Δευτέρα, 29 Μαΐου 2017

AUTOIMMUNE ADVERSE EVENTS WITH IMMUNOTHERAPY

The use of immune checkpoint inhibitors to treat cancer has markedly expanded since 2011, when the anti-CTLA-4 agent ipilimumab was approved by the United States Food and Drug Administration (U.S. F.D.A.) for the treatment of advanced melanoma. Subsequently, antibodies which target programmed death-1 (PD-1) and its ligand PD-L1 have been approved by the U.S. F.D.A. for melanoma,[1,2] non-small cell lung cancer,[3,4] bladder cancer,[5] Hodgkin lymphoma,[6] renal cell carcinoma[7]and squamous cell carcinoma of the head and neck.[8] Given the clinical efficacy of this class of drugs, several antibodies received accelerated approval, in some cases without data from a Phase III clinical trial. For example, pembrolizumab was FDA-approved for the treatment of melanoma in December of 2014, 3 months after the Phase I results were published.[9]
Investigators in early phase clinical trials quickly recognized that the administration of immune checkpoint inhibitors was associated with a unique set of inflammatory, autoimmune side effects known as immune related adverse events (irAE). The most common irAEs, such as rash, colitis, hepatitis and endocrinopathies, have been identified and are well-described in the literature (Figure 1). However, rare but serious irAEs have been identified during post-marketing surveillance, several of which are highlighted in letters to the editor in the current and upcoming issues of Annals of Oncology. Recently, Johnson et al. reported that two patients treated with the combination of nivolumab and ipilimumab died from fulminant myocarditis.[10]There is also growing recognition that the PD-1/PD-L1 inhibitors can be associated with a number of neurologic syndromes, ranging from peripheral neuropathy to aseptic meningitis and Guillain-Barré syndrome, as described by Spain et al.[11] and Aya et al..[12] Moreover, atypical adverse events that are not easily categorized are described in accompanying letters by Shenoy et al.[13] and Hoadley et al.,[14] who report atypical dermatologic and gastrointestinal adverse events associated with pembrolizumab.
Figure 1.
Approximate proportion of patients affected by immune-related adverse events of any grade upon treatment with single-agent PD-1 blockade. Precise incidence varies by study, disease and agent [19]. *Example of rare event featured in this, or an upcoming issue of Annals of Oncology.
This 'long tail' of rare autoimmune syndromes raises the questions of how to identify and manage such irAEs. When faced with atypical symptoms in any patient currently or previously treated with checkpoint blockade therapies, clinicians should consider irAEs high on the differential diagnosis. When possible, clinicians should strongly consider seeking the expertise of consultant subspecialists, for example within the fields of gastroenterology, rheumatology, endocrinology and neurology. With respect to management, the package insert of each F.D.A.-approved checkpoint blockade agent features guidance on management of irAE, including when to hold the drug and the dose of corticosteroids to initiate.[15–18] The mainstay of treatment is early administration and slow tapering of oral corticosteroids, although admission to the hospital for observation and intravenous corticosteroids should be considered for patients with high-grade irAE.[20,21]
For atypical irAEs, the bulk of the published case reports and series support the use of corticosteroids as the initial treatment modality. This principle is reinforced by the accompanying letters in this and upcoming issues of Annals of Oncology, where the administration of corticosteroids resulted in the resolution of almost all irAEs. However, clinicians would benefit from more guidance on how to manage steroid-refractory, atypical irAEs. Spain et al.[11] have proposed an algorithm for the treatment of neurologic irAEs, focusing on suppression of humoral immunity. This approach warrants further consideration; moreover, detailed investigation into both the underlying mechanisms and treatment of neurologic irAEs is needed.
Subspecialty collaboration is essential when managing patients with pre-existing autoimmunity. As described by Menzies et al.,[22] 38% of patients with pre-existing autoimmune conditions who were treated with immune checkpoint inhibitors had a flare in their autoimmune condition; however, only 4% of patients discontinued treatment due to that flare. This finding is consistent with retrospective data in patients treated with ipilimumab.[23] The sum of these data should empower clinicians to utilize immune checkpoint inhibitors in this group of patients, despite the fact that they were excluded from clinical trials of these agents. However, treatment should occur in collaboration with the patient's primary physician or specialist in order to expedite communication and modulate immunosuppression, including the addition of corticosteroids when appropriate if irAE arise.
In the post-marketing surveillance era of immune checkpoint inhibitors, it is essential to remain vigilant for new and atypical irAEs. As the prescribing indications for these drugs expand to include new cancers and combination therapies, a larger pool of clinicians will continue to gain proficiency in managing both typical and atypical irAEs. While further research is necessary to understand the underlying mechanisms of irAEs, clinicians should be reassured that the majority of irAEs can be safely managed by referring to pre-existing guidelines for the early initiation of corticosteroids and utilizing expert consultants as needed.

MANY MORE WOMEN LIVE WITH METASTATIC BREAST CANCER

A study by Mariotto et al investigating the prevalence of women living with metastatic breast cancer in the United States estimates that there are 154,794 women living with the disease. In addition, the median and 5-year relative survival for women initially diagnosed with metastatic breast cancer is improving, especially among younger women, with more than 11% of women diagnosed between 2000-2004 under the age of 64 surviving 10 years or more. An aging population and more effective treatments are likely the reason for the increase in survivors. The study findings highlight the need for more research into how to address the health care needs of women living longer with metastatic breast cancer. The study is published in Cancer Epidemiology, Biomarkers & Prevention.
The study researchers, which included scientists from the National Cancer Institute (NCI), the Metastatic Breast Cancer Alliance, and the Fred Hutchinson Cancer Research Center, used national data on breast cancer mortality and metastatic breast cancer survival from the NCI’s Surveillance, Epidemiology and End Results (SEER) registries to estimate the prevalence of women living with metastatic breast cancer in the United States, including both women initially diagnosed with metastatic breast cancer and those who have progressed to distant metastatic breast cancer. The researchers also calculated the prevalence of women diagnosed with de novo metastatic breast cancer in SEER and the United States. The SEER de novo metastatic breast cancer prevalence was compared with an estimate based on the back-calculation method to validate the method and calibrate survival.
Key Study Findings
The researchers estimated that by January 21, 2017, there will be 154,794 women living with metastatic breast cancer in the United States, 3 in 4 initially diagnosed with stage I-III breast cancer who later progressed to metastatic breast cancer.
Median survival and 5-year relative survival for de novo metastatic breast cancer increased over the years, especially in younger women. The researchers estimated a 2-fold increase in 5-year relative survival rate from 18% to 36%, for women diagnosed with de novo metastatic breast cancer at age 15 to 49 between 1992–1994 and 2005–2012, respectively.
“The increasing burden of metastatic breast cancer highlights the importance of documenting recurrence to foster more research into the specific needs of this understudied population,” concluded the study authors.
Study Significance
“These findings make clear that the majority of metastatic breast cancer patients, those who are diagnosed with nonmetastatic cancer but progress to distant disease, have never been properly documented,” said Angela B. Mariotto, PhD, Chief of the Data Analytics Branch of the Division of Cancer Control and Population Sciences at the NCI and lead author of this study, in a statement. “This study emphasizes the importance of collecting data on recurrence at the individual level in order to foster more research into the prevention of recurrence and the specific needs of this growing population.”
Marc Hurlbert, PhD, Chair of the Metastatic Breast Cancer Alliance and Chief Mission Officer of the Breast Cancer Research Foundation, adds that this study’s findings are an important first step toward a comprehensive assessment of the burden of disease on patients with metastatic breast cancer.
“One of the critical issues that the Metastatic Breast Cancer Alliance heard from breast cancer experts and metastatic breast cancer patients when the Metastatic Breast Cancer Alliance conducted its Landscape Analysis Research Report was the inadequate statistics and epidemiological data on the number of patients living with metastatic breast cancer. This is the first study report of many in the works filling in that information,” said Dr. Hurlbert.
Funding for this study was provided by the NCI.

FINAL SURVIVAL ANALYSIS OF EMILIA AND THERESA

As reported in The Lancet Oncology by Diéras et al, the final overall survival results of the phase III EMILIA trial show improved outcome with ado-trastuzumab emtansine (Kadcyla) vs capecitabine plus lapatinib (Tykerb) in previously treated HER2-positive advanced breast cancer. Approval of trastuzumab emtansine for treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab (Herceptin) and a taxane is based on progression-free survival and interim overall survival findings in the trial.
Study Details
In the trial, 991 patients previously treated with trastuzumab and a taxane were randomized between February 2009 and October 2011 to receive ado-trastuzumab emtansine at 3.6 mg/kg every 3 weeks (n = 495) or oral capecitabine at 1,000 mg/m² twice daily on days 1 to 14 of each 21-day cycle plus lapatinib at 1,250 mg orally once daily on days 1 to 21 (n = 496). In May 2012, the study protocol was amended to allow crossover from control to ado-trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified efficacy boundary.
Overall Survival
The cutoff date for the final analysis was in December 2014. The median duration of follow-up was 47.8 months in the ado-trastuzumab emtansine group and 41.9 months in the control group. Median overall survival was 29.9 months (95% confidence interval [CI] = 26.3–34.1 months) in the ado-trastuzumab emtansine group vs 25.9 months (95% CI = 22.7–28.3 months) in the control group (hazard ratio = 0.75, 95% CI = 0.64–0.88).
In the control group, 136 patients (27%) crossed over to ado-trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration = 24.1 months). In the ado-trastuzumab emtansine group, 254 patients (51%) received capecitabine and 241 patients (49%) received lapatinib (separately or in combination) after ado-trastuzumab emtansine discontinuation. A post hoc sensitivity analysis that censored patients at the time of crossover to ado-trastuzumab emtansine showed similar outcome (median = 29.9 vs 24.6 months, HR = 0.69, 95% CI = 0.59–0.82).
Adverse Events
Grade ≥ 3 adverse events occurred in 48% of the ado-trastuzumab emtansine group vs 60% of the control group. The most common events were thrombocytopenia (14%), increased aspartate transaminase (5%), and anemia (4%) in the ado-trastuzumab emtansine group and diarrhea (21%), palmar-plantar erythrodysesthesia syndrome (18%), and vomiting (5%) in the control group. Three deaths in the ado-trastuzumab emtansine group (due to metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukemia) and two deaths in the control group (due to coronary artery disease and multiorgan failure) were considered related to study treatment.
The investigators concluded: “This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population.”
The study was funded by F. Hoffmann-La Roche/Genentech.


The final overall survival results of the phase III TH3RESA trial indicate a 32% reduction in risk of death with ado-trastuzumab emtansine (Kadcyla) vs treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer. The findings were reported in The Lancet Oncology by Krop et al.
Study Details
In the trial, 602 patients previously treated with both trastuzumab (Herceptin) and lapatinib (Tykerb; advanced setting) and a taxane (any setting) and with disease progression on at least 2 HER2-directed regimens in the advanced setting were randomized 2:1 between September 2011 and November 2012 to receive ado-trastuzumab emtansine at 3.6 mg/kg every 21 days (n = 404) or treatment of physician’s choice (n = 198). Of 185 patients in the physician’s choice group who received study treatment, 153 received combination therapy including a HER2-directed agent.
In September 2012, the study protocol was amended to allow patients in the physician’s choice group to cross over to ado-trastuzumab emtansine at disease progression. As reported previously, ado-trastuzumab emtansine was associated with a significantly prolonged progression-free survival, a co-primary endpoint along with overall survival. The current report is from the second interim analysis of overall survival, which was planned to occur when approximately 67% (n = 330) of 492 expected deaths had occurred.
Improved Overall Survival
As of data cutoff in February 2015, 47% of the physician’s choice group had crossed over to ado-trastuzumab emtansine. Median follow-up was 30.5 months. At the interim analysis, median overall survival was 22.7 months (95% confidence interval [CI] = 19.4–27.5 months) in the ado-trastuzumab emtansine group vs 15.8 months (95% CI = 13.5–18.7 months) in the physician’s choice group (hazard ratio [HR] = 0.68, = .0007). The stopping boundary for overall survival was crossed, making this analysis the final analysis and resulting in study termination.
A post-hoc sensitivity analysis that censored patients at the time of crossover to ado-trastuzumab emtansine showed consistent results (median = 22.7 months vs 15.6 months, HR = 0.58, = .0002). Subgroup analyses showed consistent benefits of ado-trastuzumab emtansine according to age, number of previous treatment regimens, visceral disease involvement, tumor hormone receptor status, presence or absence of brain metastases, and type of treatment of physician’s choice.
Adverse Events
Grade ≥ 3 adverse events occurred in 40% of the ado-trastuzumab emtansine group vs 47% of the physician’s choice group. Those events that were ≥ 3% more common in the ado-trastuzumab emtansine group consisted of thrombocytopenia (6% vs 3%) and hemorrhage of any type (4% vs < 1%). Serious adverse events occurred in 25% vs 22%. Death due to adverse events occurred in nine patients (2%; three related to treatment) and three patients (2%; one related to treatment), respectively.
The investigators concluded: “In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician’s choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer and validate HER2 as a therapeutic target even after multiple lines of previous therapy.”
The study was funded by F. Hoffmann-La Roche/Genentech.
Ian E. Krop, MD, of the Dana-Farber Cancer Institute, is the corresponding author of The Lancet Oncologyarticle. 

1 IN 5 CANCERS DIAGNOSED IS RARE

About one in five cancer diagnoses in the United States is a rare cancer, according to new research from the American Cancer Society. The report, published by DeSantis et al in CA: A Cancer Journal for Clinicians, found rare cancers account for more than two in three cancers occurring in children and adolescents. The authors say the proportion of rare cancers is likely to grow as the use of molecular markers to classify cancers increases.
Rare cancers present unique challenges for clinicians and their patients. For most rare cancers, research to identify causes or to develop strategies for prevention or early detection is limited or nonexistent. In addition, rare cancers can be challenging to diagnose, often resulting in numerous physician visits, misdiagnoses, and substantial delays in diagnosis.
Treatment options for rare cancers are often more limited and less effective than for more common cancers, partly because there is less preclinical research and fewer clinical trials for rare cancers, which are often limited to select high-volume cancer centers. Consequently, rare cancers have become an area of priority for some researchers and public health advocates. There are limited published data on the burden of rare cancers in the United States.
Findings
Investigators led by Carol E. DeSantis, MPH, cancer epidemiologist and Director of Breast and Gynecological Cancer Surveillance at the American Cancer Society, used data from the North American Association of Central Cancer Registries and the Surveillance, Epidemiology, and End Results (SEER) program to comprehensively examine contemporary incidence rates, stage at diagnosis, and survival for more than 100 rare cancers (defined as an incidence of fewer than 6 cases per 100,000 individuals per year) in the United States.
They found overall, approximately 20% of patients with cancer in the United States are diagnosed with a rare cancer. Rare cancers make up a larger proportion of cancers diagnosed in Hispanic (24%) and Asian/Pacific Islander (22%) patients compared with non-Hispanic blacks (20%) and non-Hispanic whites (19%). More than two-thirds (71%) of cancers occurring in children and adolescents are rare cancers, compared with less than 20% of cancers diagnosed in patients aged 65 years and older.
Among solid tumors, 59% of rare cancers are diagnosed at regional or distant stages compared with 45% of common cancers. In part because of this stage distribution, 5-year relative survival is poorer for patients with a rare cancer compared with those diagnosed with a common cancer among both males (55% vs 75%) and females (60% vs 74%). However, 5-year relative survival is substantially higher for children and adolescents diagnosed with a rare cancer (82%) than for adults (46% for ages 65–79 years).


“Continued efforts are needed to develop interventions for prevention, early detection, and treatment to reduce the burden of rare cancers”, wrote the authors. “Such discoveries can often advance knowledge for all cancers.”

FIRST DRUG APPROVED FOR GENETIC DEFECT AND NOT TUMOR TYPE-LOCATION

The latest approval of a cancer drug by the US Food and Drug Administration (FDA) changes the paradigm of cancer treatment — the new indication specifies a genetic defect without any mention of tumor types. It allows the drug to be used in any cancer that harbors the specified genetic defect, wherever the tumor appears in the body.
This is an important first for the cancer community. Dr Richard Pazdur
"This is an important first for the cancer community," said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and director of the FDA's Oncology Center of Excellence.
"Until now, the FDA has approved cancer treatments based on where in the body the cancer started — for example, lung or breast cancers. We have now approved a drug based on a tumor's biomarker without regard to the tumor's original location."
The new approval is for the immunotherapy pembrolizumab (Keytruda, Merck & Co), which is already approved for use in several different tumor types, including melanoma and lung cancer.
But this latest approval covers the use of pembrolizumab in tumors that have microsatellite instability-high (MSI-H) or are mismatch repair deficient (dMMR).
These defects are found most commonly in colorectal, endometrial, and gastrointestinal cancers but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland, and other places, the agency notes.
Approximately 5% of patients with metastatic colorectal cancer have MSI-H or dMMR tumors, it adds.
All patients with advanced cancer who have had at least one standard therapy should be tested. Dr Dung Le
"All patients with advanced cancer who have had at least one standard therapy should be tested to see if their tumor harbors these genetic defects," Dung Le, MD, an oncologist at the Johns Hopkins Bloomberg-Kimmel Institute, Baltimore, Maryland, told Medscape Medical News. "And if the patient is found to have this defect, the next step is to try pembrolizumab."
Pembrolizumab is the drug that has the approval, but Dr Le says that she would also expect similar responses with other immunotherapies with the same mode of action, programmed cell death-1 inhibition. 
"This is a paradigm shift — now we are not looking at where the tumor started, what organ it is in, but we are looking across all tumor types — and we are bringing a treatment to patients with all types of tumors, many of whom were thought not to respond to immunotherapy," Dr Le commented
Tests for defects in mismatch repair are already widely available, costing around $300 to $600. "These tests are available everywhere, because they are already in use for identifying Lynch syndrome," Dr Le commented.  
The genetic defects, MSI-H and dMMR, interfere with the usual process of DNA repair inside cells, which results in unchecked cellular growth, a hallmark of cancer. It also results in a lot of mutations, and these tumors often have T cells infiltrating them, which make them a good target for immunotherapy, Dr Le explained in an interview.
Dr Le was the principal investigator on the first trial to show that tumors with MSI respond to immunotherapy with pembrolizumab (the Keynote 16 trial, an investigator initiated study for which Merck just provided the drug).
The results from that trial showed that patients with colorectal cancer with normal DNA repair (microsatellite stable) had zero response to pembrolizumab, whereas those with MSI and deficient DNA repair had a 50% response rate, she said. In addition, about 20% had stable disease.
This is much higher than has been seen with immunotherapy in other tumor types, where fewer than 20% patients respond, she added.
But the trial also included patients with any solid tumor and MSI, and these patients also showed the 50% response rate and 20% stable disease results.
"So it's not just colorectal cancer," Dr Le told Medscape Medical News. "We think these defects are found in about 4% of all advanced cancers," she said.
We think these defects are found in about 4% of all advanced cancers. Dr Dung Le
These defects seem to occur in all solid tumors, and the finding that all tumors with this defect respond in a similar way is new, Dr Le emphasized. It is also unique, as this has not been found with other genetic mutations and defects.
For example, BRAF-mutated melanoma responds very well to treatment with a BRAF inhibitor, as does thyroid cancer, but BRAF-mutated colorectal cancer does not have any response. It seems that different molecular circuitry is involved, with different bypass mechanisms, she added, and seems to be "hit or miss."
This is the first pan-tumor marker, and the fact that the FDA approved the drug for use in children as well as adults shows "how strong the biology is," she commented.

Accelerated Approval 

The new indication for pembrolizumab is for use of the drug in adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having MSI-H and dMMR. This indication covers patients with solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as patients with colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
This indication received priority review and an accelerated approval, based on  tumor response rates and durability of response; confirmatory trials are in progress, which will provide data on survival and clinical benefits.
The data used for approval come from five uncontrolled single-arm studies conducted in patients with MSI-H or dMMR solid tumors, the agency notes. In some of these trials, patients were required to have MSI-H or dMMR cancers, whereas in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began.
A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial, and other gastrointestinal cancers.
Pooled results from these trials show that of the 149 patients who received pembrolizumab, 39.6% had a complete or partial response; for 78% of those patients, the response lasted for 6 months or more.
The FDA notes that common side effects of pembrolizumab include fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. The drugs can also cause serious immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
The recommended dose of pembrolizumab in adults is 200 mg (in children the dose is 2 mg/kg, up to a maximum of 200 mg), and the drug is administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

THROMBOCYTOSIS INCREASE CANCER RISK

A new finding could improve early detection of cancer among individuals in the general population who are seen by family doctors, say British researchers. They found that patients with increased blood platelet counts (thrombocytosis) are at increased risk for being diagnosed with cancer within a year, particularly if they have a second raised platelet count within 6 months.
The finding comes from a large, population-based study, which was published onlinein the British Journal of General Practice on May 22.
The study showed that 11% of men and 6% of women with thrombocytosis were diagnosed with cancer within the following year.
Crucially, one third of the patients who went on to be diagnosed with lung or colorectal cancer had no other symptoms that would have prompted an urgent referral for cancer.
"It is in this group that thrombocytosis has the greatest potential to prompt earlier diagnosis, where other symptoms have not yet developed. This strongly suggests that cancer should be considered when a result is received showing thrombocytosis, even if cancer was not initially suspected," the researchers comment.
They add that thrombocytosis has not hitherto been widely regarded as a cancer risk factor.
However, their results "show that substantial proportions of lung and colorectal cancer diagnoses could be expedited by at least 2 months if thrombocytosis were to be routinely investigated."
This could yield approximately 5500 earlier diagnoses annually across the United Kingdom.
[P]eople could have their cancer diagnosed up to three months earlier if thrombocytosis prompted investigation for cancer. Dr Sarah Bailey
 Lead author, Sarah Bailey, MPH, PhD, research fellow at the University of Exeter Medical School, United Kingdom, said in a statement:  "We know that early diagnosis is absolutely key in whether people survive cancer. Our research suggests that substantial numbers of people could have their cancer diagnosed up to three months earlier if thrombocytosis prompted investigation for cancer. This time could make a vital difference in achieving earlier diagnosis."

Study Details 

The researchers conducted a prospective cohort study of data from the UK Clinical Practice Research Datalink, which holds anonymized electronic primary care records from approximately 8% of UK practices.
The team extracted a random sample of 40,000 patients aged at least 40 years who had a platelet count greater than 400 x 109/L recorded between 2000 and 2013 and also identified 10,000 age-, sex- and primary care practice–matched individuals with a normal platelet count.
After exclusions, 31,261 individuals with thrombocytosis were included in the analysis. Their median age was 67.9 years, and 69.8% were female. The final comparison cohort comprised 7969 individuals, with a median age of 68.3 years; 67.4% were female.
Within 1 year of being identified as having thrombocytosis, 11.6% of men and 6.2% of women were diagnosed with cancer. This compared to a 1-year cancer incidence among individuals with a normal platelet count of 4.1% in men and 2.2% in women.
In the second year after identification of thrombocytosis, the incidence of cancer returned to baseline levels.
However, if a second platelet count within 6 months of the first showed an increase or stable platelet count, the 1-year incidence of cancer was 18.1% in men and 10.1% in women.
Staging data were available for 1168 cancers diagnosed in the thrombocytosis group and 123 in the comparison group. This showed that 50.8% of cancer cases in the thrombocytosis group were late-stage disease, compared with 37.4% in the comparison group.
The most commonly diagnosed cancers in the thrombocytosis group were lung and colorectal cancer, at rates higher than those seen in the general population. Conversely, rates of breast and prostate cancer were lower in the thrombocytosis group.Of patients diagnosed with lung cancer, 35.7% had no symptoms that would warrant urgent investigation in line with the UK National Institute for Health and Care Excellence (NICE) guidelines, aside from thrombocytosis. In colorectal cancer, 32.9% of patients had no other urgent symptoms other than thrombocytosis.
In an interview with Medscape Medical News, lead author Dr Bailey explained that the "main theory" explaining the association between thrombocytosis and cancer risk is that a tumor releases chemicals that increase platelet counts.
While it is tempting to suppose that this could lead to novel treatment targets, Dr Bailey pointed out that there are "so many different factors involved in that process, that I think to target any of those would be a much more complex piece of work."
Another theory is that the rise in platelet counts is "occurring independently of the cancer, but promoting the spread and development of cancer," she said, which "again provides some potential targets for future work."
In terms of future studies, Dr Bailey and colleagues are planning to examine the threshold for increased platelet counts.
She said, "The results that we found were quite significantly above the threshold that NICE guidance currently uses to suggest when patients should become eligible for referral. So we're going to be looking at how raised do platelets have to be to make patients eligible for that referral."
Commenting on the study in an institional press release, coauthor Willie Hamilton, MD, professor of primary care diagnostics of the University of Exeter Medical School, said, "The UK lags well behind other developed countries on early cancer diagnosis…. Our findings on thrombocytosis show a strong association with cancer, particularly in men — far stronger than that of a breast lump for breast cancer in women. It is now crucial that we roll out cancer investigation of thrombocytosis. It could save hundreds of lives each year."
The Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis receives funding for a research programme from the Department of Health Policy Research Programme. Obioha Ukoumunne is supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula. The authors have disclosed no relevant financial relationships.

NON-600 BRAF MUTATIONS IN COLORECTAL CANCER

As reported by Jones et al in the Journal of Clinical OncologyBRAF mutations occurring outside of codon 600 are found in a small proportion of cases of metastatic colorectal cancer and are associated with improved clinical outcome.
Study Details
The retrospective cohort study involved 9,643 patients with metastatic colorectal cancer who had undergone next-generation sequencing testing at three large molecular genetics reference laboratories. Of them, 208 patients (2.2%) had non–V600 BRAF mutations, with such mutations accounting for 22% of all BRAF mutations identified.
Associations and Outcome
Compared with cases with V600 BRAF mutations, those with non–V600 BRAF mutations were younger (median = 58 vs 68 years), less likely to be female (46% vs 65%), and had fewer high-grade tumors (13% vs 64%) or right-sided primary tumors (36% vs 81%). Median overall survival was 60.7 months in patients with non–V600 BRAF mutant disease vs 11.4 months in those with V600E BRAF–mutant disease and 43.0 months in those with wild-type BRAF disease (overall P < .001). On multivariable analysis, non–V600 BRAF mutation status was significantly associated with improved overall survival (hazard ratio = 0.18, P < .001).
The investigators concluded: “Non-V600BRAF mutations occur in approximately 2.2% of patients with metastatic [colorectal cancer] and define a clinically distinct subtype of [colorectal cancer] with an excellent prognosis.”
The study was supported by a Clinical and Translational Science Award grant from the National Center for Advancing Translational Science.


Axel Grothey, MD, of Mayo Clinic, Rochester, is the corresponding author of the Journal of Clinical Oncologyarticle.

EMA REJECTS ANAMORELIN FOR CACHEXIA TREATMENT

When new data for anamorelin were presented at a large European meeting in 2014, oncology experts enthusiastically welcomed them, and hopes were raised that there may at last be a drug for cancer cachexia, the extreme wasting seen at the end stages of the disease.
But those hopes have now been dashed.
Having reviewed the clinical data, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) found only "marginal" effects and recommended that the product be refused marketing authorization in Europe.
Anamorelin, developed by Helsinn Birex Pharmaceuticals Ltd, was to have the trade name Adlumiz. The oral drug acts as an agonist at receptors of ghrelin, the so-called hunger hormone, which results in the release of growth hormone.

Results From Clinical Trials 

Data from two clinical trials with anamorelin were presented at the 2014 European Society for Medical Oncology (ESMO) annual meeting, as reported by Medscape Medical News at the time.  "For the first time ever, we have seen a consistent benefit" from a drug in cancer cachexia, commented one of the investigators, David Currow, MD, from the palliative and supportive services at Flinders University in Adelaide, Australia. "We never thought that we would change this without changing the underlying cancer," he said.
The two trials, known as ROMANA 1 (n = 484) and ROMANA 2 (n = 495), were both placebo-controlled. They were conducted in patients with unresectable advanced non-small cell lung cancer (70% with stage IV disease) who had greater than 4 months' life expectancy and who had lost 5% or more body weight in the last 6 months or who had a body mass index below 20 kg/m². The average body weight was 68 kg in one trial and 63 kg in the other. Many of the patients (60% to 80%) were receiving chemotherapy or radiotherapy, or a combination of both.
Over the course of 12 weeks, patients receiving anamorelin had significantly improved lean body mass, while the patients in the placebo control group continued to lose weight, reported principal investigator, Jennifer Temel, MD, from the Department of Medicine at the Massachusetts General Hospital in Boston.
In the ROMANA 1 study, the median increase in lean body mass was 1.10 kg with anamorelin, compared with a loss of 0.44 kg in the placebo group. In ROMANA 2, the increase was 0.75 kg, compared with a loss of 0.96 kg in the placebo group (P < .0001 for both studies).
In ROMANA 1, body weight increased by an average of 2.2 kg with anamorelin vs 0.14 kg with placebo. In ROMANA 2, body weight increased by an average of 0.95 kg in the anamorelin group but decreased by 0.57 kg in the placebo group (P < .0001 for both studies).
Another endpoint was hand-grip strength. This did not differ between the two groups; it declined in both. However, Dr Temel said that patients appeared to have had problems using this equipment.

Negative Opinions From CHMP 

The CHMP appears to have reviewed exactly these same data at its recent May meeting. In its statement, it says that it reviewed results of two placebo-controlled trials conducted in a total of around 1000 patients with NSCLC and cachexia, in which the main endpoints were changes in lean body mass and hand-grip strength.
The CHMP concluded that the studies showed a marginal effect of anamorelin on  lean body mass and no proven effect on hand-grip strength or patients' quality of life.
In addition, after an inspection at clinical study sites, the CHMP considered that the safety data on the medicine had not been recorded adequately.
"This meant that a thorough evaluation of potential risks with anamorelin was not possible," it states. "Therefore the CHMP was of the opinion that the benefits of anamorelin did not outweigh its risks and recommended that it be refused marketing authorization."

Another Product for Cachexia Refused  

Another product aimed at cachexia was also refused a recommendation for approval at the same meeting. Human IgG1 monoclonal antibody specific for human interleukin-1α (XBiotech Germany GmbH) was intended to treat debilitating symptoms of advanced colorectal cancer, including cachexia.
The product works by blocking the actions of human interleukin-1α, which is expected to slow down the growth of the cancer, thus relieving patients' symptoms, the CHMP explains.
The company presented results of a placebo-controlled study in 333 patients that looked at the effects of this medicine on lean body mass and quality of life.
The CHMP says that it had several concerns. First, the study did not show clear improvements in either lean body mass or quality of life. Second, patients taking the medicine had increased risk for infection, which was not considered acceptable in vulnerable patients who will be receiving palliative care. Last, there were inadequate controls of the manufacturing process to ensure the medicine would have the same quality as the product used in clinical trials.

Drug for Mastocytosis Refused

In addition, the CHMP also refused another product, masitinib (Masipro, AB Science), which was intended to treat the rare condition of systemic mastocytosis.
In this condition, the body produces too many mast cells in the skin, bones, and various body organs, causing symptoms such as itchy skin, hot flushes, palpitations, fainting, bone pain, weakness, vomiting, diarrhea, and depression.
Masitinib acts as a tyrosine kinase inhibitor, and these enzymes are found, among other places, in some receptors in mast cells, including those involved in stimulating the cells to grow and divide. By blocking these enzymes, masitinib helps to slow down the growth of the mast cells, the CHMP explains on its website.  
The company presented data from a placebo-controlled study involving 135 patients with systemic mastocytosis who had severe symptoms, including at least one of the following: itching, hot flushes, depression, and weakness. The main endpoint was an improvement in any of these four symptoms after 24 weeks of treatment.
However, the CHMP says it was concerned about the reliability of the study results because a routine good clinical practice inspection at the study sites revealed serious failings in the way the study had been conducted. In addition, major changes were made to the study design while the study was ongoing, which made the results difficult to interpret. Finally, data on the safety of the medicine were limited, and there were concerns regarding the drug's side effects, including neutropenia and effects on the skin and liver, which were relevant particularly because the medicine was to be used long term. Therefore, the CHMP was of the opinion that the benefits did not outweigh risks and recommended that the drug be refused marketing authorization.

Application for Vosaroxin Withdrawn 

In addition, the CHMP notes that the application for marketing authorization of vosaroxin (Qinprezo, Sunesis Pharmaceuticals) has been withdrawn by the company. This drug was intended to be used in combination with cytarabine for the treatment of acute myeloid leukemia (AML).
Vosaroxin works by blocking topoisomerase II, an enzyme involved in DNA replication, which prevents cancer cells from dividing, eventually killing them.
The company presented data from a main study in 711 patients with relapsed or refractory AML, in which vosaroxin plus cytarabine was compared with cytarabine alone, with the endpoint of overall survival.
The CHMP notes that it had already evaluated the initial documentation. It had several concerns about the data and had a provisional negative opinion. Benefit on overall survival was lacking, and there were concerns of an increased rate of infection. The CHMP was of the opinion that the benefits did not outweigh its risks.
The company withdrew its application for marketing authorization because it was unlikely to succeed — the data from the main study were not convincing enough. The company decided to focus resources on other priorities.

DRINKING INCREASE RISK OF BREAST CANCER

Drinking as little as one small glass of wine or beer a day (about 10 g of alcohol) can increase the risk for breast cancer by 5% in premenopausal women and by 9% in postmenopausal women.
This latest warning comes from a new report issued by the American Institute for Cancer Research (AICR) and the World Cancer Research Fund (WCRF).  It reviewed 119 studies from around the world, with a total cohort of more than 12 million women and over 260,000 cases of breast cancer.
Commenting on the new finding, Susan K. Boolbol, MD, chief of the Division of Breast Surgery at Mount Sinai Beth Israel Hospital, New York, said, "We have known about the link between alcohol and breast cancer as several studies have shown the association. The issue with those studies is that we did not have an exact amount of alcohol that was known to increase your risk."
"This report clearly states that 1 drink per day will increase your risk. That is major news," Dr Boolbol said in a statement.
On the flip side, the report also found that vigorous exercise (such as running or fast cycling) reduced the risk for breast cancer in both pre- and postmenopausal women, and strong evidence confirmed earlier findings that moderate exercise (such as walking and gardening) also decreases the risk in postmenopausal women.
In premenopausal women, a statistically significant 17% decreased risk was observed (relative risk [RR], 0.83) when women with the highest levels of activity were compared with those who were least active.
The same protective effect was see in postmenopausal women, although to a slightly lesser degree; the most active women had a 10% (RR, 0.90) reduced risk, which was still statistically significant.
Additionally, overall physical activity was also associated with a 13% decreased breast cancer risk (RR, 0.87) in postmenopausal women.
"It can be confusing with single studies when the findings get swept back and forth," said a lead author of the report, Anne McTiernan, MD, PhD, a cancer prevention expert at the Fred Hutchinson Cancer Research Center and a research professor at the University of Washington Schools of Public Health and Medicine, both in Seattle.
"With this comprehensive and up-to-date report the evidence is clear," said Dr McTiernan in a statement. "Having a physically active lifestyle, maintaining a healthy weight throughout life and limiting alcohol — these are all steps women can take to lower their risk."
As previously reported by Medscape Medical News, several studies have highlighted the relationship between exercise and cancer risk,  as well as the association between alcohol consumption and cancer risk.

Strong and Weak Evidence

In addition to physical activity and alcohol consumption, the researchers also found other associations with breast cancer risk.
There was a new twist to the findings on obesity increasing the risk for breast cancer. Being overweight or obese throughout adulthood increases the risk for postmenopausal breast cancer, as does a greater weight gain in adulthood, the report confirmed.
However, there was strong evidence that being overweight or obese between the ages of about 18 and 30 years had a protective effect, in that it decreased the risk for both premenopausal and postmenopausal breast cancer.   
"It was interesting that this report showed that greater body fatness before menopause protected against premenopausal breast cancer," Dr Boolbol commented. But she emphasized that "once again, this report confirmed the fact that post menopausal weight gain or high body mass index is a risk factor for the development of breast cancer."
Breastfeeding decreased the risk for breast cancer, but developmental factors leading to greater linear growth (marked by adult attained height) increased the risk.
When it comes to diet, however, the evidence was more limited. For specific dietary factors, the report found that consumption of nonstarchy vegetables, for example, might reduce the risk for estrogen receptor–negative breast cancer. The evidence also suggested an association between foods containing carotenoid (which includes carrots, apricots, spinach, and kale) and a reduced breast cancer risk, and limited evidence indicated that diets high in calcium might also lower the risk.

Suggestions for Risk Reduction

For cancer prevention in general, the authors recommend maintaining a healthy weight, keeping physically active for at least 30 minutes every day, and avoiding high-calorie foods and sugary drinks.
In addition, they recommend eating a wide variety of whole grains, vegetables, fruit, and pulses such as beans, along with limiting red meat and avoiding processed meat.
It is best to avoid alcohol, they note, but if alcohol is consumed, the amount should be limited.
"Wherever you are with physical activity, try to nudge it up a bit, either a little longer or a little harder," said Alice Bender, MS, RDN, head of AICR's Nutrition Program, in  a statement. "Make simple food shifts to boost protection — substitute veggies like carrots, bell peppers or green salad for chips and crackers and if you drink alcohol, stick to a single drink or less."
Breast cancer is the most common cancer in US women, with over 252,000 new cases expected this year. AICR estimates that one in three breast cancer cases in the United States could be prevented if women d

EMA APPROVED CERITINIB FOR FIRST LINE TREATMENT OF ALK+ NSCLC

On 18 May 2017, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for the medicinal product ceritinib (Zykadia).
The marketing authorisation holder for this medicinal product is Novartis Europharm Ltd.
The CHMP adopted a new indication as follows:
"Zykadia as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)."
For information, the full indications for Zykadia will be as follows:
"Zykadia as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).
Zykadia as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib."
In addition, since all specific obligations of the conditional marketing authorisation have been fulfilled, the marketing authorisation for Zykadia will be switched from conditional to full approval.
Detailed recommendations for the use of this product will be described in the updated summary of product characteristics, which will be published in the revised European public assessment report, and will be available in all official European Union languages after a decision on this change to the marketing authorisation has been granted by the European Commission.
Summaries of positive opinion are published without prejudice to the Commission decision, which will normally be issued 67 days from adoption of the opinion. 

Σάββατο, 20 Μαΐου 2017

WATCHFUL WAITING SAFE FOR YOUNGER PATIENTS WITH LOW RISK PROSTATE CANCER

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However, judging by comments made at the meeting, that message may be hard to hear and accept, even at academic medical centers.
Men younger than 60 years have outcomes that are "comparable" to those reported in the literature for older men, said lead study author Keyan Salari, MD, chief resident in urologic surgery at Massachusetts General Hospital (MGH) in Boston.
The new study involved 432 young men with low-risk disease who were managed with surveillance between 1990 and 2016 at MGH (n = 181) and Sunnybrook Health Sciences Center in Toronto, Ontario, Canada (n = 251).
Metastasis-free survival was 99.7% and 97.5% at 5 and 10 years, respectively.
Five patients developed metastasis (two with positive lymph nodes at time of radical prostatectomy, three with distant metastasis). There were no prostate-cancer specific deaths. The median follow-up was 5.1 years.
Typically, men of this younger age are counseled into treatment, said Dr Salari. That is because of their longer life expectancy, fewer comorbidities (compared with older men), and perceived likelihood of eventually needing definitive treatment.
There also have not been many data to indicate that watching these younger men was okay.
However, the new retrospective data provide evidence that it is more than okay, suggested Dr Salari.
There is "no need for hesitancy," he said, adding that men younger than 60 years "shouldn't be excluded" from active surveillance. The criteria for active surveillance are "expanding," he commented.
But there is, and has been, hesitancy about including younger men, even at a pioneering active surveillance center like MGH, said another coauthor.
"The data for younger men are especially important. Even some of our colleagues at MGH are hesitant to place younger men on active surveillance," said Adam Feldman, MD, a urologist at MGH who also attended the news conference and spoke up from the audience.
The new data include the estimation that 74.3% of the men were free from treatment at 5 years, and 55.4% at 10 years.
"This is very compelling for young men who at least want to delay radical treatment for a period of years," said Stacy Loeb, MD, a urologist at New York University in New York City, who acted as the news conference moderator.
It is a durable option, with very few men developing metastases and more than half free from treatment at 10 years, she summarized.
It really is possible for young men to do this. Dr Stacy Loeb
In Sweden, among men 50 to 59 years old, 88% of very low risk patients and 68% of low-risk patients were managed with active surveillance in 2014, Dr Loeb also pointed out. "It really is possible for young men to do this," she said.

Who Is Likely to Progress to Treatment 

In a 432-patient study population, the median prostate-specific antigen (PSA) level was 4.6 ng/mL, with only 11 of the men having PSA levels of 10 ng/mL or higher. Almost all the patients had Gleason 6 or lower (97.7%) and clinical stage T1 (91.9%) disease.
Dr Salari reported that 84.3% of the men had a repeat biopsy, with 62.6% showing prostate cancer, 24.5% benign, 7.7% with prostatic intraepithelial neoplasia, and 5.2% with atypia. The high proportion of benign follow-up biopsies were a result of sampling errors that are to be expected because of the imprecision of ultrasound-guided biopsies and the presence of so many low-volume tumors, said Dr Salari.
Over time, 131 men (30.3%) progressed to treatment for the following reasons: pathologic progression (64.1%), PSA progression (18.3%), patient preference (11.5%), volume progression (3.1%), and other reasons (3.1%).
Dr Salari said there were only two predictors of progression to treatment, and both conferred about a doubling of risk compared with patients who did have the measures.
Namely, patients who had more than 20% tumor tissue in any one biopsy core (compared with those with 20% or less in all of their cores) were nearly twice as likely to move onto treatment (hazard ratio, 1.87; P = .0016), as were patients with PSA density of 0.15 or higher (compared with those with less; hazard ratio, 1.98; P = .01).
Among the 131 treated patients, 62.6% underwent radical prostatectomy, 13.0% underwent high-intensity focal ultrasound therapy, 12.2% underwent external beam radiation, and 10.7% had brachytherapy.
Among the surgery patients, pathologic review after surgery showed that 88.2% (60/68) were pT2, and 11.8% (8/68) were pT3.
Active surveillance of men younger than 60 years "spares most men from intervention," and allows "adequate time" for intervention for most, concluded Dr Salari.
Dr Salari and Dr Feldman have disclosed no relevant financial relationships. Dr Loeb has disclosed financial relationships with MDx Health, Armune BioScience, Minomic, Boehringer Ingelheim, GenomeDx Biosciences, and Astellas.

CARCINOGENS FOUND IN URINE OF PERSONS ON E-CIGARETTES

The widely held belief that e-cigarettes do not pose a cancer threat may be wishful thinking, according to the results of a new pilot study that focuses on their potential impact on bladder cancer.
The small study showed that two known carcinogens, otoluidine and 2-naphthylamine, were found in the urine of e-cigarette users but not in nonusers.
"That's concerning because we know there are people who genetically susceptible to developing bladder cancer," said lead study author, Thomas Fuller, MD, a urologist at the University of Pittsburgh in Pennsylvania.
Traditional cigarette smoking is a major risk factor for bladder cancer. e-Cigarettes have gained popularity, in part because they are perceived as a safer alternative, he explained.
"No level of exposure to these carcinogens is without risk," Dr Fuller told Medscape Medical News after he discussed the study at press conference today at the American Urological Association (AUA) 2017 Annual Meeting. However, he also admitted that the clinical implication of the findings about otoluidine and 2-naphthylamine is unknown.
Previous studies of traditional cigarette smokers have identified otoluidine and 2-naphthylamine as the two most carcinogenic molecules for the bladder, Dr Fuller said.
In the new study, 12 of the 13 e-cigarette users whose urine was analyzed had both otoluidine and 2-naphthylamine detected (limits of detection were 100 ng/mL and 10 ng/mL, respectively). None of the 10 controls were positive for the compounds.
Specifically, among e-cigarette users, there were 2.3-fold mean concentration level increases for otoluidine (P = .0013) and a 1.3-fold increase for 2-naphthylamine (P = .014) compared with controls.
Notably, all study participants, when interviewed by investigators, said that e-cigarettes were "safe."
Dr Fuller also commented that, among traditional cigarette smokers, the urine levels of these molecules would be "greater."
The investigators examined study participants' urine for three other carcinogens — benz(a)anthracene, benzo(a)pyrene, and 1- hydroxypyrene — but found no significant findings for these molecules.
The study's e-cigarettes users were also ex-smokers of traditional cigarettes; they had a median of 20 years of use. Importantly, they had quit traditional cigarettes for a median of 15 months before the current study. And they had been using e-cigarettes for a median of 26 months. So, there was a period in the past in which most participants overlapped use of both forms of smoking.
Press conference moderator, Sam Chang, MD, a urologist from Vanderbilt University in Nashville, Tennessee, wondered whether there was a correlation between frequency of e-cigarette use and urine levels of the carcinogens.
Dr Fuller revealed that they could not assess that because most of the study participants (84.6%) used e-cigarettes more than 28 times a week (about four times a day). The study questionnaire had assumed that this four-times-a-day frequency would be the upper limit of use. But it turned out to be a lower limit. "We underestimated how often people are using these e-cigarettes," he said.

Bladder Cancer Research Is Just Starting

Dr Chang believes the study, despite its small size, is an important step in understanding e-cigarettes and their potential bladder cancer threat.
The new study reveals that problematic chemical molecules are "processed, end up in the urine, which end up sitting in the bladder, which inevitably will have some impact on the likelihood of the development of cancer," he said. 
Dr Chang also repeated the importance of a slide shown by Dr Fuller depicting the skyrocketing e-cigarette use among middle school and high school students from 2013 to 2015, with a jump in users from about 8% to 25% of all students over that time.
As a father of three school-aged daughters, Dr Chang said the threat of e-cigarette use in their age groups is "scary, scary."
Dr Fuller acknowledged that research into e-cigarettes and their effect on the bladder lags behind research into their effect on the lungs.
"Maybe as a community, we [urologists] bought into the idea that this was going to be a much safer alternative because there is no combustion," he said.
Dr Fuller said that a next step for research is that the new results need confirmation in a larger study. And more carcinogens must be examined. The current study looked at only five molecules that are considered carcinogenic.
The new results conflict somewhat with the message from other recent research from the United Kingdom that suggests e-cigarettes are largely safe and certainly an improvement over traditional cigarettes.
As reported by Medscape Medical News, former smokers who only used e-cigarettes or nicotine replacement therapy were substantially less likely to be exposed to carcinogens and toxins than those who continue to smoke, according to a cross-sectional study that looked at urine and blood samples.
Dr Fuller and Dr Chang have disclosed no relevant financial relationships.
American Urological Association (AUA) 2017 Annual Meeting. Abstract MP88-14. Presented May 15, 2017.
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

ASCO 2017-ADJUVANT GEFITINIB BETTER THAN CHEMOTHERAPY FOR EGFR+ NSCLC

New results could lead lung cancer experts to rethink adjuvant therapy for patients with resected stage II-IIIA non–small cell lung cancer (NSCLC).
The usual standard of care is cisplatin-based chemotherapy, but a new trial found that targeted therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa, AstraZeneca) was better in patients with EGFR mutations.
The results come from the ADJUVANT (CTONG 1104) trial and were highlighted in a premeeting presscast for the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
"The authors reported a remarkable difference in disease-free survival," said Tony Mok, MD, from State Key Laboratory in Oncology in South China, Hong Kong, who was not involved in the study.
"The current standard is not to offer adjuvant EGFR TKI after resection of an early-stage EGFR-mutation-positive lung cancer, but the CTONG study helps us to rethink this paradigm. In other words, patients may be spared the toxicity of adjuvant chemotherapy and still attain a better disease-free survival," he told Medscape Medical News.
The study is "clear evidence that we can use precision medicine not only in patients with advanced cancer but also in those with earlier-stage disease," said ASCO President-elect Bruce E. Johnson, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts.
About 30% ― or 140,000 people worldwide ― have an EGFR mutation and may benefit from adjuvant treatment with EGFR-targeted therapy to reduce the chance of recurrence, according to ASCO.
"With this information now available, I suspect many doctors will begin testing these lung cancer tumors right after surgery to see if they actually have an EGFRmutation," said ASCO's chief medical officer, Richard Schilsky, MD, during the briefing.
"That is not currently standard of care in the US, where typically the testing doesn't take place until the cancer recurs or becomes metastatic," he added.
However, he suggested that even if other studies replicate these results, there are still issues such as cost and treatment duration to weigh in the balance.

Study Details

The phase 3 trial randomly allocated 222 patients with EGFR mutations to receive either gefitinib 250 mg daily for 2 years or the standard of care cisplatin/vinorelbine-based chemotherapy every 3 weeks for four cycles.
After a median follow-up of 36.5 months, there was a significant difference between the groups in recurrence-free survival: 28.7 months for patients who received gefinitib, and 18 months for those who received chemotherapy (hazard ratio [HR], 0.60; P = .005), reported lead study author Yi-Long Wu, MD, from the Guangdong Lung Cancer Institute, Guangdong General Hospital, in Guangzhou, China.
There was also a significant difference in the rate of serious adverse events (grade 3 or higher): 12.3% in the gefitinib group vs 48.3% with chemotherapy (< .001).
Dr Wu noted that two recent trials of adjuvant targeted therapy did not show benefit in NSCLC and suggested that the negative results were due in part to the fact that they included disease of stages I, II, and III in their study. He also said that these "earlier trials only looked to see if patients showed overexpression or overactivity of EGFR, but not mutations in EGFR."
He noted that the current trial recruited patients "who had been confirmed to have activating EGFR mutations, so we believe these reasons account for why other trials showed no benefit of a targeted therapy while ours did."
Overall survival data in the current study is as yet immature, noted Dr Mok, and the results are limited because of the small sample size. But when considered along with the similar, ongoing Japanese IMPACT (WJOG6410L) study, "I trust we shall have a strong argument to offer adjuvant EGFR TKI instead of chemotherapy," he told Medscape Medscape News.
However, Dr Schilsky said that it is also important to bear in mind that in Dr Wu's trial, "we're talking about 12 weeks of chemotherapy vs 2 years of gefitinib. So it's a big commitment on the part of patients to adhere to 2 years of continuous treatment."
In addition, the cost of gefitinib is "far, far greater than the cost of 12 weeks of chemotherapy. And so I think at the end of the day, once the survival data are known, doctors and patients are going to have to have very thoughtful discussions about what is the magnitude of the survival benefit, what is the burden of the patients who take either cytotoxic chemotherapy for 12 weeks or 2 years of an oral treatment which, while it is less toxic, is not without toxicity, and what's the financial burden of that treatment choice going to be for the patient?