FIRST DRUG DESIGNED FOR CARCINOID SYNDROME

VIENNA ― The first drug developed specifically for patients with carcinoid syndrome has shown clinical benefit in a phase 3 trial.

The trial was presented in a late-breaking abstract here at European Cancer Congress (ECC) 2015.

Carcinoid syndrome develops in patients with metastatic neuroendocrine tumors (NETs) and results from the overproduction of serotonin by these tumors. Symptoms include debilitating diarrhea, facial flushing, and abdominal pain and can result in serious consequences, such as heart valve damage.

"Carcinoid syndrome has a significant impact on the lives of patients who already have been battling metastatic cancer," Maryann Wahmann, founder and president of the Neuroendocrine Cancer Awareness Network, said in a statement. "These patients can live for many years with their cancer, yet the symptoms of carcinoid syndrome are what frequently limit their lives and restrict their activities every single day. So there is a tremendous need for effective new treatment options."

The new drug, telotristat etiprate (under development by Lexicon), inhibits tryptophan hydroxylase, an enzyme that triggers the excess serotonin production within metastatic NET cells that leads to carcinoid syndrome. Although existing treatments for carcinoid syndrome reduce the release of serotonin outside tumor cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells, the company explains.

Telotristat etiprate has received Fast Track and Orphan Drug designation from the US Food and Drug Administration.

The drug was tested in a pivotal phase 3 trial, known as TELESTAR. The trial was conducted in 135 patients with carcinoid syndrome that was not adequately controlled on treatment with long- acting somatostatin analogues (SSA), which is the current standard of care.

Patients continued with their SSA therapy and were randomly assigned to receive either telotristat etiprate (250 mg or 500 mg orally, each taken 3 times daily) or placebo during a 12-week period.

The primary end point of the study was the reduction from baseline in the average number of daily bowel movements.

The results show that at both doses tested, the new drug significantly reduced the average number of daily bowel movements during the 12-week study period (P < .001).

In the placebo group (n = 35), patients had an average of 5.25 bowel movements daily at baseline; this was reduced by 17%, to an average of 4.34 daily, at week 12.

In the group taking telotristat 250 mg (n = 36), the average number of bowel movements at baseline was 5.95; this was reduced by 29%, to 4.24 daily, at week 12.

In the patients taking the higher dose of 500 mg, the average number of daily bowel movements fell from 5.94 at baseline to 3.83 at week 12, a reduction of 35%.

Patients taking the drug showed a reduction in urinary 5-HIAA, the main metabolite of serotonin, which shows that the drug was targeting serotonin overproduction, commented lead author Matthew H. Kulke, MD, director of the program in neuroendocrine and carcinoid tumors and senior physician, Dana Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, both in Boston.

Dr Kulke reported that telotristat also reduced the frequency of flushing episodes and the intensity of abdominal pain compared with placebo, but these differences did not reach statistical significance. About 39% of patients had these symptoms at baseline, he noted.

Serious adverse events were uncommon and were similar for all the treatment groups, Dr Kulke reported. He commented specifically on nausea and depression as adverse events of interest, and said that reports of these symptoms were mild or moderate and did not lead to discontinuation.

Nausea was reported by 11.1% of patients receiving placebo, by 13.3% by those receiving telotristat 250 mg, and by 28.9% by those receiving telotristat 500 mg.

Depression was reported by 6.7% with placebo, by 2.2% with the lower dose, and by 17.7% with the higher dose. Depressed mood was reported by 0, 2.2% and 4.4% respectively.

Telotristat has a favorable safety profile, he commented, and concluded: "We believe this is a promising new treatment approach."

He noted that 87% of patients in the study continued with open-label treatment with the higher dose of the drug, telotrsistat 500 mg tid.

The drug was specifically designed not to cross the blood-brain barrier, which is important because reducing serotonin levels in the brain results in depression, explained discussant for the study David Cunningham, MD, FRCP, consultant medical oncologist at the Royal Marsden Hospital, Sutton, and director of clinical research at the Institute of Cancer Research, United Kingdom.

Dr Cunningham commented that the reduction in bowel movements was significant when compared with placebo but that the reduction was "relatively modest," he said. He added that the drug had no significant effect on reducing flushing and abdominal pain.

He emphasized that the chronic diarrhea associated with carcinoid syndrome can be debilitating ― it can be severe and unpredictable, and it can prevent patients from going about their daily activities and going to new places. He said that quality-of-life data were needed to show what effect this new drug had on patients' lives. "We need careful health economic evaluation of this treatment approach," he concluded.

The TELESTAR study was funded by Lexicon.

European Cancer Congress (ECC) 2015: Abstract 37LBA. Presented September 29, 2015.

CANCER CAN DAMAGE HEART BEFORE TREATMENT

VIENNA, AUSTRIA — Although the link between some chemotherapy agents and cardiac damage is well-known, new research suggests that some cancers on their own may contribute to cardiac dysfunction^[1].

A study of more than 500 cancer patients, none of whom had undergone prior cardiotoxic cancer therapy, showed that levels of high-sensitivity troponin T (hs-TnT) and five cardiovascular neurohormones were elevated at baseline and increased as tumor stage progressed.

In addition, hs-TnT, N-terminal pro B-type natriuretic peptide (NT-proBNP), midregional pro–atrial natriuretic peptide (MR-proANP), midregional pro–adrenomedullin (MR-proADM), C-terminal pro–endothelin-1 (CT-proET-1), and copeptin were all significant predictors of all-cause mortality within 25 months, the primary end point.

The results suggest "the presence of subclinical functional and morphological myocardial damage directly linked to disease progression," write the researchers, led by Dr Noemi Pavo (Medical University of Vienna, Austria).

Coinvestigator Dr Martin Hülsmann (Medical University of Vienna) told  heartwire from Medscape the most important finding for him was that the neurohormones were so predictive even after extensive adjustment.

However, "I currently have no recommendations for clinicians because I think we have found more questions than answers," said Hülsmann.

The findings were published online September 28, 2015 in Heart.

Revealing "Cross talk"

Past research has shown that malignant cancer cells can produce vasoactive peptides (such as ADM and ET-1) and cardiac hormones (such as ANP and BNP), note the investigators. However, an "underlying morphological cardiac substrate" has not been commonly found for the latter group. "Elevated levels of natriuretic peptides have been, therefore, considered to be false-positive findings," they add.

Still, after results from some small animal studies suggested that CV neurohormones "are less innocent bystanders and equally that TnT should not be overlooked," the researchers sought to conduct their own trial "to reveal the humoral cross talk between cancer and cardiac disease."

They enrolled 555 consecutive cancer patients (60% women) at Vienna General Hospital between April 2011 and June 2013. Tumor existence and stage were measured at baseline and at follow-up (mean 25 months). In addition, blood samples were taken.

At follow-up, 34% of the study participants had died. Although the strongest predictor of all-cause mortality, as shown in univariate analysis, was NT-proBNP, all of the following were significant:

Adjusted* Hazard Ratio (HR) for All-Cause Mortality

Variable	HR (95% CI)	P
hs-TnT	1.21 (1.13–1.32)	<0 .001="" td="">
NT-proBNP	1.54 (1.24–1.90)	<0 .001="" td="">
MR-proANP	1.40 (1.10–1.79)	<0 .01="" td="">
MR-proADM	1.31 (1.19–1.44)	<0 .001="" td="">
CT-proET-1	1.21 (1.14–1.30)	<0 .001="" td="">
Copeptin	1.22 (1.04–1.42)	0.01

*Adjusted for age, stage 4 tumor, tumor entity, cardiac status, and glomerular filtration rate

When the model was also adjusted for hs-TnT, there was still a significant association with mortality for all of the variables except for MR-proANP, "highlighting the independent impact of these hormones in cancer."

In addition, patients at tumor stage 4 had significantly higher levels of the proinflammatory cytokine interleukin 6 (IL-6), the inflammatory marker C-reactive protein (CRP), haptoglobin, and serum amyloid A than those at stages 1 through 3 (all comparisons, P<0 .05="" p="">

Finally, the following three hormones were significantly associated with IL-6 and CRP: NT-proBNP, MR-proANP, and MR-proADM; hs-TnT was associated with CRP only.

"Whether the effect on mortality is primarily due to a detrimental local influence on the tumor microenvironment or is induced by systemic cardiovascular dysregulation cannot be determined," write the investigators.

Still, "the results provide intellectual support of heart-failure therapy in patients with cancer beyond the current focus on preventing therapy-related cardiotoxic side effects."

Hülsmann noted that he is now interested to see what happens with the neurohormones in cancer patients over time. "Does [risk for CVD] steadily increase after diagnosis, and does it decrease if the patient is cured? We're also very interested in what happens during therapy."

Important Discovery

"This is an important discovery that these peptides are elevated significantly on a routine basis in cancer patients," Dr Steven Ewer (University of Wisconsin School of Medicine and Public Health, Madison) told heartwire . "And I think this reflects some complex interactions between the malignancy and cardiovascular disease in ways that are not yet fully understood but are probably important," he added.

"There could be some preexisting subclinical cardiac disease in these patients. Whether that's due to comorbidities or to age or to specific tumor-related vasoactive peptides is a little bit unclear," he said. "But it was an important trial-design aspect that they didn't have any cardiotoxic treatment before measurements."

Ewer, who was not involved with this research, established his university's cardio-oncology clinic in 2009.

When asked if there are any clinical implications from the study, Ewer said there are potential systemic effects of the tumor-related peptides that deserve further exploration. "But whether that can be carried out in the clinical setting yet is doubtful."

Limitations of the study that he cited included that it study looked only at all-cause mortality and did not distinguish between cancer death and CV death.

Still, "it's important to realize these molecules are circulating in the bloodstream and could be having potential effects on the cardiovascular system and potentially even contributing to mortality. So I think this study is an important first step," said Ewer.

"If some of these peptides do contribute to cardiotoxicity, that may represent an area we could research to find out if manipulation of these pathways might be protective for the heart."

The study was funded by a grant from Thermo Fisher. The study authors and Ewer report no relevant financial relationships. 

COMBINATION DABRAFENIB-TRAMETINIB FOR MELANOMA

The latest results from a trial of a combination of two targeted therapies (dabrafenib [Tafinlar] and trametinib [Mekinist]) to treat advanced melanoma have shown that patients are living significantly longer on the combined therapy than patients treated with vemurafenib (Zelboraf) alone. Caroline Robert, MD, PhD, of the Institut Gustave Roussy, presented these results at the 2015 European Cancer Congress in Vienna, Austria (Abstracts 3301, 3345).

Survival Improvement

Dr. Robert reported that not only is the median overall survival longer for patients receiving the combination treatment but also that 51% of patients receiving the combination treatment are alive after 2 years, compared with 38% of patients receiving vemurafenib alone.

Analysis of data up to March 13, 2015, showed that the median overall survival among patients with metastatic melanoma harboring V600 mutations in the BRAF gene who received the combination treatment was 25.6 months. Among patients receiving vemurafenib alone, it was 18 months. On the basis of this finding, the European Commission approved the combination of dabrafenib and trametinib for use in Europe for these patients on September 1, 2015.

“We observed a statistically significant reduction of 34% in the risk of death among patients receiving the combination therapy,” Dr. Robert said. “The increased survival among these patients is remarkable, and this median overall survival of more than 2 years is the longest in this category of patients in a phase III randomized trial.”

Results From COMBI-v Trial

These new results come from an analysis of all data from the COMBI-v phase III trial, which randomized previously untreated patients with the V600E or V600K mutations of the BRAF gene to receive either 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily or 960 mg of vemurafenib alone twice daily.

By March 2015, approximately 50% (349 of 704) of patients had died, and the researchers had followed the patients for approximately 18 months.

“Since our last report from this trial we have an additional 11 months of follow-up and 127 more deaths. This provides data that are mature enough to demonstrate definitively the effect on overall survival and the benefit to patients,” said Dr. Robert.

The updated analysis also reported that patients receiving the combination treatment survived significantly longer without their disease progressing than patients receiving vemurafenib alone: 12.6 and 7.3 months, respectively. “The 12.6 months of progression-free survival for patients on the combination treatment is the longest achieved in a randomized study for patients with the BRAF V600 mutation to date,” said Dr. Robert.

Rates of severe side effects remain similar in both groups of patients, with no unexpected effects noted during the longer follow-up. Results from an associated study of the patients’ health-related quality of life showed significant and clinically meaningful improvements among those receiving the combination treatment, compared with those receiving vemurafenib alone. Overall health; physical and social functioning; and specific symptoms such as pain, insomnia, loss of appetite, diarrhea, and fatigue were all improved.

The international trial started in 2012, and patients recruited to it have unresectable and/or metastatic melanoma. Between 40% and 60% of patients with melanoma have mutations in the BRAF gene that are driving the cancer, and the majority of these patients have the V600E or V600K type of BRAFmutation.

Dabrafenib, vemurafenib, and trametinib are targeted therapies that block proteins playing key roles in the cell-signaling pathways that are often overactive in cancer; dabrafenib and vemurafenib block the BRAF protein, and trametinib blocks the MEK proteins. Because anti-BRAF treatment alone is associated with more than 50% of patients relapsing after 6 to 8 months, researchers wanted to see whether a combination of the BRAF and MEK inhibitors would produce better outcomes for patients. These latest results from the COMBI-v trial confirm this hypothesis.

Although the study was stopped in July 2014 when it became clear that the combination therapy was superior to vemurafenib alone, patients have the option to continue with their treatment, and the researchers are continuing to collect follow-up data.

“This combination therapy is already available in the United States, and now also in Europe, as a result of the European Commission’s decision to approve its use. This long-term benefit in terms of overall survival confirms the major potential of this combination in patients with metastatic melanoma. A further question to investigate is the combination treatment versus new immunotherapies or combined with them,” concluded Dr. Robert.

PEMBROLIZUMAB FOR NASOPHARYNGEAL CARCINOMA

Pembrolizumab (Keytruda), an anti–PD-1 therapy, may be effective as monotherapy in patients with advanced unresectable nasopharyngeal carcinoma whose tumors express programmed cell death-ligand 1 (PD-L1). Data from a phase Ib study, KEYNOTE-028, showed an overall response rate of 22.2% in 27 evaluable patients who were treated with pembrolizumab.

Chiun Hsu, MD, of the National Taiwan University Hospital, presented results from the trial at the 2015 European Cancer Congress in Vienna, Austria (Abstract 2801).

“Advanced nasopharyngeal carcinoma is a severe form of head and neck cancer often associated with a poor prognosis,” said Dr. Hsu. “These data represent the potential for new approaches to treat this type of cancer, for which there are currently limited options, and further support the need for additional research into how pembrolizumab may work for certain types of head and neck cancer.”

Merck has initiated a comprehensive clinical development program evaluating pembrolizumab in head and neck cancer across multiple lines of therapy as monotherapy and in combination with chemotherapy as well as other agents. In KEYNOTE-028, pembrolizumab is being evaluated in patients with advanced unresectable nasopharyngeal carcinoma that is not responding to current therapy or for which current therapy is not appropriate. This is the second study to show early activity of pembrolizumab in patients with head and neck cancer, and the first study of an anti–PD-1 therapy to demonstrate clinical activity in patients with recurrent or metastatic nasopharyngeal carcinoma.

Trial Details

KEYNOTE-028 is an ongoing multicohort, nonrandomized phase Ib basket trial evaluating the safety, tolerability, and antitumor activity of pembrolizumab monotherapy (10 mg/kg dosed every 2 weeks) in more than 450 patients across 20 different tumor types. The study was designed to evaluate patients with advanced solid tumors that express PD-L1 and have not responded to current therapy or for which current therapy is not appropriate.

These early findings from 27 heavily pretreated patients with advanced nasopharyngeal carcinoma demonstrated an overall response rate of 22.2% (n = 6/27; per RECIST v1.1), including six partial responses (95% confidence interval [CI], 8.6–42.3). Additionally, 55.6% of patients had stable disease (n = 15/27; 95% CI, 35.3–74.5); the disease control rate was 77.8% (n = 21/27; 95% CI, 57.7–91.4); and tumor shrinkage was achieved in 67% of patients. The 6-month progression-free survival rate was 49.7%, and the 12-month progression-free survival rate was 28.9%. The median follow-up duration for evaluable patients was 12.9 months (range, 2.2−15.0), and the median response duration was 10.8 months (range, 4.8–10.8).

Adverse events were generally consistent with previously reported safety data for pembrolizumab. Grade 3-5 investigator-assessed, treatment-related adverse events were hepatitis (n = 2); pneumonitis (n = 2); anemia (n = 1); facial pain (n = 1); increased blood creatine phosphokinase (n = 1); proteinuria (n = 1); and sepsis (n = 1). Immune-mediated adverse events were hypothyroidism (n = 5), hepatitis (n = 4), and pneumonitis (n = 3). There was one treatment-related death due to bacterial sepsis.

EVEROLIMUS FOR LUNG AND GASTROINTESTINAL NETs

VIENNA — The latest clinical trial with everolimus (Afinitor, Novartis) in the treatment of neuroendocrine tumors (NETs) has shown that the drug is effective for NETs originating in the gastrointestinal tract and the lungs.

The effect on lung NETs is "remarkable," as no other drug has shown this before, said Christoph Zielinski, MD, director of the clinical division of oncology and coordinator of the Comprehensive Cancer Center at Medical University Vienna. He predicted that the new results would change clinical practice. Generally, NETs have a low mutational burden and are not responsive to targeted therapy, or to chemotherapy, he explained.

Dr. Zielinski was commenting on the new results during a press briefing here at the European Cancer Congress 2015. He was not involved with the study.

Everolimus is already approved for use in the treatment of pancreatic NETs, on the basis of results from the RADIANT-3 trial, which showed that the drug significantly improved progression-free survival compared with placebo.

The latest study, known as RADIANT-4, was conducted in 302 patients with NETs of gastrointestinal or lung origin. About 30% of patients had lung NETs, and 24% had NETs in the ileum, commented lead investigator James Yao, MD, chair of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

All patients received best supportive care, and were randomized 2:1 to receive either everolimus or placebo.

The results show a significant improvement in progression-free survival, with median progression-free survival (assessed by central review) of 11 months with everolimus vs 3.9 months with placebo (hazard ratio, 0.48; P < .00001). The overall survival data are not yet mature, but they show a positive trend suggesting that everolimus reduces the risk for death by 37%, Dr. Yao said.

Another secondary end point was overall response rate, which was 64% with everolimus vs 26% on placebo.

"Although we knew from previous studies that everolimus could delay the growth of pancreatic NETs, this is the first time that we have been able to conclusively show that it is effective in other NET sites," Dr. Yao said in a statement. These are "rare and aggressive cancers, with limited treatment options," he added.

The patients in this trial had previously been treated with somatostatin analogues such as octreotide (used in 53% of everolimus patients and 56% of placebo patients), chemotherapy (26% and 24%), and radiotherapy (22% and 20%).

Novartis, the manufacturer of everolimus, said that it will file these new data with regulatory authorities worldwide. The company also noted that the RADIANT series of trials is the largest ever clinical program in patients with advanced NET.

Adverse events reported in this trial were similar to what has been seen before, Dr. Yao noted. He said that 63% of patients on everolimus developed mouth ulcers, but he also commented that this adverse event appears to be associated with efficacy of the drug, as the patients who develop these mouth ulcers are also the ones who respond.

The most common treatment-related grade 3 or 4 adverse events were stomatitis (9% with everolimus vs 05 with placebo), diarrhea (7% vs 2%), and infections (7% vs 0%).

Effect Consistent, But New Player Is Coming

Discussing this presentation at the meeting, Enrique Grande, MD, from the Department of Medical Oncology at Ramón y Cajal University Hospital in Madrid, said that the RADIANT series of trials is "the most ambitious program in NET."

The results of all the RADIANT trials "are consistent and they support the use of everolimus for NET whatever the origin," he said.

However, he added, "despite the encouraging picture, we do not have the whole picture yet." The median progression-free survival of 11 months seen with everolimus in RADIANT-4 is not superior to what has been seen in other studies, he noted. For example, median progression-free survival of 14 months was achieved with octreotide LAR in the PROMID study (J Clin Oncol. 2009;27:4656-4663), while in the SWOG S0518 trial (J Clin Oncol 2015;33 Suppl;abstr 4004), a median progression-free survival of 16.6 months was achieved by a combination of octreotide LAR and bevacizumab (Avastin), and a median progression-free survival of 15.4 month by a combination of octreotide LAR plus interferon.

Also, there is a new player coming into this arena, Dr. Grande pointed out. The radiopharmaceutical 77Lu-DOTATATE (Lutathera, under development by Advanced Accelerator Applications) has achieved the "most impressive PFS that we have seen in NETs," Dr. Grande commented. The data on this product were presented at the same presidential session at the meeting, and while the median progression-free survival has not yet been reached, it is estimated at around 40 months, as reported by Medscape Medical News.

The RADIANT studies are funded by Novartis, the manufacturer of everolimus. 

European Cancer Congress (ECC) 2015: Abstract LBA5. Presented September 27, 2015.

FIRST TARGETED TREATMENT FOR SCLC

Small cell lung cancer (SCLC) is an aggressive disease that is difficult to treat and is frequently diagnosed only when it has metastasized. Five-year survival rates in SCLC, which accounts for about 14% of all lung cancers, are very low, at only 6%. Researchers presented novel findings (Abstract 7LBA) with important implications for treatment of SCLC at the 2015 European Cancer Congress.

M. Catherine Pietanza, MD, Assistant Attending Physician at the Memorial Sloan Kettering Cancer Center, reported on results from a phase I trial of a novel agent, rovalpituzumab tesirine (Rova-T, or S16LD6.5), in 79 patients with SCLC who had progressed after first-line or second-line therapy.

“While other cancers have multiple treatment options, there is only one agent approved in SCLC, and none available in the third-line setting; the outlook for these patients is dismal,” Dr. Pietanza said.

Study Details

The patients ranged in age from 44–81, with a median age of 62 years. They received escalating doses of Rova-T once every 3 weeks until toxicity reached a point at which the increase in dose needed to be stopped. The drug was designed to bind to DLL3 (delta-like protein 3), a protein that is highly expressed in approximately 70% of SCLCs.

“Of the 48 tumor samples we were able to analyze, 33 were positive for DLL3. Among the 29 DLL3-positive patients we could treat at the maximum tolerated dose of Rova-T, 10 (34%) had a partial response and 9 (31%) had disease stabilization. The duration of response among these patients was more than 178 days, with no cases of disease progression,” Dr. Pietanza reported.

Rova-T is an antibody drug conjugate consisting of three components—an antibody, a linker, and the active chemotherapy, or cytotoxic payload. The antibody portion of an antibody drug conjugate can recognize cell surface receptors specific to and that are overexpressed in cancer cells, allowing the delivery of the chemotherapy directly to the tumor. This means the treatment is more effective and also minimizes its exposure to normal cells, with a consequent reduction in toxicity.

Biomarker Identified

“The high response rate is exciting in itself, and above that we have been able to identify a biomarker for SCLC in DLL3-positive patients, thus enabling us to ‘target’ treatment in SCLC. The activity of the drug that we have seen is remarkable, and importantly, the durable, long-term responses are notable in such an aggressive disease where progression is normally very rapid,” said Dr. Pietanza.

Whereas the most common treatment for early-stage non–small cell lung cancer is surgery, SCLC is not usually diagnosed in time for this to be a viable possibility, and chemotherapy is the standard of care. Currently, standard first-line therapy is the chemotherapy combination etoposide/platinum, which is combined with radiation therapy to the chest in limited-stage disease, and second-line chemotherapy consists of topotecan. Because SCLC can spread quickly to the brain, cranial radiation therapy may also be given.

“The first-line therapy [for SCLC] has not changed for four decades, and there is no third-line treatment at present, so it is clear that Rova-T is likely to fulfill an unmet need for these patients. I would like to see additional, larger trials to develop it further in settings where there is a clear need in this disease. We are looking forward to further assisting in its development and to gaining a better understanding of its value in all cases of SCLC,” Dr. Pietanza concluded.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®

CANCER SURGERY DISPARITIES

VIENNA — Surgery has a bigger impact on cancer than any other treatment modality, with potential to cure more than 50% of patients, and yet worldwide, fewer than 25% of cancer patients have access to safe and affordable care.

There is a huge shortfall in the worldwide provision of cancer surgery, say experts, and they suggest that a combination of research, improvements to surgical systems, and the incorporation of surgery into national cancer plans is needed to tackle the crisis.

The shortfall is revealed in a major analysis presented here at the European Cancer Congress 2015 and published simultaneously in Lancet Oncology as part of a Commission on access to cancer services. It found that worldwide, less than 25% of cancer patients have access to safe, affordable surgery, while in low-income countries, up to 95% do not receive basic surgical care.

With cancer incidence rates rising as people live longer, the number of procedures needed annually is set to reach 45 million. However, without major investment, three-quarters of cancer patients in low- and middle-income countries (LIMCs) are expected to die from cancer in 2030, compared with less than half in high-income countries.

Together, the cumulative losses to the global economy resulting from a lack of surgical care could top $20 trillion, or 1.3% of the projected global economic output.

"This Commission clearly outlines the enormous scale of the problem posed by the global shortfall in access to cancer surgery and current deficiencies in pathology and imaging," said Richard Sullivan, MD, PhD, Institute of Cancer Policy, King's Health Partners Comprehensive Cancer Centre, King's College London, United Kingdom, in a release.

"The evidence outlined by the Commission, contributed by some of the world's leading experts in the field, leaves no doubt of the dire situation we are facing. It is imperative that surgery is at the heart of global and national cancer plans," he said.

"A powerful political commitment is needed in all countries to increase investment and training in publicly funded systems of cancer surgery," Dr Sullivan emphasized.

However, there is hope for the future. "The good news is that surgery is effective and surgery is cost-effective.... In fact, it's the most cost-effective treatment," coauthor Riccardo Audisio, MD, FRCS(Engl), consultant surgical oncologist and honorary professor at the University of Liverpool, United Kingdom, and president of the European Society of Surgical Oncology, said during a press briefing.

"The bad news, unfortunately, is that only one in five surgery patients will receive the appropriate surgical treatment," he added.

Discussing how to bridge that gap, he said: "It all revolves around setting guidelines or, if you want, instead of dreaming of guidelines that cannot be implemented because of the local facilities, we are looking to establish minimum standards, and 'minimum standards' is something that needs to be accomplished from the top academic places to the very basic institutes."

More Than 80% Cancers Need Surgery

o develop the Commission, the authors used published evidence, such as the findings from Global Surgery 2030, commissioner meetings, and original analyses to examine the state of surgery globally and across all income settings. The aim was to produce evidence-based solutions to strengthen cancer surgical systems, education, and research.

The analysis showed that, of the 15.2 million cancer cases diagnosed worldwide in 2015, more than 80% will need surgery. Of the new cancer cases, 57% will have occurred in LMICs. Moreover, of the 8.8 million cancer deaths predicted for 2015, 65% will have occurred in LMICs.

The Commission found, however, that less than 25% of cancer patients worldwide have access to safe, affordable surgical care when it is needed, with only 5% of patients in low-income countries and 22% of those in middle-income countries having access to basic cancer surgery. There is also a serious shortage of cancer surgeons in 82% of countries.

By 2030, it was projected there will be 21.6 million new cancer cases, of whom 17.3 million will require surgery and 10.0 million of whom will be from LMICs. Overall, 45 million cancer surgery procedures will be needed annually. It is also expected that 75% of cancer patients in LMICs will die in 2030, compared with 46% of those in high-income countries.

Without urgent investment in cancer surgery services, the Commission argues, the global economic losses from cancers that could have been treated by surgery will total $12 trillion in 2030. The proportional impact of this loss equates to an annual loss of gross domestic product (GDP) of 1.0% to 1.5% in high-income countries and 0.5% to 1.0% in LMICs.

When looking at the impact of cancer morbidity and mortality in terms of the value of statistical life, which can be equated to financial losses, it was calculated that the global annual economic welfare losses are estimated at $7 trillion for surgical cancer mortality and $400 billion for surgical cancer morbidity. This represents an annual loss of GDP of 10% and 6% in high- and upper-middle-income countries, respectively.

The researchers also emphasized that there are micro-, as well as macro-, economic losses resulting from a lack of access to surgery for cancer patients. For example, a study of out-of-pocket costs, catastrophic expenditure, and discontinuation of treatment in more than 4500 patients in Southeast Asia revealed that 31% of patients with surgically operable cancer experienced financial catastrophe and 23% discontinued treatment.

Solutions — "Not One-Size-Fits-All"

Turning to potential solutions for the issues that the Commission identified, Dr Sullivan said: "Well, first of all, it's about building systems, and this is not a one-size-fits-all."

"We're talking around 277 different surgical procedures across six complexity levels. At least 110 of those require specialist cancer surgeons, in gynecological oncology, urology, head and neck.... So it's different horses for different courses," he said.

"The first thing we call for, of course, is to have surgery integrated into national cancer control plans [NCCPs]," he said, and many more of these are needed. "When we looked at NCCPs which are out there at the moment, only about 50% of countries globally have NCCPs.

"Only 9% of those programs actually have elements that you could identify as developing capacity and capability in cancer surgery, and that needs to radically increase," he explained.

However, Dr Audisio commented, "policy makers at all levels still have little awareness of the central importance of surgery to cancer control. Even recent studies of capacity building for cancer systems in Africa barely acknowledged the importance of surgery, focusing mainly on chemotherapy instead."

Massive Deficit in Research

Another important aspect that the Commission identified for improving surgical oncology was research. "The analysis...shows that, globally, the amount of research dedicated to cancer surgery is less than 5%, which is unbelievable, but it's true," said Dr Sullivan.

"Most of the money at the moment goes into fundamental research, and you won't be surprised [that it's for] medicines and biomarkers. The reality is that for radiation, surgery, palliative care, we come a long way down the list."

He added: "Even more worrying for the future is a that lot of this research is focused in high-income countries. So, of the totality of surgical cancer research, only about 17% is relevant to a lot of the emerging and low-income economies. That's a massive deficit in research."

The Commission estimated that just 1.3% of the annual global cancer research and development budget goes toward surgery. Moreover, 93.0% of global research in cancer surgery is carried out by only 34 of 195 countries.

Nevertheless, Dr Audisio does not believe that clinical trials per se are the best way of plugging the research gap.

"You need to know that only less than 2% of the cancer population is entering trials, and this skews the results, because it's not representative of the real population," he said.

"It's not representative because, when compared to real patients, these patients are different. They are more educated, they've got less aggressive treatment, they are better nourished, and so on."

Dr Audisio continued: "The findings are therefore different and, most importantly, trials with negative findings are never published, so what do you do? You look at the results of several trials to make a meta-analysis, but, by definition, you forget the negative trials that you don't consider in your meta-analysis because they are not worth mentioning."

He noted that observational studies of real-world outcomes have shown that surgical procedures can achieve up to 50% survival in cancer patients.

"So you don't need the trial; you have huge evidence that this is what is working," Dr Audisio said. "The trial mentality only works when you don't have end results to sell, when you cannot convince your providers that it's worth investing a huge amount of money into a treatment which is achieving 3-month, 6-month local disease-free gains."

Referring to the differences in outcomes between surgery and "a new molecular magic bullet," he said: "We are talking curing patients. We're not talking delaying for months or weeks, we're talking curing over 50% of cancer patients. That's a strong message."

He added: "It's not extending survival or improving wellbeing, this is saving human lives. This is something which is not being taken into account."

Summarizing, Dr Audisio said: "I am very grateful for being given the opportunity to run up the surgical oncology flag and to remind the community how crucially important [it] is."

Coauthor Mark Shrime, MD, from the program in global surgery and social change at Boston Children's Hospital, Harvard Medical School, reports received personal fees from Ethicon.

European Cancer Congress (ECC) 2015: Abstract LBA9. Presented September 28, 2015.

DISPARITIES IN CANCER TREATMENT IN EUROPE

VIENNA ― Although survival for cancer patients in Europe has improved in recent years, there are substantial variations between countries and regions, particularly for hematologic malignancies, reveals a series of analyses of outcomes for more than 10 million patients.

Data presented here at European Cancer Congress (ECC) 2015 and simultaneously published in a collection of 11 articles in the European Journal of Cancer show that 5-year relative cancer survival is typically lower in Eastern Europe than in Central and Northern Europe.

Lead researcher Milena Sant, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy, emphasized that the findings, which are from the EUROCARE 5 study, can help identify regions with poor cancer survival where "action is needed to improve patient outcomes."

"Population-based survival information is essential for physicians, policy makers, administrators, researchers, and patient organizations who deal with the needs of cancer patients, as well as with the issue of the growing expenditure on healthcare," she said in a statement.

She added: "In connection with the publication of the EUROCARE 5 results, the European Cancer Patient Coalition calls for a reduction in the fragmentation of care services and the promotion of comprehensive multidisciplinary cancer care centers in order to help reduce survival inequalities across Europe, and it stresses that survival is also affected by the organization and funding of healthcare systems."

Commenting on the findings, President of the European CanCer Organisation (ECCO) Martine Piccart, MD, PhD, professor of oncology at the Université Libre de Bruxelles, in Belgium, said: "I find it quite distressing to see that we have such big differences in the chance of surviving a cancer 5 years across European countries."

"I would like to stress the fact that these cancer registries are incredibly important, but they are not sufficiently funded in many, many countries.

"So the data that the scientists there are able to put together are very often not standardized from one cancer registry to another, not detailed enough," she said, speaking at a press briefing to announce the findings.

Dr Piccart explained that although it is clear that the chances of surviving cancer are much less in some countries than in others, the lack of standardization means "it's going to be not so easy to go back and find what is the reason."

She stressed how important she believes it is "to support these cancer registries," adding: "It's the only way we can monitor how well or poorly we are treating cancer patients."

Building on Previous Data

The current set of analyses builds on previous work from the EUROCARE project. These include an evaluation of adults and children diagnosed with cancer between 2000 and 2007 that showed that overall cancer survival has improved throughout Europe during the past decade.

A further analysis published last year also showed that 5-year survival rates for most patients with hematologic malignancies have increased during the past 15 years in Europe. However, regional variations in survival were identified in both studies

The latest results are based on data on more than 10 million cancer patients diagnosed between 1995 and 2007, which were provided by 107 cancer registries from 29 European countries. The patients were followed until 2008.

Five-year relative survival and trends were then estimated by European region ― Northern, Central, Southern, Eastern, and Ireland/UK ― and, for some cancers, by morphology.

The average 5-year relative survival for Hodgkin's lymphoma was the highest for all the blood cancers, at 81%, and had the smallest regional variation, ranging from 74.3% in Eastern Europe to 85% in Northern Europe.

In contrast, the greatest variation was seen for chronic myeloid leukemia, at an average 5-year relative survival of 53.0%, which ranged from 33.4% in Eastern Europe to 51% - 58% in the rest of Europe.

The regional variations tended to be larger for cancers associated with a good prognosis. For example, the average 5-year relative survival was 82% for breast cancer, but ranged from 74% in Eastern Europe to 85% in Northern Europe.

Average 5-year relative survival was 57% for patients with colon cancer (range: 49% in Eastern Europe to 61% in Central Europe), 56% for those with rectal cancer (range: 45% in Eastern Europe, 60% in Central Europe), 83% for melanoma (range: 74% in Eastern Europe, 88% in Northern Europe) and 83% for patients with prostate cancer (range: 72% for Eastern Europe, 88% for Central Europe).

The variations were smaller for cancers associated with a poor prognosis. For example, patients with lung cancer had an average 5-year relative survival of 13%, which ranged from 9% in Ireland and the UK to 15% in Central Europe.

For ovarian cancer, the average was 38%; it ranged from 31% in Ireland and the UK to 41% in Northern Europe. The average for stomach cancer was 25% (range: 17% in Ireland and the UK, 30% in Southern Europe); the average for pancreatic cancer was 7% (range: 5% in Northern Europe and Ireland and the UK, 8% in Southern Europe).

The average 5-year relative survival for patients with esophageal cancer was also low, at 12% (range: 8% Eastern Europe, 15% Central Europe); for those with brain cancer, it was 20% (range: 18% in Ireland and the UK, 24% in Northern Europe).

In general, 5-year relative survival rates adjusted for causes of death other than cancer increased steadily during the study period for the majority of cancers, particularly in Eastern Europe.

Dr Sant said: "Between [the periods] 1999-2001 and 2005-2007, the largest increases in 5-year relative survival were seen in cancers such as chronic myeloid leukemia, where survival increased from 32% to 54%; prostate cancer, which increased from 73% to 82%; and rectal cancer, which increased from 52% to 58%."

Low Rates in Denmark, the UK, and Eastern Europe

Another analysis published as part of the European Journal of Cancer collection examined overall survival for all cancers in Europe, using data on more than 7.5 million cancer patients in 29 European countries.

This revealed that Denmark, the UK, and Eastern European countries had lower survival rates than their neighboring countries.

Taking into account patient age, the researchers found that 5-year relative cancer survival was 59.6% in Northern Europe vs 58% in Central Europe, 54.3% in Southern Europe, 50.1% in Ireland and the UK, and 45% for Eastern Europe. In Denmark, 5-year survival was 50.9%.

Survival was significantly lower than the Eastern European regional average in Bulgaria, Latvia, and Poland, at 39%, 42%, and 41%, respectively.

Dr Sant commented: "Survival correlated with gross domestic product [GDP] and total national expenditure on health [TNEH]."

"Countries with recent higher increases in GDP and TNEH had a higher increase in cancer survival. However, this was not the case for countries such as Denmark and the UK, which continue to perform worse than expected for their level of TNEH."

She said that there were a number of factors at play, including differences in cancer biology and behavior, in screening and diagnosis, in the availability of newer treatments, and in socioeconomic status, lifestyle, and general health.

Summarizing, Peter Naredi, MD, PhD, professor of surgery at Sahlgrenska University Hospital, in Gothenburg, Sweden, and scientific co-chair of ECC 2015, said in a release: "EUROCARE 5 once again shows how important it is that we follow the outcome of cancer care in Europe. When we improve diagnostics and treatments of a cancer type, it does not take long to improve survival for that patient population as well."

"But what Dr Sant and coworkers also indicate is that improved survival does not come without a financial incentive from the governments. I hope this will continue to encourage the European community to spend money on cancer care and research."

EUROCARE 5 was funded by the Italian Ministry of Health and the European Partnership for Action Against Cancer. The authors and participants have disclosed no relevant financial relationships.

European Cancer Congress (ECC) 2015. Abstract LBA 1. Presented September 26, 2015.

TAILORx RESULTS

Some women with early-stage breast cancer can skip chemotherapy without putting themselves at heightened risk for disease recurrence or spread at 5 years, according to new research.

The finding is important because it is from the first prospective evaluation of a widely used genetic test. Previous investigations of the popular 21-gene assay for breast cancer recurrence risk (Oncotype DX, Genomic Health) have been retrospective, so the evidence is less desirable.

In this study — known as TAILORx (Trial Assigning Individualised Options for Treatment) — the assay was used to determine which women had a low risk for recurrence and could therefore forgo chemotherapy and be treated with endocrine therapy alone.

Results were presented at the European Cancer Congress (ECC) 2015 in Vienna, and published online simultaneously in the New England Journal of Medicine.

The TAILORx study involved 10,253 women with hormone-receptor-positive, HER2-negative breast cancer and no disease spread to the lymph nodes. The women (15.9%) with a recurrence risk score condsidered low (range, 0 to 10) were eligible to receive an aromatase inhibitor, tamoxifen, or a combination of the two for 5 years — with no chemotherapy.

The women with intermediate and high recurrence risk scores were managed in the two other study groups. Those results are not yet available.

In the low-risk group, the rate of invasive disease-free survival at 5 years was 93.8% (95% confidence interval [CI], 92.4 - 94.9). The rate of freedom from recurrence at 5 years was 98.7% (95% CI, 97.9 - 99.2). And the rate of freedom from recurrence of breast cancer at a distant site (i.e., metastatic disease) was 99.3% (95% CI, 98.7 - 99.6), report Kathy Albain, MD, from Loyola University in Chicago, and colleagues.

In addition, there were 88 cases of either invasive cancer or death during the 5-year study period, and 30 deaths from other causes. The rate of overall survival at 5 years was 98.0% (95% CI, 97.1 - 98.6).

"There was outstanding survival with endocrine therapy alone. The test provides us with greater certainty of who can safely avoid chemotherapy," Dr Albain said in a press statement.

In regular clinical practice, all of the women in the study would have been candidates for chemotherapy, according to the National Comprehensive Cancer Network (NCCN) guidelines, because of their clinicopathologic features.

In an accompanying editorial, Clifford Hudis, MD, from the Memorial Sloan Kettering Cancer Center in New York City, says that "this result is numerically good enough to exclude any potentially meaningful benefit for additional chemotherapy," referring to the almost complete absence of metastatic spread at 5 years in the women who received endocrine therapy alone.

The results are a "confirmation" that the 21-gene assay, which has been used for about 10 years by clinicians, "can identify a cohort of patients who should be spared chemotherapy," writes Dr Hudis.

However, he adds, the TAILORx results are "both reassuring and frustrating."

Dr Hudis believes results from this and other prospective trials "cannot come soon enough," given the already "widespread adoption" of the assay by clinicians. But there is a problem, he says: the investigators changed the recurrence risk scoring scale for the study.

Dr Albain and her colleagues explain that because they wanted "to minimize the potential for undertreatment of the participants enrolled in our trial," they tightened the definitions of risk.

Thus, recurrence scores used in the TAILORx study are different than those generally applied in the widely used assay for low (≤10 vs <18 18="" 25="" 30="" and="" high="" intermediate="" p="" ranges.="" to="" vs="">

Dr Hudis is worried about the changed low-risk definition. "For the many physicians already using the test, the gap between this cutoff point of 10 and the higher 'standard' cutoff point of 18 may be a concern."

And he anticipates trouble. "There will be two conflicting guides to their treatment that need to be reconciled: the cutoff point used in this trial and the previously available cutoff point that is associated with the commercial test," he explains.

But Dr Hudis suggests that the snafu is not overwhelming, in part, because it is likely that other multigene tests will also be proven to "provide a prediction of chemotherapy benefit."

Less expensive tests would be helpful, especially for global use, he says. The Oncotype DX is regularly cited as costing $4000.

More Study Details

The study authors provide some context for their study. In 2014, more than 100,000 women in the United States received a diagnosis of estrogen-receptor-positive breast cancer with negative axillary lymph nodes. It is well known that endocrine therapy is good enough treatment for most of these women.

"Although approximately 85% of these women may be recurrence-free at 10 years with adjuvant endocrine therapy alone, the addition of chemotherapy leads to a relative reduction in the risk of recurrence of approximately 30% on average, which translates into an absolute benefit in the rate of freedom from recurrence of up to 5 percentage points," they report.

Thus, the aim of the trial is to help define who can skip chemotherapy safely.

The women in TAILORx were 18 to 75 years of age, and all met the NCCN guideline recommendations for adjuvant chemotherapy (primary tumor size of 1.1 to 5.0 cm; or 0.6 to 1.0 cm for a tumor of intermediate or high histologic grade or nuclear grade, or both).

All low-risk patients were assigned to endocrine therapy alone. The 1730 (16.9%) high-risk patients — with a recurrence risk score of at least 26 — were assigned to chemotherapy plus endocrine therapy.

The 6897 (67.3%) patients with a midrange score of 11 to 25 were randomly assigned to chemotherapy plus endocrine therapy or to endocrine therapy alone.

In various news reports from the ECC, a number of clinicians pointed out that the intermediate-risk group is the most interesting and clinically important because of uncertainty about chemotherapy use. But those results are not yet available. Maybe they will be at next year's conference.

This study was sponsored by the National Cancer Institute, and was coordinated by the ECOG and subsequently the ECOG–ACRIN Cancer Research Group. Some of the study authors report financial ties to industry, including Genomic Health, the makers of the Oncotype DX test. Dr Hudis reprots receiving grant support from Genomic Health.

European Cancer Congress (ECC) 2015: Abstract 5BA. Presented September 28, 2015.