True burden of head and neck cancer in France underestimated by more than one-third

A nationwide study of head and neck cancers in France has revealed that the true burden of the disease is underestimated by at least one-third, and that head and neck cancers carry a very high risk of secondary primary cancers, according to two presentations at the ESMO 2016 Congress in Copenhagen.

The EPICORL study is the first nationwide prognosis study of head and neck cancers in France, using data from the French National Hospital Discharge database from 2008-2012. It identified 131,965 patients discharged with head and neck cancer from French hospitals, 41% of whom later died in hospital, representing an overall five-year survival rate of 34%.^1,2

Distant metastases at diagnosis were recorded in 12% of patients, which was associated with a six-fold increase in the risk of death (HR = 6.2). Relapse during follow-up was recorded in 31% of patients diagnosed at an early stage and 57% of patients diagnosed at an advanced stage, and was also associated with a nearly six-fold increase in the risk of death (HR = 5.9).¹

“Due to its main risk factors of tobacco smoking and alcohol use disorders, head and neck cancer carries a very high risk of secondary primary cancers and significant burden of severe comorbidities,” said investigator Dr Florence Huguet from the Department Of Radiation Oncology at Tenon Hospital in Paris.

More than half the patients in the study had a cancer other than head and neck cancer, or had severe Charlson comorbidities other than cancer, which were associated with significantly lower survival.

Researchers also noted a high incidence of secondary primary head and neck cancers, which were observed in 6.1% of patients at diagnosis and 2.3% of patients during follow-up.

“We found cumulative incidences of relapse and secondary metachronous H&N cancer in the range of previous reports, though each risk was significantly increased in patients with advanced stage at diagnosis as compared to patients with early stage at diagnosis,” Dr Huguet said.

The EPICORL researchers also found that the national cause of death statistics underestimated the burden of head and neck cancer by 38%.² Investigator Dr Caroline Even, from the department of Head and Neck Cancer at Gustave Roussy said this was likely due to the fact that 43% of the 41,503 patients who died in hospital with advanced head and neck cancer were also treated for a cancer other than head and neck.

“Because determining the underlying cause-of-death is conflicting in presence of multiple primary cancer sites, we found unsurprisingly that the presence of former or synchronous cancers other than head and neck cancer were a major explanatory factor of the mortality gap observed in National Statistics,” Even said.

While the incidence of head and neck cancer has been reported as decreasing with the decline in the two main risk factors – tobacco smoking and alcohol consumption – the study found the annual death toll of head and neck cancer increased in hospital over the study period.

Commenting on the study, Professor Sandrine Faivre, medical oncologist at Hôpitaux Universitaires Paris Nord Val de Seine, France, said “this study is a major piece of data giving the nationwide spectrum of analysis in a country were the population has been exposed to tobacco and alcohol for the last decades.”

“HPV infection does not appear to impact positively in this recent French epidemiology report, which shares the classical features of tobacco/alcohol-induced head and neck cancers”. 

“The study highlights the burden and the poor prognosis of head and neck cancers linked to tobacco/alcohol, which also induce significant comorbidities in this population of patients. Besides recurrence, of note is the high incidence of second primary other cancers, which warrants screening or explorations toward organ sites of risk, such as other head and neck sites or lung.”

“This is a message of warning to physicians in France treating patients with head and neck cancer: in practice we should be reminded of the fragility of such patients who may have multiple comorbidities, making them especially vulnerable to the toxicities of treatments,” Faivre concluded.

Málaga acoge el II Congreso Internacional de Fisioterapia y Movimiento los días 8 y 9

El Palacio de Ferias y Congresos de Málaga acoge los días 8 y 9 de octubre el II Congreso Internacional de Fisioterapia y Movimiento ‘Motion for life”, organizado por el Colegio Profesional de Fisioterapeutas de Andalucía. Al acto de inauguración, celebrado hoy sábado, 8 de octubre, ha asistido el presidente de la Diputación de Málaga, Elías Bendodo.

En el marco de la misma, Bendodo ha hecho una valoración sobre las oportunidades de trabajo para los fisioterapeutas que existen en los pueblos del interior de la provincia.  El presidente ha considerado que todos los habitantes de la provincia "merecen y necesitan" una atención sanitaria como las que los fisioterapeutas ofrecen. Asimismo, ha recordado la labor de la Diputación de Málaga por el envejecimiento activo y saludable mediante la práctica deportiva, por cuyo programa han pasado en el útimo año 90.000 mayores.

Con un amplio programa de ponencias y comunicaciones, el congreso se centra en la importancia del movimiento, la actividad física y la fisioterapia para la mejora y el mantenimiento de la salud en personas de cualquier edad.

Ipilimumab as adjuvant therapy improves overall survival in high risk stage III melanoma

 Ipilimumab as adjuvant therapy significantly improves overall survival in patients with high risk stage III melanoma, according to the EORTC 18071 phase III trial results presented for the first time today at the ESMO 2016 Congress in Copenhagen.

“Ipilimumab is an immune checkpoint inhibitor that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4),” said lead author Professor Alexander Eggermont, director general, Institut Gustave Roussy, Villejuif, France. “It was approved in 2011 for first-line treatment of advanced melanoma in the US and Europe. The next question was its utility in the adjuvant setting.”

The EORTC 18071 phase III trial evaluated ipilimumab as adjuvant therapy for patients with high risk stage III melanoma. During 2008 to 2011, 951 patients were randomised to ipilimumab or placebo. Interferon was not used as the comparator because in Europe it is not routinely used nor accepted as a standard of care.

As reported in 2015, the study met its primary endpoint after a median follow up of 2.3 years, with ipilimumab significantly improving recurrence-free survival.² The drug was subsequently approved by the US Food and Drug Administration as adjuvant therapy for stage III melanoma.

Now, at 5.3 years median follow up, the impact on overall survival is reported and represents a 28% reduction of the relative risk of death (hazard ratio 0.72, p=0.001). There was consistency across all endpoints with hazard ratios of 0.76 for recurrence-free survival and distant metastases-free survival (p<0 .001="" 11="" absolute="" and="" arm="" at="" five="" higher="" in="" ipilimumab="" nbsp="" overall="" p="" placebo="" rate="" survival="" terms="" than="" the="" was="" years="">

Ipilimumab is known to create immune-related adverse events. At 5.3 years, there were no additional toxicities or deaths since the initial report at 2.3 years. The most important grade 3-4 adverse events were gastrointestinal (16%), hepatic (11%) and endocrine (8%). These were managed by established algorithms and usually resolved within 4-8 weeks. Endocrine adverse events took much longer to resolve or required permanent hormonal replacement therapies.

Eggermont said: “Ipilimumab adjuvant therapy brings a significant improvement of overall survival and has a favourable risk-benefit ratio. It clearly represents a serious option for patients with stage III melanoma.”

Commenting on the results, Dr Olivier Michielin, head of Personalised Analytical Oncology, CHUV, Lausanne, Switzerland, said: “This was the first attempt to use checkpoint blockade in the adjuvant setting of melanoma. The effect was a 28% reduction in the risk of death, which is statistically and clinically significant, and an 11% absolute gain in overall survival at five years.”

“This was also an important scientific discovery,” added Michielin. “Ipilimumab works by stimulating the immune system against tumour antigens. In the adjuvant setting there is microscopic residual disease and, until now, it was not clear if there was a sufficient amount of antigens to trigger a response.”

He continued: “The risks and benefits of this option should now be discussed with our patients. The toxicity is not negligible and patients need to be aware of the adverse event profile. The 10 mg/kg regimen used in the trial is associated with potentially severe toxicities and should be reserved for experienced centres.”

Michielin concluded: “This trial represents an important milestone in the treatment of melanoma. These results open the door for other studies based on checkpoint blockade to try and improve cure rates in the adjuvant setting of melanoma as well as other disease types. We are currently waiting for the results of several trials including EORTC 1325 which is investigating pembrolizumab, a PD-1 checkpoint blocking antibody, compared to placebo in the adjuvant setting.”

Immunotherapy shows promising results in first and second line treatment of metastatic bladder cancer

Immunotherapy has shown promising results in first and second line treatment of metastatic bladder cancer in two phase II trials presented at the ESMO 2016 Congress in Copenhagen.

Up to half of patients with metastatic bladder cancer are not eligible for survival prolonging first line treatment with cisplatin-based chemotherapy. Survival in these patients is just nine to ten months with currently available alternative chemotherapy.

The phase II KEYNOTE-052 trial¹ evaluated the efficacy and safety of PD-1 blockade with pembrolizumab as first line therapy in cisplatin ineligible patients with metastatic or locally advanced bladder cancer. Today researchers presented the preliminary analysis of the first 100 patients enrolled in the trial. The primary endpoint of objective response rate was 24%. The biomarker cut point to identify patients who are most likely to respond to the drug was determined to be 10% or greater total PD-L1 expression in immune cells or tumour cells. Thirty patients had this level of expression of whom 11 (37%) responded to treatment. The median duration of response has not yet been reached and treatment was well tolerated.

Lead author Dr Arjun Balar, Assistant Professor, NYU Langone Medical Centre, New York, US, said: “Pembrolizumab has substantial activity with a favourable safety profile as first line therapy in cisplatin ineligible patients with metastatic bladder cancer. The biomarker cut point will need to be validated in the larger study population, but seems to identify patients most likely to respond to pembrolizumab well. Immunotherapy is rapidly redefining our treatment approach for patients facing this dreadful disease.”

For several decades, there had been no global standard of care for second line treatment of patients with metastatic bladder cancer who progress despite platinum-based chemotherapy until the recent development of immune checkpoint blockade. In another study presented today, the phase II CheckMate 275 trial² assessed the activity and safety of the PD-1 inhibitor nivolumab in 270 patients with metastatic bladder cancer who have progressed despite first line platinum-based chemotherapy. CheckMate 275 is the largest study of a PD-1 inhibitor in bladder cancer reported to date.

In the 265 patients who could be evaluated for efficacy, the primary endpoint of objective response rate was 19.6%. The median duration of response has not yet been reached, with a median follow-up of seven months. In both patients with tumours expressing higher and lower levels of PD-L1 (including those with less than 1% PD-L1), the objective response rate was above that achieved historically with chemotherapy.

“This data is being submitted to support registration of nivolumab for patients with metastatic urothelial cancer that has progressed despite platinum-based chemotherapy, an indication for which the US Food and Drug Administration has granted breakthrough therapy designation to nivolumab,” said lead author Professor Matthew Galsky, Professor of Medicine, Mount Sinai School of Medicine, New York, US. “Immune checkpoint blockade has become the most promising approach for these patients.”

Commenting on the current management of bladder cancer, Dr Maria De Santis, Associate Clinical Professor for Oncology, Cancer Research Centre, University of Warwick, UK, said: “There are insufficient treatment options for patients ineligible for cisplatin and for those progressing on cisplatin-based chemotherapy.”

She continued: “This year the first immune check point inhibitor, atezolizumab, was approved for patients with bladder cancer and CheckMate 275 provides similar results with nivolumab in the second line setting.”

“KEYNOTE-052 confirms that immunotherapy is also active as first line therapy in cisplatin ineligible patients, with a slightly lower response rate than chemotherapy,” said De Santis. “However, the duration of response with pembrolizumab seems to exceed that of chemotherapy in historical controls. The protocol included a new biomarker definition and cut-off which needs further evaluation.”

She concluded: “Immune check point inhibitors have started to alter the therapeutic landscape for bladder cancer. We expect even more dramatic changes in the coming years with the use of immunotherapy in other clinical stages and as combination therapy.”

Targeting estrogen receptor improves progression-free survival in advanced breast cancer

Fulvestrant significantly increases progression-free survival in women with hormone-receptor-positive advanced breast cancer, particularly those with less aggressive lower-volume disease, researchers reported at the ESMO 2016 Congress in Copenhagen.

Fulvestrant is a selective estrogen receptor degrader that targets the function of the hormone receptor so, unlike aromatase inhibitors such as anastrozole, it does not interfere with estrogen levels themselves.

The randomized, double-blind, multi-center phase III trial enrolled 462 women with inoperable locally-advanced or metastatic ER-positive, HER-negative breast cancer, who had not received prior hormone therapy.

Half the patients (n=230) were randomized to 500mg intramuscular injections of fulvestrant (Days 0, 14, 28, then every 28 days), or to 1mg of anastrozole daily (n=232), and were also allowed one line of chemotherapy.

After a median follow-up of 25 months, patients treated with fulvestrant had a statistically significant 21% improvement in progression-free survival compared to those treated with anastrozole (16.6 months vs. 13.8 months, p = 0.048).

However subgroup analysis showed an even greater impact on progression-free survival in patients whose disease had not spread to the liver or lungs at baseline (22.3 vs. 13.8 months).

“For patients with non-visceral disease whose life isn’t immediately threatened by breast cancer – a group for whom physicians would typically choose endocrine therapy as a first approach – it looks like fulvestrant could be a new standard of care compared to anastrozole,” said the study’s principle investigator Dr. Matthew Ellis, from the Lester and Sue Smith Breast Center, Baylor College of Medicine in Houston, Texas, USA.

Both groups showed a similar health-related quality of life, and the most common adverse events were arthralgia (joint pain) (16.7% vs. 10.3%) and hot flushes (11.4% vs. 10.3%) for fulvestrant and anastrozole, respectively.

“It’s tolerated as well as anastrozole, and better than other drugs that could potentially be used in this setting such as chemotherapy or CDK4 inhibitors,” Ellis said.

“In patients for whom you are looking for a low toxicity approach, such as older patients or those with low volume disease, it looks like a good option.”

Researchers also observed a significantly greater duration of response to treatment in the fulvestrant group compared to the anastrozole group, which Ellis suggested could account for the increase in progression-free survival.

Commenting on the study, Dr Nicholas Turner, team leader at the Institute of Cancer Research and Medical Oncologist at the Royal Marsden, London, UK, said the results represent an important advance in the treatment of the most common form of breast cancer, and suggest a potential benefit for using fulvestrant earlier in a patient’s treatment.

“However two factors complicate moving this new finding into routine clinical practice: firstly, the study only included patients with no prior hormone treatment yet many patients presenting with advanced breast cancer have previously been treated for the primary breast cancer,” Turner said.

“Secondly, since the design of the study, the standard of care for these women has moved on, with the CDK4/6 inhibitor palbociclib now licensed in US, in combination with an aromatase inhibitor, for the same group of patients. Further studies will help define the most optimal sequence of therapy for women with advanced breast cancer.”

Niraparib significantly improves outcome of ovarian cancer patients in landmark trial

The PARP inhibitor niraparib significantly improves the outcome of platinum-sensitive recurrent ovarian cancer, according to full data from the ENGOT-OV16/NOVA trial presented for the first time at the ESMO 2016 Congress in Copenhagen¹ and published in the New England Journal of Medicine (NEJM)². The trial met its primary endpoint, with niraparib considerably prolonging progression-free survival compared to placebo.

“There are limited treatment options in recurrent ovarian cancer,” said lead author Dr Mansoor Raza Mirza, chief oncologist, Rigshospitalet, Copenhagen University Hospital, Denmark and medical director of the Nordic Society of Gynaecological Oncology (NSGO). “Cumulative toxicity with platinum-based chemotherapy and lack of additional benefit limits its use. We then pause treatment until the next relapse and start combination chemotherapy.”

“The current options for maintenance therapy in the EU are bevacizumab, which can only be given once and improves progression-free survival by just a few months, and the PARP inhibitor olaparib, which is only approved in patients with a germline BRCA mutation (about 10–15% of ovarian cancer patients). No maintenance therapy is approved outside the EU,” he continued.

This phase III trial was performed in collaboration with European Network of Gynaecological Oncology Trial groups (ENGOT). The ENGOT-OV16/NOVA trial evaluated the efficacy and safety of the PARP inhibitor niraparib as maintenance therapy in patients with recurrent ovarian cancer who respond to platinum-based chemotherapy. Patients were assigned to cohorts by BRCA mutation status and randomised 2:1 to receive niraparib 300 mg or placebo once daily.

The trial included 553 patients, of whom 203 had the germline BRCA mutation and 350 did not. Niraparib significantly improved the primary endpoint of progression-free survival compared to placebo in both cohorts, as well as in all subgroups.

Median progression-free survival with niraparib compared to placebo was 21.0 vs 5.5 months in the germline BRCA mutation group (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.173 to 0.410, p<0 .0001="" 0.243="" 0.338="" 0.38="" 0.45="" 0.586="" 0.607="" 12.9="" 3.8="" 3.9="" 9.3="" 95="" a="" and="" brca="" ci="" cohort="" deficiencies="" dna="" group="" had="" homologous="" in="" months="" mutation="" non-germline="" non-mutation="" of="" p="" recombination="" repair="" subgroup="" the="" to="" vs="" who="">

More than 10% of patients had grade 3/4 adverse events following treatment with niraparib, of whom 28% had thrombocytopaenia, 25% had anaemia, and 11% had neutropaenia. These were resolved with dose adjustments and patients could continue their treatment. Patient-reported outcomes were similar with niraparib and placebo. Patients on niraparib maintained symptom control and had a quality of life comparable to those on placebo.

Significant improvements were also observed in all secondary endpoints. Compared to placebo, niraparib significantly prolonged the second progression-free survival, time to first subsequent treatment, and chemotherapy-free interval in the mutation and mutation-free groups, and in the HRD subgroup.

“This is a breakthrough for patients with ovarian cancer,” said Mirza. “We have never seen such large benefits in progression-free survival in recurrent ovarian cancer. Niraparib significantly improved all endpoints across a broad patient population representing 70% of all ovarian cancer patients. These landmark results could change the way we treat this disease.”

He concluded: “Once it is approved by the regulatory authorities, I’ll consider niraparib for all my patients with recurrent ovarian cancer who respond to platinum regardless of BRCA status.”

Commenting on the results, Dr Andrés Poveda, head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain, said: “This study more than doubles the population of patients who benefit from a PARP inhibitor.”

“Personalised medicine has arrived in high grade serous ovarian cancer,” he continued. “This was the first trial to use HRD to select patients for treatment and showed that it is a useful strategy. We also know that PARP inhibitors benefit patients with BRCA mutations.”

Poveda concluded: “Future studies are needed to unravel which patients with HRD are not responders to PARP inhibitors and why, and which patients are long responders and why. We also need to know if there are other non-HRD factors, such as cyclin E positivity, that predict which patients will respond to treatment.

Ribociclib improves progression-free survival in advanced breast cancer

he addition of the CDK4/6 inhibitor ribociclib to letrozole therapy significantly improves progression-free survival in postmenopausal women with hormone receptor-positive advanced breast cancer, researchers reported today at the ESMO 2016 Congress in Copenhagen.

The first interim analysis of data from the randomized, double-blind MONALEESA2 study showed a 44% improvement in progression-free survival with ribociclib plus letrozole as a first-line treatment combination.

“This was THE definitive study to demonstrate the superiority of the combination of ribociclib and letrozole over letrozole alone,” said principle investigator, Professor Gabriel Hortobagyi, from the University of Texas MD Anderson Cancer Center in Houston, Texas, US.

Researchers randomized 668 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, who had not undergone any prior systemic treatment, to ribociclib (600 mg/day, 3 weeks on/1 week off) and letrozole (2.5 mg/day, continuous), or letrozole plus placebo.

In the ribociclib arm, there was a 44% improvement in the primary objective of progression-free survival compared to the placebo arm (HR: 0.556, p = 0.00000329). Median progression-free survival was 14.7 months in the placebo arm, but was not reached in the ribociclib arm at data cut-off.

“The results of this trial represent a compelling proof of principle, and suggest a paradigm shift in metastatic, HR+ breast cancer. They also suggest that testing combinations of ribociclib with other inhibitors of various signaling pathways might lead to additional progress in the management of several subtypes of breast cancer,” Hortobagyi said.

Patients with measurable disease at baseline showed a significantly higher objective response rate to ribociclib plus letrozole compared to letrozole alone (53% vs. 37%; p=0.00028), and improved clinical benefit rate (80% vs. 72% p=0.02).

Serious adverse events occurred in fewer than 5% of patients in both arms but other adverse events were significantly more common in the ribociclib arm. Neutropenia occurred in 59% of patients in the ribociclib arm compared to 1% of the placebo arm; leukopenia occurred in 21% vs 1%; lymphopenia in 7% vs. 1%, and patients in the ribociclib arm had a higher incidence of elevated alanine aminotransferase and elevated aspartate aminotransferase.

The number of deaths in the study was too low to enable a reliable analysis of the impact of ribociclib therapy on overall survival.

Commenting on the findings, Professor Giuseppe Curigliano, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy, said, “I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib (already FDA approved) and abemaciclib (under development).”

“The addition of ribociclib to letrozole does increase the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib.”

Curigliano also suggested that further studies of ribociclib should examine the use of cancer biomarkers to better identify patients who would respond to the combination.