Κυριακή, 17 Σεπτεμβρίου 2017

ESMO 2017-CANCER PATIENTS CAN NOT UNDERSTAND CLINICAL TRIALS

Cancer patients struggle to understand what is involved in a clinical trial, even when they have participated in them. In a survey of 1090 adult cancer patients, more than half did not understand the concepts of clinical equipoise or randomization.
In the survey, 63% of patients thought that "my doctor would make sure that I got the better treatment in a clinical trial," and 55% said that "my doctor would know which treatment in a clinical trial was better."
The concept of randomization was also not understood. The survey involved 1090 patients who were attending 14 cancer centers in Ireland. About a third (30%) had already taken part in a clinical trial, but more than half of these patients did not understand that randomization means that the treatment would be allocated by chance. Among the cancer patients who had not participated in a clinical trial, the proportion was even higher ― 73% did not think that the choice of treatment was made on the basis of chance.
"This shows poor understanding of randomization, and we know this is a difficult concept for patients," commented lead author Catherine Kelly, MD, associate professor of medical oncology at the Mater Misericordiae University Hospital and University College in Dublin, Ireland.
"There is also the concept of clinical equipoise, that the reason you are doing the clinical trial is because there is uncertainty over which is the best option," she said in an interview. The results here were rather surprising, she said, because even patients who had been in a clinical trial still felt that the treating physician would choose the best treatment and, even more worrying, that the physician would make sure that they were getting the best treatment.
These responses show that patients "very much trust their cancer doctors, with the expectation that the doctor will know what is the best treatment and will ensure that they get it," Dr Kelly said.
The findings suggest that oncologists and their research teams need to explain more clearly these concepts and suggest a need for more training of communication skills, Dr Kelly suggested.
"Doctors have a responsibility to properly inform their patients in this regard, because they are the ones patients trust the most," Dr Kelly said.
"To provide informed consent when participating in a trial, patients need to understand these key concepts ― and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating. For example, many didn't realize that clinical trials are not just an option for when standard treatment has failed," she observed.
Reacting to the findings, Dr Bettina Ryll, chair of the ESMO Patient Advocates Working Group, commented: "The question of whether patients understand clinical trial methodology is a very valid one, and what makes this study so interesting is that more than a quarter of the patients questioned had actually been on clinical trials before," she said.
"However, I was surprised at the median age of the cohort: 60 years. It would be interesting to compare the data collected here with younger patient groups, who access information in a very different way," Dr Ryll observed. "I would also expect to see differences across tumor groups: among breast cancer patients, for instance, who make up almost a third of the study cohort and for most of whom there is a well-established standard of care, clinical trials are likely to be of less interest than among lung cancer patients, for whom the standard treatment is less effective."
Dr Ryll further cautioned: "When we talk about understanding, it is important to consider that patients and physicians approach clinical trials from different perspectives. For example, the concept of randomization is one that many patients question from a moral standpoint. Equipoise, by contrast, may be a laudable moral concept, but it is difficult to uphold if the results of earlier trials are already known: finding out whether a treatment is, say, 51% better or only 49% may matter to an HTA [health technology assessment] assessor but not to a patient. This undermines the conclusion that patients simply do not understand equipoise."
European Society for Medical Oncology (ESMO) 2017 Congress. Abstract 1465P_PR, presented September 10, 2017.

HOLD OF IMMUNOTHERAPY TRIALS IN HEMATOLOGY

Because of safety concerns, the US Food and Drug Administration has placed full or partial holds on clinical trials of three immunotherapies — pembrolizumab (Keytruda, Merck), nivolumab (Opdivo, BMS), and durvalumab (Imfinzi, AstraZeneca) — that are being used experimentally in combination with other drugs for the treatment of multiple myeloma and other blood cancers.
In the case of pembrolizumab, there was an increased risk for death associated with its use in combination with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of patients with multiple myeloma compared with controls who did not receive pembrolizumab.
On September 1, the FDA issued a statement about the mortality risk associated with pembrolizumab in multiple myeloma, as reported by Medscape Medical News. The statement was a follow-up to an FDA action in early July that halted the conduct of two clinical trials (KEYNOTE-183 and KEYNOTE-185) exploring the use of pembrolizumab in this setting, both of which showed an increased death risk.
Last week, the FDA expanded the trial restrictions to rival immunotherapies, nivolumab and durvalumab, according to statements from the drugmakers.
With regard to nivolumab, the agency placed a partial hold on three clinical trials testing the agent in combination with other medicines for multiple myeloma — because of the risks seen in similarly designed studies involving pembrolizumab, according to Bristol-Myers Squibb.  Both pembrolizumab and nivolumab are programmed cell death (PD)-1 inhibitors.
Patients with relapsed multiple myeloma in the trials who experienced clinical benefit will be allowed to continue treatment, but no new patients will be enrolled at this time, the company said.
Then, after the announcement from Bristol-Myers Squibb, AstraZeneca and Celgene said that the FDA had placed a partial hold on five trials testing durvalumab in combination with Celgene drugs and a full hold on one other study, according to a Reuters report.
Again, the actions were based on safety concerns from the pembrolizumab trials.
Most of the affected combination studies were for multiple myeloma. However, one of the trials under partial hold is evaluating durvalumab in patients with lymphoma or chronic lymphocytic leukemia. Durvalumab is a PD ligand 1 inhibitor.
The FDA's actions and concerns do not apply to the approved, on-label indications of these immunotherapies. 

ADVERSE NEUROLOGIC EFFECTS BY IMMUNOTHERAPY

Fewer than 3% of cancer patients developed neurologic adverse events (AEs) after treatment with two of the newer immune checkpoint inhibitors, results from a single-center, retrospective cohort study show.
Although this rate may seem low, clinicians can expect to see more serious neurologic complications more often, as treatment with anti–programmed death-1 (anti-PD-1) monoclonal antibodies is extended to other cancers, say Justin C. Kao, MBChB, of the Mayo Clinic in Rochester, Minnesota, and colleagues.
Their cohort study, published online September 5 in JAMA Neurology, describes the first case of necrotizing vasculitis associated with the anti-PD-1 immunotherapy agents pembrolizumab (Keytruda, Merck, Sharp & Dohme) and nivolumab (Opdivo, Bristol-Myers Squibb), the study authors say. The first cases of anticerebellar ataxia and bilateral internuclear ophthalmoplegia associated with these anti-PD-1 therapies are also described for the first time, they add.
"Our series demonstrates the importance of careful clinical evaluation and testing, as well as pathological confirmation, to understand these conditions and guide treatment," the investigators write. "These AEs have a diverse phenotype, with more frequent neuromuscular complications. The time of onset is unpredictable, and evolution may be rapid and life-threatening."
Last year, as previously reported by Medscape Medical News, two cases of severe demyelinating polyradiculoneuropathy occurring after treatment with pembrolizumab or advanced melanoma were described by clinicians in France. Given that hundreds of clinical trials involving checkpoint inhibitors are currently ongoing, clinicians need to proceed with caution, warn experts.
In an accompanying editorial, Roy E. Strowd III, MD, of the Wake Forest School of Medicine, Winston-Salem, North Carolina, says the current study takes an important "first step" toward better understanding the immune-related neurologic complications associated with nivolumab and pembrolizumab. However, he notes, risk factors for the development of neurologic immune-related AEs (irAEs) have not yet been described.
"Important questions remain unanswered," says Dr Strowd. "Neurologists and oncologists need to be aware of the important checkpoints ahead in patient care."
Checkpoint inhibition has been associated with a broad spectrum of unique irAEs in more than 70% of treated patients, he points out. Severe irAEs of grades 3 or 4 have been reported in up to 13% of patients treated with nivolumab and in up to 16% of patients treated with pembrolizumab.
Reduced survival has not been demonstrated to date in spite of concerns that treatment of irAEs could reduce the effectiveness of checkpoint inhibitors and expose patients to opportunistic infections, said Dr Strowd. Given the unpredictable onset and devastating neurologic sequelae associated with irAEs, however, now may be a good time to keep that neurology consult on speed dial.
Early recognition and prompt treatment are important," Dr Strowd notes. "Consultation calls from the cancer center are all too familiar for neurologists, and this pattern appears likely to persist in the era of immunotherapy."
The study coincided with the US Food and Drug Administration approval of pembrolizumab in September 2014 and nivolumab in December 2014 for the treatment of metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. The study ended in May 2016.
Using the Mayo Cancer Pharmacy Database, the investigators identified 347 patients, of whom 205 were treated with pembrolizumab and 142 were treated with nivolumab. After a median of 5.5 treatment cycles and within 12 months of anti-PD-1 therapy, 10 patients developed AEs (eight men and two women; median age, 71 years). Seven had been receiving pembrolizumab therapy, and three had been receiving nivolumab therapy. The researchers excluded from their study patients with neurologic complications caused by metastatic disease or other treatments.
Myopathy was observed in two patients, autoimmune retinopathy in one patient, and headache in one. Varied peripheral neuropathies were seen in four patients, and five patients experienced systemic immune-mediated complications, such as hypothyroidism, colitis, and hepatitis.
The median score on the modified Rankin Scale (mRS) was 2.5, indicating mild to moderate disability. The time within which symptoms reached maximum severity varied widely, from 1 day to more than 3 months.
Anti-PD-1 therapy was discontinued in all patients. Seven were treated with corticosteroids, three received intravenous immunoglobulin, and one patient underwent plasma exchange. Of the 10 patients, nine improved, with a median mRS score of 2. The remaining patient, who had severe necrotizing myopathy, did not respond to corticosteroid therapy or the addition of plasma exchange and died.
When approached for comment, Jeffrey S. Weber MD, PhD, deputy director, Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York City, said the neurologic consequences of checkpoint inhibitor therapy may be a bit less common than previously thought but still require vigilance by treating physicians.
Organizations such as the American Society of Clinical Oncology and the National Comprehensive Cancer Network are developing guidelines for the management of immune-related adverse events resulting from the use of checkpoint inhibitors, particularly neurologic complications, Dr Weber pointed out. "This will increase awareness of these side effects and provide education to practitioners who may be new to the use of these drugs," he told Medscape Medical News. 
Continuing education and increased experience will reduce the morbidity from these drugs, Dr Weber predicted. He noted that more resources are being dedicated to understanding the etiology of AEs, which "will help reduce the immune-related side effects of checkpoint inhibitors."
Ryan Joseph Sullivan, MD, of Massachusetts General Hospital Cancer Center in Boston, agreed. "The most important thing that needs to happen is the dissemination of information about neurological complications of these therapies," said Dr Sullivan, who was not affiliated with the study. "The widespread use of these agents will certainly lead to an increase in the incidence of these toxicities."
Initially, clinicians should consider the possibility that any new or worsening toxicity could be related to anti-PD-1 inhibitors, he told Medscape Medical News. Although toxicity is rare, "early diagnosis and treatment are critical to successful management of severe immune-related side effects," he said.
As with any other treatment, the risk/benefit ratio of checkpoint inhibitor therapy must be taken into account with each patient. "In my opinion, the knowledge of these neurologic risks does not shift the risk/benefit in a significant way," said Dr Sullivan.
Early referral to subspecialists with knowledge of the diagnosis and treatment of inflammatory conditions is key, he added, noting that attempts should be made to confirm the immune-related adverse effect diagnosis through biopsy or other testing.
No funding was reported for this study. Dr Kao has disclosed no relevant financial relationships. Coauthor Michelle L. Mauermann, MD, reports relationships with Ionis Pharmaceuticals and Alnylam Pharmaceuticals. Dr Weber has consulted for BMS, Merck, and Genentech. Dr Sullivan has disclosed no relevant financial relationships.

NEW APPROVALS BY EMA

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorization to an array of anticancer agents, including branded, generic, and biosimiliar products, for marketing approval at its September meeting.
The CHMP recommended niraparib (Zejula, Tesaro) for use in the maintenance treatment of patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Niraparib is a poly ADP-ribose polymerase (PARP) inhibitor, but unlike other drugs in this class, it is active both in patients with and those without BRCA mutations. It was approved by the US Food and Drug Administration earlier this year.
The basis of the new approval is the drug's ability to improve progression-free survival (PFS) compared to placebo in this setting. The PFS results from the phase 3 trial known as NOVA are unprecedented. "We have never seen such large benefits in PFS in recurrent ovarian cancer," said lead investigator Mansoor Mirza, MD, of the Copenhagen University Hospital-Rigshospitalet, Denmark, in 2016.
The most common side effects with niraparib are nausea, thrombocytopenia, fatigue/asthenia, anemia, constipation, vomiting, abdominal pain, neutropenia, insomnia, headache, decreased appetite, nasopharyngitis, diarrhea, dyspnea, hypertension, dyspepsia, back pain, dizziness, cough, urinary tract infection, arthralgia, palpitations, and dysgeusia.

Padeliporfin

The CHMP also recommended giving marketing authorization to padeliporfin (Tookad, Steba Biotech) for the initial treatment of low-risk prostate cancer.
Padeliporfin is administered as part of focal vascular-targeted photodynamic therapy and acts as a sensitizer. When activated with laser light, padeliporfin triggers a cascade of pathophysiologic events that result in focal necrosis within a few days, according to the CHMP materials. The therapy improves the likelihood of a negative biopsy result at 24 months and delays disease progression compared with active surveillance.
The most common side effects are urinary and reproductive system disorders.

Trastuzumab Biosimilar

The CHMP also recommended authorization for a trastuzumab biosimilar (Ontruzant, Samsung Bioepis UK Limited) for the treatment of early and metastatic breast cancer and metastatic gastric cancer.
Data show that Ontruzant has comparable quality, safety, and efficacy to Herceptin(trastuzumab, Genentech).
Also, the CHMP recommended authorization for the generic product Imatinib Teva BV, which is for the treatment of leukemia and gastrointestinal stromal tumors.
The new product is a generic form of imatinib (Glivec, Novartis), which is a protein kinase inhibitor. Studies have demonstrated the satisfactory quality of Imatinib Teva BV and its bioequivalence to the reference product, Glivec, according to the CHMP.
The full indication says that Imatinib Teva BV is indicated for the treatment of the following: pediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl)–positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplant is not considered as the first-line of treatment; pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis; adult patients with Ph+ CML in blast crisis; adult and pediatric patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy; adult patients with relapsed or refractory Ph+ ALL as monotherapy; and adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements.

CHEMORADIATION BEST TREATMENT FOR ADVANCED CERVICAL CANCER

A 14-year randomized trial in more than 600 patients has concluded that chemoradiation should remain the standard treatment for patients with locally advanced cervical cancer. The findings were reported at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid (Abstract 928O_PR).
The trial demonstrated no improved disease-free survival with neoadjuvant chemotherapy followed by surgery.
Chemoradiation, which refers to radiation delivered simultaneously with cisplatin-based chemotherapy, has been the standard treatment for patients with locally advanced cervical cancer since 1999 when it was shown to improve outcomes compared to radiation alone.
“Even with chemoradiation, some patients relapse and die of their disease, so there is a need for better treatments,” said first author Sudeep Gupta, MBBS, medical oncologist at Tata Memorial Centre, Mumbai, India. “Previous trials have found that neoadjuvant chemotherapy followed by surgery results in superior outcomes compared to radiation alone, but no trial has tested this strategy against standard treatment with chemoradiation.”
Study Findings
This trial examined whether neoadjuvant chemotherapy followed by surgical removal of the tumor could improve outcomes in patients with locally advanced cervical cancer compared to standard treatment with chemoradiation.
The trial included 633 patients with stage IB2, IIA, or IIB squamous cell cervical cancer who were randomized to either neoadjuvant chemotherapy (paclitaxel and carboplatin) followed by radical hysterectomy or chemoradiation (standard pelvic radiation plus cisplatin). The primary endpoint was disease-free survival, which was defined as survival without relapse or death due to cancer.
After a median follow-up of 58.5 months, the primary endpoint occurred in 30% of patients in the chemotherapy/surgery group and 23% of patients in the chemoradiation group. The corresponding 5-year disease-free survival rates were 69.3% in the chemotherapy/surgery group and 76.7% in the chemoradiation group (P = .038).
“We found the reverse of our hypothesis was true,” said Dr. Gupta. “Patients who received chemotherapy followed by surgery were less likely to be alive and disease-free at 5 years than those who received standard treatment with chemoradiation.”
When the researchers included death due to any cause in the definition of disease-free survival, they found no significant difference between the two treatment groups, although there was a trend towards increased disease-free survival with chemoradiation. There was no statistically significant difference in overall survival between the two groups.
Dr. Gupta said, “Chemoradiation should continue to be the standard treatment for patients with locally advanced cervical cancer.”
Commentary
Commenting on the results for ESMO, Sandro Pignata, MD, PhD, Director, Uro-Gynecological Department, Istituto Nazionale Tumori IRCCS "Foundation G. Pascale”, Naples, Italy, said, “This is the first direct comparison between these two strategies and it shows that chemoradiation should remain the standard treatment.”
“Cervical cancer is caused by infection with human papillomavirus (HPV) and can be prevented with vaccination and screening,” he continued. “As a result, the incidence of locally advanced cervical cancer is decreasing in Europe, but is still high in developing countries, where modern radiation therapy may not be available. In these situations, neoadjuvant chemotherapy followed by surgery may still be the best option.”
Dr. Pignata pointed out that an ongoing European Organisation for Research and Treatment of Cancer (EORTC) trial will be the second study comparing chemoradiation with neoadjuvant chemotherapy followed by surgery. He said, “When the EORTC trial has completed, a combined analysis of the two studies may provide further insights into the most effective treatment for locally advanced cervical cancer.”

FLOT SUPERIOR THAN ECF IN ESOPHAGOGASTRIC CANCER

The superiority of docetaxel-based triplet therapy over standard of care in patients with resectable esophagogastric cancer has been confirmed in late-breaking results from the FLOT4 trial presented at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid (Abstract LBA27_PR).
Survival in resectable esophagogastric cancer is poor. Five-year overall survival is around 25% with surgery, and is increased to 36% by adding a perioperative regimen of epirubicin, cisplatin, and infused fluorouracil (ECF). Phase II studies have shown encouraging pathologic response rates with perioperative docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT).
FLOT4 Trial
The phase III FLOT4 trial randomized 716 patients with resectable gastric or gastroesophageal junction adenocarcinoma to perioperative FLOT or ECF. As previously reported, FLOT was superior to ECF for all efficacy endpoints, including curative resection rates, progression-free survival, and overall survival.
At ESMO, researchers reported the results of multivariate, subgroup, and sensitivity analyses for the first time.
The relative effect of FLOT was observed in all subgroups, including the elderly and signet cell tumors, and was particularly pronounced in Siewert type 1 esophageal tumors (hazard ratio [HR] = 0.60), Barrett tumors (HR = 0.62), small tumors (HR = 0.66), and node-negative tumors (HR = 0.64).
Lead author Salah-Eddin Al-Batran, MD, Director, Institute of Clinical Cancer Research, UCT-University Cancer Centre, Krankenhaus Nordwest, Frankfurt, Germany, said: “These new analyses confirm the superiority of FLOT, which is the new standard of care in the perioperative treatment of patients with resectable gastric or gastroesophageal junction adenocarcinoma.”
He concluded,“Some oncologists believe that patients with small tumors and those with signet cell cancer should not be treated preoperatively. The results of the FLOT4 trial contradict this and show that these patients do benefit.”
Commentary
Commenting for ESMO, Michel Ducreux, MD, PhD, Head, Gastrointestinal Oncology Unit, Gustave Roussy, Villejuif, France, said: “The triplet regimen used in the FLOT4 trial was developed to improve the results of ECF. It decreased toxicity by replacing epirubicin with low-dose docetaxel and using oxaliplatin instead of cisplatin. FLOT is also more convenient to use, with one 24-hour infusion every 2 weeks rather than continuous infusion of fluorouracil in the ECF protocol.”
“The results show that FLOT is clearly the new standard of care,” continued Dr. Ducreux. “The new analysis presented at the ESMO 2017 Congress shows that the advantage of the FLOT regimen was seen across all subgroups, including those with a very poor prognosis, such as the elderly and patients with signet cell tumors.”


He concluded, “FLOT will be the best backbone of chemotherapy that we can use in this setting. A step forward would be to try to improve the results by adding targeted therapies or immune checkpoint inhibitors. It would also be interesting to know if the FLOT regimen shows different levels of effectiveness in the four molecular biologic subgroups of gastric cancer.”

ASCO GUIDELINES FOR PATIENT-CLINICIAN COMMUNICATION

Effective communication is an essential part of all patient-centered oncology care, and a new guideline from the American Society of Clinical Oncology (ASCO) now offers a framework of specific practices that can improve communication with patients.
The guidance was published September 11 in the Journal of Clinical Oncology.
"The guideline is both patient-centered and relationship-centered. It underscores that an important skill for each provider is to understand the patient as an individual and their families' unique needs," said Walter F. Baile, MD, co-chair of the ASCO Expert Panel that developed the guideline.
"The recommendations can help doctors form a trusting relationship with patients that is characterized by empathy, honesty, and a human connection with the patient and family," Dr Baile said in a statement.
Cancer is a devastating diagnosis, the authors point out in their paper, and clinicians must learn to support patients and to help them cope. This includes the ability to efficiently build rapport, give them adequate information, and address any concerns within the time constraints of clinical practice.
Most patients do not have an educational background that allows them to fully comprehend the complexity of a cancer diagnosis and treatment. In addition, many clinicians have only limited training to "prepare them to deliver information about complex health issues in a manner that results in comprehension and retention by patients and other nonexperts," the ASCO authors write.
In the past, say the authors, good communication skills were often viewed as being something innate or that could be acquired by emulating role models. Clinicians were often simply expected to figure it out by themselves, but research suggests that well-designed training programs can improve both the communication skills of providers and patient experience
Thus, this new paper is designed to guide oncology clinicians on effective communication, which will in turn optimize the patient-clinician relationship and patient care.

Key Recommendations       

The goal of the guidelines was to answer this question: What communication skills and tasks can clinicians use to optimize the patient-clinician relationship, patient and clinician well-being, and family well-being?
A panel of medical oncology, psychiatry, nursing, hospice and palliative medicine, and communication skills experts along with experts in health disparities and advocacy was convened, and a systematic review of literature published from January 1, 2006, through October 1, 2016, was conducted.
The guideline offers recommendations for core communication skills and discussion of goals for care and prognosis, treatment options and clinical trials, end-of-life care, and cost of care.
It also offers strategies for using communication to facilitate family involvement in care, communicating effectively when barriers exist, meeting the needs of underserved populations, and for clinician training for improving communication skills.
In the past, say the authors, good communication skills were often viewed as being something innate or that could be acquired by emulating role models. Clinicians were often simply expected to figure it out by themselves, but research suggests that well-designed training programs can improve both the communication skills of providers and patient experience
Thus, this new paper is designed to guide oncology clinicians on effective communication, which will in turn optimize the patient-clinician relationship and patient care.

Key Recommendations       

The goal of the guidelines was to answer this question: What communication skills and tasks can clinicians use to optimize the patient-clinician relationship, patient and clinician well-being, and family well-being?
A panel of medical oncology, psychiatry, nursing, hospice and palliative medicine, and communication skills experts along with experts in health disparities and advocacy was convened, and a systematic review of literature published from January 1, 2006, through October 1, 2016, was conducted.
The guideline offers recommendations for core communication skills and discussion of goals for care and prognosis, treatment options and clinical trials, end-of-life care, and cost of care.
It also offers strategies for using communication to facilitate family involvement in care, communicating effectively when barriers exist, meeting the needs of underserved populations, and for clinician training for improving communication skills.

NEW GUIDELINES FOR CERVICAL CANCER SCREENING

The US Preventive Services Task Force (USPSTF) has issued new draft recommendations for cervical cancer screening.
The major change from their 2012 recommendation is that testing for high-risk strains of human papillomavirus (hrHPV) alone is now recommended as an alternative to cytology or Papanicolaou (Pap) screening alone beginning at age 30 years; cotesting is no longer recommended.
As in the 2012 recommendation, the USPSTF continues to recommend that women aged 21 to 29 years undergo Pap screening every 3 years.
They recommend against screening in women younger than age 21 years because there is adequate evidence that regardless of sexual history, screening younger women does not reduce cervical cancer incidence or mortality.
The USPSTF also continues to give a thumbs down to screening in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, as well as in women who have had a hysterectomy and their cervix removed and do not have a history of a high-grade precancerous lesions or cervical cancer.
 "Cervical cancer is highly curable when found and treated early," says Task Force member Carol Mangione, MD, MSPH, in a statement. "Most cases of cervical cancer occur in women who have not been regularly screened or treated. Therefore, making sure all women are adequately screened and treated is critical to reducing deaths from cervical cancer."
Most cases of cervical cancer occur in women who have not been regularly screened or treated. Dr Carol Mangione
None of these recommendations apply to women who have been diagnosed with a high-grade precancerous cervical lesion or cancer, were exposed to diethylstilbestrol in utero, or have a compromised immune system.
The draft recommendation statement and draft evidence review are posted for public comment on the Task Force website. The public comment period is open through October 9, 2017.

Change in Guidelines

The guidelines for women aged 30 to 65 years were changed because the existing literature shows that screening with cytology alone and hrHPV testing alone "offer a reasonable balance between benefits and harms" in this age group.
Modeling and clinical trial evidence also suggest that cotesting nearly doubles the number of follow-up tests and does not lead to increased detection of cervical intraepithelial neoplasia 3+ or cervical cancer as compared with screening with hrHPV testing alone.
The recommendations are similar to those of the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) for women aged 21 to 29 years. For those 30 to 65 years, they recommend screening every 5 years with cytology and HPV cotesting or screening every 3 years with cytology alone.
Guidelines from the American Academy of Family Physicians' guidelines agree with those from ACS/ASCCP/ASCP.
The American College of Obstetricians and Gynecologists (ACOG) says that cotesting with cytology and HPV testing every 5 years is preferred, but screening with cytology alone every 3 years is acceptable.

An Expert Comments

In a statement, Linus Chuang, MD, professor of obstetrics, gynecology and reproductive science, Icahn School of Medicine at Mount Sinai in New York City, said that this update "formally endorses the use of HPV primary screening" at 5-year intervals in women aged 30 to 65  years.
Dr Chuang, who was not involved in the guidance development, said that the USPSTF recommendations also support the ASCCP and Society of Gynecologic Oncology interim guideline from 2015 and 2016 and the American Society of Clinical Oncology resource-stratified cervical cancer screening guideline, which calls for primary HPV screening beginning at 25 years or older.
"Strategies such as self-collection of HPV DNA as a strategy should be explored in the future as nearly half of the women with cervical cancer in the United States have not received any cervical cancer screening in the past 5 years," he noted.

DIET AS GOOD AS PPIs FOR GERD

A primarily plant-based, Mediterranean-style diet with alkaline water showed significantly greater improvement for laryngopharyngeal reflux (LPR) symptoms than treatment with proton-pump inhibitors (PPIs), according to a retrospective study published September 7 in JAMA Otolaryngology–Head & Neck Surgery
"This study indicates that, by supplementing with alkaline water and a Mediterranean-style diet, effective control of symptoms as defined by the RSI [Reflux Symptom Index] may be obtained without PPI use," write Craig H. Zalvan, MD, from New York Medical College in Valhalla, and colleagues. "Other benefits of this diet-based approach include decreased risk for and improved control of cardiovascular disease, diabetes, stroke, and cancer, and avoiding the risks of drug interaction or complication."
The researchers retrospectively analyzed the medical records of two cohorts from different timeframes who received different treatments for LPR. One cohort of 85 patients, from 2010 to 2012 with a median age of 60 years, took esomeprazole twice daily or dexlansoprazole daily. They also followed standard reflux dietary precautions, including avoiding coffee; tea; chocolate; soda; alcohol; and greasy, fried, fatty, and spicy foods.
The other cohort, 99 patients from 2013 to 2015 with a median age of 57 years, received alkaline water and a 90% plant-based Mediterranean-style diet in addition to standard reflux precautions. (The water had a pH above 8.0.) Patients with potentially confounding comorbidities, such as a cough, a history of neuropathic pain, or dysphonia, were excluded.
The researchers compared the change in RSI scores between the two groups after 6 weeks of treatment. Among those taking PPIs, 54.1% of the patients had at least a 6-point reduction in their RSI, the minimum improvement deemed clinically meaningful. The average reduction in RSI across the group was 27.2%.
Meanwhile, 62.6% of those receiving the alkaline water and diet had a meaningful improvement in their RSI (difference between the groups, 8.05; 95% confidence interval [CI], –5.74 to 22.76). This group had a 39.8% average reduction in RSI (difference between groups, 12.1; 95% CI, 1.53 - 22.68).
However, when RSI was treated as a continuous variable there was no significant difference in the mean change in RSI between the two groups (–5.92 vs –7.05; difference in means, 1.12; 95% CI, –1.00 to 3.24)
Patients in both groups had differing symptoms, such as cough, dysphagia, and dysphonia, but too little power existed to analyze statistically significant differences in subgroups. This is a future research goal of the authors.
The authors acknowledge that the lack of a gold standard in LPR diagnostic testing makes it difficult to compare studies' findings. Further, the study design of retrospectively reviewing charts carries multiple potential biases with it, and some patients with dual diagnoses may have slipped through participant criteria and added confounding. The authors also could not link the improvement in symptoms specifically to the alkaline water or diet independently.
"Treatment of LPR is controversial," writes Robert T. Kavitt, MD, MPH, from the University of Chicago, Illinois, in an accompanying editorial. The American Gastroenterological Association advises that patients with the condition who lack typical symptoms avoid PPIs, whereas the American Academy of Otolaryngology-Head and Neck Surgery guidelines suggest that most patients with the condition take PPIs twice a day for at least 6 months.
"Given the conflicting approach of society guidelines, as well as limited data regarding the role of medical therapy in the treatment of LPR, it is important to assess additional options to offer patients," Dr Kavitt writes.
Although PPIs are the most effective current pharmacologic treatment for LPR, adverse effects can be an obstacle to ongoing treatment. The authors cite past research finding that 40% to 80% of people should not receive a PPI prescription.
"Proton pump inhibitors can cause adverse drug effects, such as abdominal pain, nausea, diarrhea and constipation," Dr Zalvan and colleagues write. "In addition, they have been associated with a variety of other adverse events, including fundic gland polyps secondary to hypergastrinemia, hypomagnesemia, hypocalcemia, bone fractures, decreased absorption of vitamin B12, diarrhea, and pneumonia, though evidence for the clinical significance of these relationships is limited."
The authors also note a link identified between PPI use and increased risk for myocardial infarction, dementia, stroke, and cardiovascular mortality. Further, PPIs are known to interact with other medications, and "drug reactions and interactions account for a considerable percentage" of deaths resulting from medical errors, the authors write.
"In this era when patients frequently raise concerns regarding the chronic use of PPIs owing to the potential adverse effect profile, it would be of great benefit to be able to offer additional options beyond acid-suppressive medications to patients with LPR," Dr Kavitt writes. He also identified other limitations to the study that future research could address, such as the lack of data on participants' weights, especially because weight loss from the diet may have influenced the findings.
"Nonetheless, the findings from this study are intriguing and suggest a possible change in future treatment paradigms in the management of LPR should the findings be confirmed," Dr Kavitt concludes.  
Dr Zalvan serves on Restech Corporation's scientific advisory board but receives no monetary compensation. The other authors and Dr Kavitt have disclosed no relevant financial relationships.
JAMA Otolaryngol Head Neck Surg. Published online September 7, 2017. AbstractEditorial
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Τρίτη, 12 Σεπτεμβρίου 2017

ESMO 2017-TARGETED THERAPY FOR BRAF+ NSCLC

Activating mutations in the BRAF gene, which are generally mutually exclusive from EGFR mutations or ALK rearrangements, act as an alternative oncogenic driver in metastatic non-small cell lung cancer (NSCLC). The most common of these mutations, BRAFV600E, is observed in 1–2% of lung adenocarcinomas. Combined BRAF and MEK inhibition has shown superior efficacy compared with BRAF inhibitor monotherapy in patients with BRAF-mutated metastatic melanoma, potentially contributing to sustained pathway inhibition and delay or prevention of resistance.
Three-fourths of patients with previously untreated BRAF V600E–mutated NSCLC, receiving a combination of a BRAF inhibitor dabrafenib plus a MEK inhibitor trametinib, achieved complete or partial response or stable disease by investigator assessment and independent review, according to findings from a phase II trial presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
David Planchard, Department of Medical Oncology, Institute Gustave Roussy in Villejuif, France presented the results of the third (cohort C) of three sequentially enrolled cohorts in the phase II study of patients with BRAF V600E–mutated metastatic NSCLC (NCT01336634). In this cohort, 36 patients with BRAF V600E–mutated metastatic NSCLC received first-line treatment with 150 mg twice daily of dabrafenib and 2 mg once daily of trametinib. The patients had not received prior systemic therapy for metastatic disease.
Dr. Planchard pointed out that substantial clinical activity has been previously demonstrated by the combination in patients with previously treated BRAF V600E–mutated metastatic NSCLC (cohort B), who showed an investigator-assessed confirmed overall response rate (ORR) of 67%, median progression-free survival (PFS) of 10.2 months, and median overall survival (OS) of 18.2 months.
In the findings presented at ESMO 2017, the patients had a median age of 67 (range 44 to 91) years, 61% were female (61%), 83% were white, and 72% of patients were current or former smokers.
Investigator-assessed ORR was the primary endpoint and secondary endpoints included duration of response (DOR), PFS, overall OS, and safety.

Durable responses observed with dabrafenib and trametinib

At data cut-off on 8 April 2017, 11 (31%) patients remained on treatment.
After a median follow-up of 15.9 months, the investigator assessed ORR was 64% (95% confidence interval [CI] 46%, 79%). Two (6%) patients receiving the combination experienced a complete response (CR), and 21 (58%) patients demonstrated partial response (PR). Overall, 4 (11%) patients had stable disease (SD) lasting ≥ 12 weeks as their best response, thus the disease control rate (DCR = CR+PR+SD) was 75% (95% CI 58%, 88%). 

First-Line-Dabrafenib-And-Trametinib-Shows-Substantial-Clinical-Activity-In-BRAF-V600E–Mutated-Metastatic-NSCLC
Investigator-assessed maximum change in target lesion by best response.
© David Planchard.
The independent review committee assessment supported these results.
The investigator-assessed median DOR was 10.4 (95% CI 8.3, 17.9) months. The median PFS was 10.9 (95% CI 7.0,16.6) months and median OS was 24.6 (95% CI 12.3, not estimable) months.
All (100%) of the patients experienced ≥ 1 adverse event (AE), and 69% had ≥ 1 grade 3/4 AE. Serious AEs (SAEs) occurring in > 2 patients included alanine aminotransferase increase in 14%, pyrexia in 11%, aspartate aminotransferase increase in 8%, and ejection fraction decrease was reported in 8% of patients.
A total of 24 patients progressed or died; of these 17 patients died. One patient death was due to due to a SAE of cardiorespiratory arrest that was determined to be unrelated to study treatment.

Regulatory agencies approvals

The US Food and Drug Administration (FDA) first approved the combination of dabrafenib and trametinib for patients with metastatic melanoma in January 2014. The European Commission approved the dabrafenib/trametinib combination for adults with unresectable or metastatic melanoma with a BRAF V600 mutation a year later.
In April 2017, the European Commission approved the combination of dabrafenib and trametinib for patients with BRAF V600-positive advanced or metastatic NSCLC.
On 22 June, 2017, the US FDA granted regular approvals to dabrafenib and trametinib administered in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test.

Conclusions


The investigators concluded that combined dabrafenib and trametinib represents a new targeted therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAF V600E–mutated metastatic NSCLC, and noted that these results supported the recent approvals by the European Commission and US FDA.

ESMO 2017-NEW IMMUNOTHERAPY FOR RENAL CANCER

Promising clinical benefit was demonstrated in the trial of rocapuldencel-T plus standard-of-care therapy (SOC) versus SOC therapy alone in patients with newly diagnosed metastatic renal cell carcinoma (mRCC), according to findings from an analysis presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
In addition, a statistically significant association between overall survival (OS) and an increase in the number of rocapuldencel-T induced memory T cells was reported.
These promising long-term data come from the phase III ADAPT trial, which is ongoing after trial discontinuation was advised. In February, 2017 the ADAPT trial’s Independent Data Monitoring Committee recommended that the study be halted following a planned interim data review that showed 75% of the targeted number of 290 events (deaths) had been reached and the OS hazard ratio in the rocapuldencel-T/SOC treatment arm was greater than the pre-defined futility boundary of 0.98 for the 3rd interim assessment.
The trial’s sponsor discussed the preliminary trial data with the US Food and Drug Administration (FDA) and the decision was made to keep the ADAPT trial open, based upon the safety profile, maturing survival data, and the mechanism of action of rocapuldencel-T, which involves the induction of long-term memory immune responses. Rocapuldencel-T is an individualised immunotherapy formulated with RNA isolated from each patient's tumour to activate autologous dendritic cells with tumour-specific antigens to induce an immune response including tumour-specific memory T-cells targeting each patient's specific tumour antigens.
Robert Figlin of the Division of Hematology Oncology, Cedars-Sinai Medical Center in Los Angeles, USA presented findings from the ADAPT trial of rocapuldencel-T plus SOC versus SOC in patients with newly diagnosed mRCC.
The trial recruited adults with synchronous, clear cell mRCC who were eligible for nephrectomy. The ADAPT is an ongoing phase III trial that is being conducted at 107 sites across North America, Europe, and Israel.
A total of 462 patients were randomised 2:1 to receive either three 0.2 mL intradermal injections of rocapuldencel-T plus SOC or SOC alone.

Treatment with SOC/rocapuldencel-T showed a potential survival benefit in patients with mRCC

At a median follow-up of 20 months, the majority of patients in both treatment groups were still alive.
A review of data from 154 of the first third of patients randomised having the longest duration of follow-up and least censored data (44%), suggest a potential survival benefit for the combination.
The researchers also observed a statistically significant correlation between OS and an increase in the number of rocapuldencel-T induced memory T cells (CD8+/CD28+/CD45RA-) in the 114 patients who had received 7 doses of rocapuldencel-T and had data that had been analysed.
Rocapuldencel-T was well-tolerated and demonstrated a safety profile that was consistent with that shown in an earlier phase II trial.

Conclusions

The ADAPT trial is ongoing to further evaluate the long-term effects of this well-tolerated individualised immunotherapy. The finding of a potential survival benefit is worthy of further assessment.
Helen Gogas, Professor in Medical Oncology at First Department of Medicine, National and Kapodistrian University of Athens, Greece who discussed the study results has agreed that censoring may impact assessment of both median survival and potential tail-of-the curve effect which is supported by phase II results. However, she doubts this will be a positive trial as >50% of subjects are censored in both treatment groups at interim analysis. The IDMC recommended to discontinue the study for futility and to the best of her knowledge when IDMC recommendation is termination for futility no trial has turned to be positive. Trials may be positive or may be negative. This is clinical research. She pointed out that we have to accept it and it is the reason we conduct phase III randomised clinical trials.

ESMO 2017-COMBINATION THERAPY FOR HEAD-NECK CANCER

Treatment with the checkpoint inhibitor nivolumab combined with ISA 101, a synthetic long-peptide vaccine directed against human papilloma virus 16 (HPV16) improved response in patients with incurable oropharyngeal cancer, compared to historical data with nivolumab alone, according to findings presented during ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
ISA 101 comprises 13 synthetic long peptides derived from the E6 and E7 oncogenic proteins of the HPV16, which is responsible for 50% of human cervical cancers and cervical intra-epithelial neoplasias and approximately 80-90% of HPV-positive head and neck cancers, anal cancers and premalignant HPV-induced anal lesions, or anal intra-epithelial neoplasia. ISA 101 caused regression of vulvar intra-epithelial neoplasia, but is not active in invasive cervical cancer.
These findings suggest that an immunosuppressive tumour microenvironment may impose limits on efficacy of HPV vaccines.  Bonnie S. Glisson, professor at The University of Texas MD Anderson Cancer Center in Houston, USA, and colleagues reasoned that vaccine-induced T cell activity may be amplified through treatment with immune checkpoint antibodies such as nivolumab.
The researchers conducted a phase II trial of the synthetic long-peptide HPV16 vaccine, ISA 101, plus nivolumab in patients with incurable HPV16-positive cancer. The trial was open to all patients with HPV16-related cancers regardless of organ of origin and accrued 24 patients; 22 patients had oropharyngeal cancer and one patient each had anal and cervical cancer. HPV-genotype 16 was confirmed using Cervista HPV16/18 in all tumours.
The patients had ECOG performance status 0-1 and had received up to one prior regimen for recurrence; 18 (75%) patients had progressed within 6 months of receiving platin, 12 (50%) had received cetuximab, and just one patient was platin-naive.
Treatment with ISA 101 plus nivolumab was frontline for recurrence in 10 patients and second line in 14 of the 24 enrolled patients. All patients were treated with ISA 101 at 100 mcgs/peptide on days 1, 22, and 50 plus nivolumab at 3 mg/kg intravenously every 2 weeks beginning on day 8 for up to one year. Imaging was obtained at baseline, week 11 and every 6 weeks thereafter.
The primary objective was assessment of overall response rate (ORR) with a target of 30%  and the secondary objectives included tolerability, progression-free survival (PFS), and overall survival (OS).

The primary endpoint of overall response rate was met with ISA 101 and nivolumab

The ORR of 33% was higher than the target, thus meeting the primary objective. In all, 8 patients showed a response including two complete response (CR) and 8 partial responses (PR), with one unconfirmed PR. Stable disease (SD) was achieved by 3 (13%) patients and 13 (54%) patients showed progressive disease (PD). The median duration of response is not reached, 39+ weeks (range 21-59) with 5/8 remaining in response. Six of the patients achieving PR had progressed within 6 months of prior platin.

Combined-Therapy-With-Nivolumab-And-ISA-101-Vaccine-Results-in-Promising-Efficacy-In-HPV-Positive-Oropharyngeal-Cancer
Percentage change in target lesions.
© Bonnie S. Glisson.
All responses occurred in patients with oropharyngeal cancer, where the ORR was 36% (8/22). Response was positively correlated with tumour cell PD-L1 positivity (≥1%).
Regarding the secondary endpoints, at a median follow-up of 8.6 months the median PFS was 2.7 months (95% confidence interval [CI] 2.3, 8.0 months) and median OS was not reached.
The 6-month PFS rate was 33%, (95% CI 16%, 52%) and the 6-month OS rate was 74% (95% CI 51%, 87%).
PD-L1 ≥ 1% on tumour cells was identified in 39% (7/18) of baseline tumour specimens and was associated with probability of response.   
The combination of the ISA 101 vaccine plus nivolumab was well tolerated with only grade 1 and 2 toxicity, including fever in 5 patients, injection site reaction in 6, and transaminase elevation, fatigue, and nausea which each occurred in 3 patients. Grade 3 elevated transaminase and grade 4 lipase elevation each occurred in one patient.

Conclusions

The authors pointed out that the ORR of 36% in patients with oropharyngeal cancer compares favourably to the ORR of 16% demonstrated for nivolumab monotherapy in patients with p16-positive platin-refractory oropharyngeal cancer participating in the in Checkmate 141 study.1

These data support the hypothesis that the efficacy of vaccine-induced T cells can be augmented by anti-PD-1 therapy, thus mitigating the influence of an immunosuppressive microenvironment. The investigators concluded that these findings merit confirmation in a larger randomised trial which is being planned.

ESMO 2017-ATEZOLIZUMAB FOR HEAD-NECK CANCER

Monotherapy with the checkpoint inhibitor atezolizumab demonstrated promising efficacy in patients with advanced head and neck cancer that was independent of both PD-L1 expression status on immune cells and the presence of human papilloma virus (HPV) infection, according to findings presented during ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Atezolizumab is an anti–PD-L1 checkpoint inhibitor that restores tumour-specific T-cell immunity by blocking the binding of PD-L1 to both PD-1 and B7.1.
Rastislav Bahleda of the Early Drug Development Department, Gustave Roussy in Villejuif, France presented data from this phase Ia study (NCT01375842) evaluating the safety and clinical activity of single-agent atezolizumab in patients with advanced head and neck cancer.
The first 10 patients were non-selectively enrolled; however, upon identification of PD-L1 as a potential biomarker, subsequent enrolment was based on PD-L1 status of > 5% expression on immune cells (IC2/3) as detected by immunohistochemistry using the VENTANA SP142 antibody. Determination of HPV status was made by PCR.
Of the 32 enrolled patients, 84% were male with a median age of 62 years (range 32 to 78 years), 66% of patients were ECOG performance status 1, and the majority (66%) of patients reported current or previous tobacco use. All patients had been heavily pre-treated, with 53% of patients receiving ≥ 2 prior lines of therapy. Most (56%) patients had a primary tumour in the oropharynx and other common primary tumour sites included the oral cavity in 22%, and nasopharynx in 13% of patients.
Atezolizumab was initially administered intravenously every 3 weeks for 16 cycles or up to 1 year but patients were subsequently treated until loss of clinical benefit was observed.

Atezolizumab monotherapy was safe in patients with head and neck cancer

The primary endpoint of this study was safety.
The duration of follow-up was 14 months or more and the median treatment duration was 3.4 months.
Most (66%) patients experienced a treatment-related adverse event (TRAE). Grade 3 TRAEs of tumour lysis syndrome, hyponatremia, pruritus, and colitis occurred in 3 (9%) patients. One (3%) patient had grade 4 treatment-related cardiac tamponade.
No grade 5 TRAEs were seen.

Atezolizumab showed activity in the overall population and in subgroups of patients with low to no and higher PD-L1 expression status


Single-Agent-Atezolizumab-in-Head-and-Neck-Cancer-01
© Rastislav Bahleda. 


Single-Agent-Atezolizumab-in-Head-and-Neck-Cancer-02
© Rastislav Bahleda. 
PD-L1 expression in immune cells was <5 7="" and="" in="" patients="">5% (IC2/3) in 25 patients. In all patients, regardless of PD-L1 expression, the confirmed objective response rate (ORR) by RECIST v1.1. was 22%; median progression-free survival (PFS) was 2.6 months (range 0.5 to 48.4 months) and median overall survival (OS) was 6.0 months (range 0.5 to 51.6+ months).
The subgroup of 25 IC2/3 patients with higher PD-L1 expression demonstrated an ORR of 24% that consisted entirely of partial responses, and the disease control rate (DCR) was 28%. In responding patients, the median duration of response (DoR) was 26.2 (range 2.8 to 45.8) months.
In the subgroup of 7 patients with low PD-L1 expression, the ORR was 14%, which represented one partial response. The DCR was 43% and the DOR was 7.4 months in responding patients.

Conclusions


The authors concluded that atezolizumab was well-tolerated in patients with advanced head and neck cancer. Encouraging responses and long-term survival were observed. These findings warrant further investigation.