifically in HER2-positive breast cancer."
Because T-DM1 is not toxic, it can be administered for a long period of time, which leads to long-term progression-free survival.
"We are entering in a new era with this trial," said Dr. André. "At the very beginning, to obtain a response the drug is not better. Once we have a response and once the drug is working, we can administer the drug for a longer time period and know that the patient is not going to present with progressive disease, but at the opposite end -- in patients treated with trastuzumab and docetaxel -- we have to stop both the chemotherapy agents. Then the patient is going to have a progressive disease. In terms of induction of the response, there is not any major difference between T-DM1 and a combination of trastuzumab and docetaxel, but then duration of the response is very long. We are going through a scenario where we have induction with T-DM1, and once the patient has a response, then the response can be long lasting."

2. Lung Cancer Screening Comes of Age

The landmark National Lung Screening Trial,^[9] which enrolled 53,000 persons,showed that screening with low-dose spiral CT reduced mortality from lung cancer by 20%. CT screening was compared with chest radiographs, which have not shown any mortality reduction in previous trials.
The study was accompanied by expressions of enthusiasm from the American oncology community. "It's gratifying. We've been looking for this kind of good news in lung cancer for a long time," Otis Brawley, MD, Chief Medical Officer at the American Cancer Society, told Medscape Medical News. "It's simply an amazing result with an immediate impact on this disease," Mark G. Kris, MD, Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center, reported in a Medscape commentary.
"Finally we have a screening test that meets that gold standard and has a substantial opportunity to decrease the death rate for lung cancer," said Dr. Kris. "In the group that was screened, all patients had smoked 30 pack-years, which is the equivalent of 1 pack per day for 30 years, 2 packs per day for 15 years, and so on. Based on these data, it makes sense to recommend screening with a low-dose helical CT for any person who has smoked 30 pack-years."
In November, the National Comprehensive Cancer Network in an updated set of guidelines came out in favor of lung cancer screening, recommending the use of low-dose CT screening for select patients at high risk for disease.

1. The Top Game Changer for 2011 in Oncology

Unprecedented Advances in Melanoma

In 2011, 2 studies and 2 drug approvals revolutionized therapy for patients with metastatic melanoma. Vemurafenib and ipilimumab quickly became household names after studies on their efficacies in metastatic melanoma were highlighted in the plenary session of the 2011 ASCO® annual meeting.
In a phase 3 study^[10] that was accompanied by much praise and grand declarations, the targeted therapy vemurafenib was shown to dramatically improve progression-free and overall survival, compared with standard chemotherapy, in patients with advanced melanoma with no previous treatment.
Vemurafenib targets the V600E mutations in the BRAF gene, and an estimated 40%-60% of melanoma patients have this type of BRAF mutation.
The progression-free survival data constitute "an unprecedented level of difference," said lead author Paul Chapman, MD, from Memorial Sloan-Kettering Cancer Center.
This study is "practice changing," said Lynn Schuchter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. Responses with the new oral therapy can be dramatic -- patients can have improvement within 72 hours of treatment, she said.
In August, vemurafenib was approved by the FDA for the first-line treatment of both metastatic and unresectable melanomas, as reported at the time by Medscape News. The drug is specifically indicated for patients with melanoma whose tumors have V600E mutations in the BRAF gene.
A phase 3, international, multicenter study showed ipilimumab, a human monoclonal antibody, to be effective as first-line therapy in melanoma,^[11] increasing the number of patients who can benefit from the drug, which has just been approved for use as second-line therapy.
The data on first-line use were presented at the 2011 ASCO® annual meeting and published online in The New England Journal of Medicine to coincide with the presentation.
Ipilimumab in combination with dacarbazine improved overall survival in patients with previously untreated metastatic melanoma, compared with dacarbazine plus placebo, said senior author Jedd Wolchok, MD, from Memorial Sloan-Kettering Cancer Center. The drug was approved in March by the FDA as second-line therapy for patients with advanced melanoma, based on a study of previously treated patients. At the time of its approval, ipilimumab was the first agent ever proven to improve survival in advanced melanoma, as reported at the time by Medscape.
Overall survival in the study was significantly longer in the ipilimumab group than in the placebo group (11.2 vs 9.1 months; hazard ratio [HR] for death, 0.72; P < .001), Dr. Wolchok and his coauthors reported. The ipilimumab group had higher survival rates than the placebo group at 1 year (47.3% vs 36.3%), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%). The 3-year results are "very mature," commented Dr. Wolchok.
"Today we are in the very fortunate position of having 2 medicines approved for metastatic melanoma, the first time in 13 years that any medicine has been approved by the FDA for melanoma," said Dr. Wolchok. "Importantly, both of these medicines were approved on the basis of the gold standard endpoint -- namely, improvement of overall survival. We believe these newly approved treatments are a source of great hope to patients, their families, and their physicians."