The American Society of Clinical Oncology (ASCO) has summarized the major advancements in clinical oncology breakthroughs of 2013, published in the December 10 issue of JCO.Each year, ASCO has a panel of distinguished oncologists who peer evaluate the most important advances in the clinical field during the current year, and 2013 marks the ninth year of this process. This year the panel focused on 76 advances, and a short summary of the most important clinical events are listed in this article. Patient Treatment Patients often do not understand the purpose of cancer treatment. A study evaluating more than 1,000 cancer patients found that the majority believed they could be cured. Researchers found that 70% of lung cancer patients and 80% of colorectal cancer patients did not believe they had an incurable disease and did not understand that the purpose of their treatment was only palliative.ASCO says that these findings “highlight how information is communicated to patients and whether patients are making well-informed choices about treatment.” The guidelines do not support off-label use of chemotherapy drugs. A study of chemotherapy drug use found that about 30% of chemotherapy drugs were used for “off-label use,” and only about half of off-label uses met the National Comprehensive Cancer Network (NCCN) (JClinOncol. 2013;31:1134-1139) guidelines. commented that this needs to be carefully evaluated. Reference to antibiotic use guidelines may improve outcomes in granulocytopenic fever (FebrileNeutropenia). A study of 25,000 patients hospitalized with granulocytopenic fever from 2000 to 2010 found that adherence to guideline-recommended antibiotic use was associated with better outcomes (JAMAInternMed. 2013;173:559-568). In patients with low-risk granulocytopenic fever, rational use of antibiotics based on guideline recommendations significantly improves patient survival. Intravenous administration of CaMg does not reduce oxaliplatin-induced sensory neurotoxicity. A study enrolling 353 patients showed that titrating calcium and magnesium away does not reduce oxaliplatin-induced sensory neurotoxicity, and therefore the practice should be discontinued. This study was just published in the December 2, 2013 issue of JCO. Hematologic Malignancies Ibrutinib is a promising drug for the treatment of chronic lymphocytic leukemia and sleeve cell lymphoma resistant to prior therapy. It is an oral drug with a novel mechanism of action that inhibits Bruton’s tyrosine kinase. The results of a study on relapsed or treatment-resistant set-cell lymphoma showed that the therapeutic effect of the above drug was significantly better than that of salvage therapy (NEngJMed. 2013:369;507-516), which led to the approval of ibrutinib by the US FDA for the treatment of the above diseases. Another study of relapsed or treatment-resistant chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma showed that ibrutinib resulted in long-term remission (NEngJMed. 2013;369:32-42).The FDA is still reviewing whether CLL is an indication for ibrutinib. Engineered T cells may be effective in treating infiltrating, chemoresistant acute lymphoblastic lymphoma. A study of chimeric antigen receptor-modified T cells for acute lymphoblastic lymphoma (ALL) was only tested in a small population of adult and pediatric patients (NEngJMed. 2013;368:1509-1518). The latest study was presented at the just held American Society of Hematology annual meeting. Two New Drugs Approved for the Treatment of Chronic Myeloid Leukemia.FDA Grants Expedited Approval to 2 New Drugs:Omacetaxinemepesuccinate (Synribo) is approved for the treatment of chronic-phase and accelerated-phase chronic myeloid leukemia (CML) that has progressed after treatment with at least 2 tyrosine kinase inhibitor drugs. Ponatinib was initially approved for the treatment of adult patients with chronic-phase, accelerated-phase, and acute-phase CML who were resistant or refractory to prior tyrosine kinase inhibitor therapy, as well as patients with Philadelphia chromosome-positive ALL; however, reports of adverse effects led to the temporary withdrawal of the drug from the U.S. market, and it was later reintroduced to the market, with limitations on the indications and additional warnings. Pomalidomide (Pomalyst) is approved for the treatment of multiple myeloma. Pomalyst is approved for multiple myeloma in patients who have progressed despite at least 2 prior therapies, including lenalidomide (Revlimid) and bortezomib. Again, it was granted fast-track approval status. Lenalidomide (Revlimid), a lenalidomide capsule, was approved for the treatment of sleeve cell lymphoma. For patients with relapsed or progressive disease (treated with at least 2 prior therapies, 1 of which was bortezomib), Lenalidomide is approved for the treatment of these patients. This is another indication for lenalidomide, which has long been marketed for the treatment of multiple myeloma and myelodysplastic syndromes. Breast Cancer Itamoxifen treatment for 10 years instead of 5 years may further reduce the risk. Taking tamoxifen for 10 years instead of the 5 years recommended by current guidelines for patients with hormone-receptor-positive early-stage breast cancer after surgical treatment may further reduce the risk of breast cancer recurrence and death. The above results were derived from 2 large studies, the so-called ATLAS (Lancet. 2013;381:805-816) and aTTom (JClinOncol. 2013;31:6s; supplement, abstract5) studies. Paclitaxel has the same effect as once-weekly versus twice-weekly dosing. A randomized trial showed that giving this drug at a lower dose resulted in the same efficacy with fewer adverse effects than the higher dose given twice weekly. Ado-trastuzumabemtansine (Kadcyla) approved Kadcyla is approved for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and paclitaxel. It becomes the fourth targeted treatment option for patients with HER2-positive breast cancer after trastuzumab, lapatinib and patuximab. Gastrointestinal Cancer OctreotideLA (SandostatinLA) injection prolongs survival in patients with neuroendocrine tumors of the midgut.Long-term results from the PROMID study confirmed that the drug prolonged overall survival and found that the greatest benefit was seen in patients with a low liver load (JClinOncol. 2013;31:250s. supplement,abstract4030).ASCO commented that these results would stimulate clinicians to use octreotide in these patients. Capecitabine and bevacizumab can be used as a standard conservative treatment option for colorectal cancer. This combination regimen is now established as standard maintenance therapy, and the CAIRO3 study showed that the above combination therapy group improved survival in patients with metastatic colorectal cancer who were progression-free and inoperable without prior therapy and after initial treatment with capecitabine, oxaliplatin, and bevacizumab, compared with the placebo-treated group (JClinOncol. 2013;31:205s. supplement,abstract3502). Another combination regimen of bevacizumab plus chemotherapy has likewise been approved for the maintenance treatment of colorectal cancer (based on the ML18147 study). Colorectal cancers harboring mutations in the NRAS gene do not benefit from panitumumab treatment (Vectibix). Colorectal cancer patients should be tested for harboring KRAS mutations (in about 40% of cases) before considering administration of panitumumab, but currently there is a need to test for NRAS mutations again (in only 10% of cases) because both of these mutations render panitumumab treatment ineffective.The relevant findings for the NRAS mutations come from a new analysis of the data from the PRIME study (NEngJMed. 2013;369: 1691-1703). Albumin-bound paclitaxel (Nab-paclitaxel (Abraxane)) is approved for the treatment of pancreatic cancer. In addition, the MPACT trial established this drug in combination with gemcitabine as the new standard of care for metastatic pancreatic cancer (NEngJMed. 2013;369:1691-1703). Albumin-bound paclitaxel, now marketed for the treatment of breast cancer, has recently been approved for the treatment of non-small cell lung cancer. S-1 chemotherapy improves survival in pancreatic cancer. Another phase 3 trial showed that S-1 substantially improved survival in Asian patients compared with gemcitabine (JClinOncol. 2013;31:244s;supplement,abstract4008), and the ASCO review suggests that the above results suggest that S-1 could be considered as a new standard of care, but notes that to date the drug has only been shown to be effective in Japan and some other countries, and that its preliminary results suggest more toxic reactions when used in European patients, requiring dose reduction. Genitourinary Cancer Cabozantinib has shown unusual activity in the treatment of prostate cancer. Including the disappearance of bone metastases seen on scans (JClinOncol. 2013;31:314s;supplement,abstract5026), the effect was described as “unprecedented”. However, when used at high doses with adverse effects, the ASCO review concluded that further studies are needed, and a large phase 3 trial to collect survival data is underway. Cabozotinib is a multi-receptor tyrosine kinase inhibitor also approved for the treatment of medullary thyroid cancer. A study directly comparing pazopanib and sunitinib for the treatment of metastatic renal cell carcinoma found similar efficacy. However, sunitinib had more adverse effects (NEngJMed. 2013;369:722-731). Immunotherapy is expected to be used for renal cell carcinoma treatment. Patients who progressed despite multiple treatments showed activity with anti-PD-LIMPDL3280A therapy (JClinOncol. 2013;31:391s;supplement,abstract5026); this drug has also shown activity against a variety of other tumor types. Radium 223 (Xofigo) is approved for the treatment of advanced prostate cancer.Xofigo is FDA-approved for the treatment of patients with advanced prostate cancer and patients with bone metastases who have painful symptoms. AbirateroneAbiraterone (Zytiga) was approved for the first-line treatment of prostate cancer. Along with the approval the FDA also broadened the indications for the drug’s use in the treatment of this type of disease; it was also approved for use after chemotherapy. Gynecologic Cancer Simeatinib (Selumetinib) is expected to be used in the treatment of plasma ovarian cancer (LancetOncol. 2013;14:134-140). This investigational drug, a novel MEK inhibitor has also shown activity when applied to several other tumors and has become the first drug available for uveal melanoma. Bevacizumab plus chemotherapy improves survival in advanced ovarian cancer.The ASCO review considered the GOG240 study a landmark trial (JClinOncol. 2013;31:6s;supplement,abstract3). However, bevacizumab is not approved for this pathway (yet). Lung Cancer Afatinib (Gilotrif) is approved for the treatment of NSCLC. A study showed a 4.2-month improvement in disease-free survival compared to chemotherapy.Gilotrif is approved for first-line treatment of patients harboring EGFR mutations. Erlotinib (Tarceva) is approved for the first-line treatment of EGFR+ve NSCLC. Erlotinib was approved for the first-line treatment of EGFR+veNSCLC after a study showed that it improved patient survival by 5.2 months compared to chemotherapy, and the FDA approved a companion diagnostic kit. Erlotinib, which has long been marketed for the treatment of non-small cell lung cancer, was expanded for this indication, but the approved indication was previously only for second- or third-line treatment. Melanoma Dabrafenib (Tafinalar) and trametinib (Mekinist) are approved for melanoma treatment. dabrafenib is a BRAF inhibitor and is approved for the treatment of patients with melanoma harboring the BRAFV600E mutation, while trametinib is a MEK inhibitor that is is approved for the treatment of patients with melanoma harboring mutations in the BRAFV600E or V600K genes. Results from trials of PD1-targeted immunotherapy for melanoma have been encouraging. Here, ASCO highlights several trial drugs, including nivolumab, lambrolizumab (MK-3475), and MPDL3280A, a study (NEngJMed. 2013;369:122-133) using ibritumomab in combination with nivolumab that showed “truly remarkable” remission. Sarcoma Imatinib (Gleevec) for gastrointestinal mesenchymal stromal tumor (GIST) retreatment provides moderate benefit. A report from South Korea used imatinib for the first time in patients with GIST that progressed after first-line treatment with imatinib or sunitinib. The results showed a moderate benefit from retreatment, which ASCO considered suggestive of a small but statistically significant improvement in both progression-free survival and overall survival (JClinOncol. 2013;31:632s;supplement,abstractLBA10502). Regorafenib (Stivarga) tablets were approved for the treatment of treatment-resistant GIST. The approval specifically targets the population of advanced and inoperable patients who have progressed after prior treatment with imatinib and sunitinib. One study showed a nearly four-fold improvement in progression-free survival in patients. This is another indication for regrafinib tablets, which are marketed for use in patients with colorectal cancer. Didinossemide (Denosumab (Xgeva)) was approved for the treatment of giant cell tumor of bone. The drug’s approval provides another treatment option for patients who cannot be surgically removed, and in clinical trials it led to tumor regression in 47% of patients. The approval adds another indication for Didinossemide, which is already marketed for the treatment of cancer patients with osteoporosis and those with bone metastases. Other cancers Sorafenib tablets (Sorafenib (Nexavar)) block the growth of treatment-resistant thyroid cancer.The DECISION trial showed that the drug improved progression-free survival in patients (JClinOncol. 2013;31:6s;supplement,abstract4). Sorafenib was recently confirmed for the treatment of metastatic differentiated thyroid cancer, becoming the first drug in this indication in 40 years. Sorafenib is marketed for the treatment of hepatocellular carcinoma. Recent results have shown advances in the treatment of oligodendroglioma (oligodendroglioma). Long-term follow-up of 2 trials in degenerative oligodendroglioma showed no significant improvement in survival when chemotherapy was added to radiation. 1p/19q-deficient patients may derive benefit, and ASCO commented that the results of the trials in the above patient subgroups may change the standard of care. Crizotinib (Xalkori) showed activity. Crizotinib showed extraordinary activity in young patients with treatment-resistant solid tumors carrying ALK gene variants, including adult neuroblastoma, inflammatory adult myofibroblastoma, thought patients with degenerative large cell lymphoma (ALCL). Some patients experienced complete remission (LancetOncol. 2013;14:472-480). Prevention and Screening Daily multivitamin supplementation may generally reduce cancer risk in men. This conclusion comes from an analysis of the Physicians’ Health Study 2 program, which included 14,641 male physicians, no less than 50 years of age (JAMA. 2012;308:1871-1880), with a median follow-up period of 11 years, and found that men taking multivitamins showed a small, but statistically significant, reduction in the incidence of cancer when compared to the population of patients taking placebo (17.6% vs. 18.8%).ASCO commented, “Supplementation with a low-dose multivitamin is more effective than supplementation with a high-dose single vitamin.” HPV Cancers Increase, but HPV Vaccine Coverage Uneven Across U.S. Regions. The national annual report notes a decline in cervical cancer rates from 2000 to 2009, but an increase in the occurrence of a number of HPV-related cancers, including oropharyngeal, anal, and vulvar cancers in both men and women. The same report also noted that only 32 percent of 13- to 17-year-olds have completed all three HPV vaccinations. Finasteride is not approved for chemoprevention of prostate cancer. This topic has been debated for several years. The use of finasteride was supported by data from the Prostate Cancer Prevention Trial, which showed a 25% decrease in prostate cancer incidence in patients using finasteride compared to those taking placebo, but at the same time, it found an increased incidence of high-grade cancers in the finasteride group. As a result, finasteride is not approved for chemoprevention of prostate cancer. Currently, long-term follow-up (median follow-up period of 18 years) found no difference in overall survival between the finasteride and placebo groups.