chemotherapy

Pembrolizumab: New standard of care in head and neck cancer

Source: www.medscape.com
Author: Roxanne Nelson, RN, BSN

Immunotherapy with pembrolizumab (Keytruda, Merck & Co), either as monotherapy or in combination with chemotherapy, offers a new standard of care for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), say experts discussing the results from the company-sponsored KEYNOTE-48 trial.

Pembrolizumab plus chemotherapy yielded a significant survival benefit in comparison with standard therapy for both the total patient population and for patients whose tumors were positive for programmed cell death–ligand-1 (PD-L1).

Monotherapy with pembrolizumab yielded a significant overall survival benefit for patients with tumors that were PD-L1 positive; and in the total study population, overall survival was noninferior.

“Thus, pembrolizumab monotherapy is a new standard of care, first-line therapy option for patients with PD-L1-positive recurrent or metastatic HNSCC. Pembrolizumab with chemotherapy is also a new option for all patients, regardless of PD-L1 status,” comment Robert L. Ferris, MD, PhD, from the University of Pittsburgh, Pennsylvania, and Lisa Licitra MD, from the University of Milan, Italy, in a commentary that accompanies article in the Lancet.

“The positive results of KEYNOTE-048 represent substantial progress for patients with recurrent or metastatic HNSCC,” Ferris and Licitria add.

These comments echo the reactions from experts when the study was presented earlier this year at the annual meeting of the American Society for Clinical Oncology (ASCO), as reported by Medscape Medical News at that time.

Presenter Danny Rischin, MD, from the Peter MacCallum Cancer Center, Melbourne, Australia, said: “These data support pembrolizumab plus platinum-based CT [chemotherapy] and pembrolizumab monotherapy as new first-line standard-of-care therapies for relapsed/metastatic head and neck squamous cell carcinoma.”

At the ASCO meeting, the study was highlighted as “most important” by Francis P. Worden, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor. He predicted that pembrolizumab in combination with chemotherapy will replace the EXTREME regimen (cetuximab with platinum-based therapy and fluorouracil) as first-line therapy in HNSCC.

However, while agreeing that the data are practice changing, Vinita Noronha, MD, of the Tata Memorial Cancer Center in Mumbai, India, emphasized that several questions remained unanswered.

In a discussion of the paper, Noronha pointed out that the findings do not provide guidance on which patients should receive pembrolizumab alone or in combination with chemotherapy, and there are also questions as to why both the response rate and progression-free survival rate failed to improve. It was also unclear whether there was a role for sequential therapy or whether all patients should receive the combination up front. Some of these questions have been addressed in the commentary to the Lancet article.

Study Details
KEYNOTE-048 was a randomized, phase 3 study that included 882 participants with untreated locally incurable recurrent or metastatic HNSCC. It was conducted at 200 sites in 37 countries.

November, 2019|Oral Cancer News|

Year in review: Head and neck cancer

Source: www.medpagetoday.com
Author: Ian Ingram, Deputy Managing Editor, MedPage

In 2019, headlines in head and neck cancer were dominated by a new first-line approval in squamous cell carcinoma (SCC), further attempts at treatment deintensification in the lower-risk human papillomavirus (HPV) population, and a provocative trial looking at patients’ quality of life following either robotic surgery or radiation.

Immunotherapy OK’d in First-line
Based on data from the three-arm KEYNOTE-048 trial, the FDA approved pembrolizumab (Keytruda) for the first-line treatment of metastatic or unresectable recurrent head and neck SCC. The PD-1 immune checkpoint inhibitor was approved in combination with chemotherapy for all patients, or as monotherapy for those with PD-L1 expression.

Final results of the study demonstrated a 23% reduction in the hazard for death for the group treated with pembrolizumab plus platinum chemotherapy (cisplatin or carboplatin) and 5-fluorouracil. This group had a median overall survival of 13.0 months, as compared with 10.7 months for those treated with the EXTREME regimen of platinum chemotherapy plus 5-fluorouracil and cetuximab (Erbitux).

A pembrolizumab monotherapy arm of KEYNOTE-048 showed non-inferiority to EXTREME in all comers and superiority in patients with a PD-L1 combined positive score (CPS) ≥1, as represented by a 22% reduction in the hazard for death over the study period. In this CPS ≥1 population, which made up about 85% of the study population, median overall survival was 12.3 with pembrolizumab alone versus 10.3 months with EXTREME.

ORATOR Trial Upends Assumption of Surgical Superiority
In the first randomized trial to pit transoral robotic surgery (TORS) against radiotherapy for patients with oropharyngeal SCC, the ability to swallow and other outcomes appeared to be better with radiation — contradicting previous retrospective data that favored surgery.

With roughly 2 years of follow-up, the phase II trial of 68 patients met its primary endpoint, showing a statistically significant improvement in swallowing 1 year after treatment in the radiotherapy group.

This group had a nearly 7-point advantage on the 100-point MD Anderson Dysphagia Inventory (MDADI) scale compared with the surgery cohort (86.9 vs 80.1, respectively, P=0.042), suggesting that these patients may have improved swallowing function — the trial had prespecified that a 10-point difference would be considered “clinically meaningful.”

Investigators said the findings indicate that patients should be offered both treatment options.

Less Therapy in HPV-Positive Disease
At the American Society for Radiation Oncology (ASTRO) annual meeting, results from the HN002 trial showed impressive results with two de-escalation strategies in low-risk HPV-positive head and neck cancer. Among the 306 mostly non-smoking patients in the phase II multi-institutional study, those assigned to lower-dose (60 Gy) intensity-modulated radiotherapy (IMRT) plus weekly cisplatin had a 2-year progression-free survival (PFS) of 90.5%, as compared with 87.6% in a group treated with IMRT at 60 Gy alone.

Only the combination arm met the investigators’ prespecified PFS target, while both met their swallowing-related quality-of-life criteria. On the MDADI scale, patients reported scores of 85.3 (5.6-point decline from baseline) in the combined modality arm and 81.8 (6.2-point decline) in the radiation-alone arm. Overall survival (OS) rates at 2 years were greater than 95% for the two arms.

Meanwhile, a prospective study from the University of North Carolina reported 2-year rates of locoregional control and OS of 95% with a dual strategy of deintensified treatment for HPV-positive oropharyngeal cancer.

PFS at 2 years was 86%, and 91% of the 114 patients remained free of distant metastases. No grade ≥3 late adverse events occurred, and global quality of life improved from pretreatment to 2 years.

Experts emphasized, however, that deintensification should only be attempted in clinical trials

“What is the best treatment for patients with low-risk oropharynx cancer?” said ASTRO discussant Beth Beadle, MD, of Stanford University Medical Center in California, in discussing the HN002 trial. “Standard of care is standard of care, we do not have phase III data supporting de-escalation off protocol.”

Standard of care remains 70 Gy with concurrent cisplatin for patients with low-risk disease.

Retrospective Studies Provoke
A single-arm trial in New York reported that a treatment delay greater than 2 months from diagnosis was significantly associated with worse OS in patients with head and neck SCC.

In a group of 956 patients treated at an urban academic center, those with a time to treatment initiation (TTI) longer than 60 days were significantly more likely to die from their disease (odds ratio [OR] 1.69, 95% CI 1.32-2.18) and have disease recurrence (OR 1.77, 95% CI 1.07-2.93) compared to those treated within this timeframe. The 5-year overall survival for patients dropped from 64.5% to 47.0% when the TTI stretched beyond 60 days.

“If I invented a drug that could give a 20% improved survival in head and neck cancer patients, a disease where survival has not changed for many years, I would probably be getting handed a large amount of funding,” study author Vikas Mehta, MD, MPH, of Montefiore Medical Center in New York City, told MedPage Today.

“This study is just as important,” he continued. “Getting patients to treatment in a timely manner can independently improve survival.”

Another retrospective study pointed to the possible benefit of regular use of aspirin or other common nonsteroidal anti-inflammatory drugs (NSAIDs) for head and neck cancers with a particular gene mutation.

In 75 patients with PIK3CA mutations or amplification, users of NSAIDs for at least 6 months after curative treatment had significantly prolonged disease-specific survival (HR 0.23, 95% CI 0.09-0.62) and OS (HR 0.31, 95% CI 0.14-0.69) compared with non-regular NSAID users. The effect was seen regardless of patients’ HPV status. Predicted 5-year OS rates were 78% for the regular NSAID users and 45% for non-regular users.

Is Magic Mouthwash Just an Illusion?
Two medicated mouthwashes led to reductions in oral mucositis pain for head and neck cancer patients treated with radiotherapy, but not at a level deemed clinically important, a randomized phase III study found.

Within 4 hours of radiotherapy, pain from oral mucositis dropped by 11.7 points (as defined by the area under the curve) with a diphenhydramine-lidocaine-antacid rinse — or “magic mouthwash” — and 11.6 points with a doxepin mouthwash, compared with 8.7 points with placebo, researchers reported.

Compared with placebo, diphenhydramine-lidocaine-antacid led to a 3.0-point improvement (95% CI 0.1-5.9) while the doxepin mouthwash led to a 2.9-point improvement, both of which were less than what the investigators said would be clinically important differences going into the trial.

“These data tell us that magic mouthwash (or doxepin) is not the sole answer to managing mucositis — physicians should not prescribe magic mouthwash and expect magic!” Arjun Gupta, MD, of the Sidney Kimmel Comprehensive Cancer Center in Baltimore, who was not involved in the study, told MedPage Today.

“Most providers do not know the contents or concentrations of the ingredients in these mixed-medication formulations,” he said. “They could also contain unnecessary and harmful ingredients such as steroids and antibacterials/antifungals. How many other drugs do physicians prescribe without knowing the contents or concentration?”

November, 2019|Oral Cancer News|

Anti-malarial drug can make cancer chemotherapy more effective

Source: medicalxpress.com
Author: Emma McKinney, University of Birmingham

Scientists at the University of Birmingham have found an anti-malarial drug was effective in treating head and neck cancer in mice.

The drug quinacrine was used extensively to prevent and treat malaria in soldiers fighting in mosquito-ridden areas during World War Two. It is similar to the quinine that makes tonic water glow, has minimal side-effects, and is now used for treating parasite infections and other conditions.

Each year around 11,900 people are diagnosed with head and neck cancer in the UK. Current treatment relies heavily on debilitating surgery and toxic chemotherapy, but despite this, it has a poor outcome with three to seven in 10 people surviving their disease for five years or more.

The drug, quinacrine, was tested through a number of methods, including on cell cultures, in tumour biopsies from patients with head and neck cancer, and in mice.

The research results, published in Oncotarget, show that in mice quinacrine can make standard chemotherapy more effective—suggesting a lower dose may be used, reducing toxic side effects.

The results also showed the drug to be effective at reducing the growth of cancer cells grown in the lab, and in tumors.

Significantly, the research in mice showed a combination therapy of quinacrine and chemotherapy, and so allowed for the chemotherapy dose to be halved while still maintaining the same impairment of tumor growth.

Lead author Dr. Jennifer Bryant, of the University of Birmingham’s Institute of Head and Neck Studies and Education, said: “This is important research in the laboratory and demonstrates the real potential in repurposing drugs.

“The team is now looking to translate these research findings into a clinical trial for head and neck cancer patients.”

Corresponding author Professor Hisham Mehanna, Director of the Institute of Head and Neck Studies and Education at the University of Birmingham and Consultant Head, Neck and Thyroid Surgeon at University Hospitals Birmingham NHS Foundation Trust, said drug repurposing is particularly exciting due to known safety in humans and low cost, which mean they can be rapidly translated from the lab to the clinic.

He added: “Head and neck cancer patients have limited treatment options, often associated with severe, potentially life-threatening, side effects, it is important, therefore, that we find different treatments.

“My team has developed a drug repurposing platform called “AcceleraTED’ which assesses drugs that treat other non-cancerous conditions and have been approved by the Food and Drug Administration and the European Medicines Agency to see if they have the potential to be effective anti-cancer agents against head and neck cancer.

“This research is an example of the success we are having in the laboratory through this platform in identifying promising drugs that can be candidates to be used in patients in clinic.”

October, 2019|Oral Cancer News|

Psychological impact of head and neck cancers

Source: pharmafield.co.uk
Author: Emma Morriss

Bristol-Myers Squibb (BMS), in partnership with patient groups The Swallows and the Mouth Cancer Foundation, have announced the results from a patient survey into the psychological impact of head and neck cancers. The research explored the long-term burden of treatment on head and neck cancer patients.

After undergoing treatment for head and neck cancer, which can include surgery, chemotherapy or radiotherapy, many patients report an ongoing impact on their day-to-day life. However, 55% of the 118 patients surveyed indicated they did not receive the right level of information in preparation for the complications encountered from treatment.

There are around 11,900 new head and neck cancer cases in the UK every year and the incidence of head and neck cancer has increased by 32% since the early 1990s.

Following treatment, the survey showed 56% of patients had problems with simple things like swallowing, often experiencing severe pain, while two-thirds of patients experienced changes in their voice or speech. The survey also showed self-reported change from pre- to post- treatment in vital areas including a drop in the ability to communicate (37%), memory loss (21%), and trouble sleeping (20%).

As well as physical symptoms, treatment can have severe implications on mental health too. 52% of patients reported feelings of anxiety before treatment, which only reduced to 48% following treatment. However, emotional and psychological support was only offered to 46% of patients.

A majority of patients did receive access to a clinical nurse specialist, however there was still 23% who were not offered this service. Clinical nurse specialists use their skills and expertise in cancer care to provide physical and emotional support, coordinate care services and inform and advise patients on clinical as well as practical issues, which have been shown to lead to more positive patient outcomes.

“These results show the impact treatment may have on head and neck cancer patients. The continued problems and symptoms experienced by patients after treatment significantly impacts patients’ daily life. We also know physical disfigurement can increase social anxiety. It is important that we raise the awareness of this and work together to provide solutions to improve and support patient outcomes.” said Mouth Cancer Foundation, Clinical Ambassador, Mr Mahesh Kumar.

“With the incidence of head and neck cancers increasing, it is vital we understand what we can do to help patients. We are so pleased to have worked in collaboration with BMS and the Mouth Cancer Foundation to help raise awareness of this disease and understand where patients might need more help to reduce the impact on their lives. We know head and neck cancers, and the associated complications, do not get a lot of attention so it’s crucial for awareness days such as World Head and Neck Cancer Day to be used to shine a light on the disease. By doing so, it will help to improve detection, treatment and outcomes for patients.” commented Chris Curtis, Chairman of The Swallows.

Merck’s Keytruda wins FDA approval to treat head and neck cancer

Source: Reuters
Date: June 11, 2019
Author: Reporting by Aakash Jagadeesh Babu; Editing by Shailesh Kuber

(Reuters) – Merck & Co Inc said on Tuesday its blockbuster cancer drug Keytruda won approval from the U.S. Food and Drug Administration to treat a type of head and neck cancer.

The drug was approved for use as a monotherapy, as well as in combination with a common chemotherapy regimen, to treat previously untreated patients with head and neck squamous cell carcinoma, Merck said.

The approval is based on results from a late-stage trial, where Keytruda showed a significant improvement in overall survival in cancer patients, Merck said.

Keytruda, a type of immunotherapy called a PD-1 inhibitor, is already an approved treatment for several forms of cancer, including lung and skin cancers.

Head and neck cancer includes tumors in the mouth, tongue, nose, sinuses, throat and lymph nodes in the neck.

Merck estimates that there will be more than 65,000 new cases of head and neck cancer diagnosed in 2019 in the United States.

Keytruda works by increasing the ability of patients’ immune system to help detect and fight tumor cells.

The drug has been amassing approvals as a standalone therapy and in combination with other drugs to treat several forms of cancer. It is the leading immunotherapy for treating lung cancer, ahead of rival drugs from Bristol-Myers Squibb, Roche and AstraZeneca.

Keytruda, first approved for advanced melanoma in 2014, is Merck’s most important growth driver. It has overtaken Bristol’s Opdivo as the industry’s immuno-oncology leader with sales expected to top $10 billion this year and $20 billion in 2024, according to IBES data from Refinitiv.

Keytruda brought in revenue of $7.17 billion for Merck in 2018, while Bristol’s Opdivo earned $6.74 billion.

June, 2019|Oral Cancer News|

Merck’s Keytruda wins FDA approval to treat head and neck cancer

Source: www.pharmalive.com
Author: staff, Reuters Health

Merck & Co Inc said on Tuesday its blockbuster cancer drug Keytruda won approval from the U.S. Food and Drug Administration to treat a type of head and neck cancer.

The drug was approved for use as a monotherapy, as well as in combination with a common chemotherapy regimen, to treat previously untreated patients with head and neck squamous cell carcinoma, Merck said.

The approval is based on results from a late-stage trial, where Keytruda showed a significant improvement in overall survival in cancer patients, Merck said.

Keytruda, a type of immunotherapy called a PD-1 inhibitor, is already an approved treatment for several forms of cancer, including lung and skin cancers.

Head and neck cancer includes tumors in the mouth, tongue, nose, sinuses, throat and lymph nodes in the neck.

Merck estimates that there will be more than 65,000 new cases of head and neck cancer diagnosed in 2019 in the United States.

Keytruda works by increasing the ability of patients’ immune system to help detect and fight tumor cells.

The drug has been amassing approvals as a standalone therapy and in combination with other drugs to treat several forms of cancer. It is the leading immunotherapy for treating lung cancer, ahead of rival drugs from Bristol-Myers Squibb, Roche and AstraZeneca.

Keytruda, first approved for advanced melanoma in 2014, is Merck’s most important growth driver. It has overtaken Bristol’s Opdivo as the industry’s immuno-oncology leader with sales expected to top $10 billion this year and $20 billion in 2024, according to IBES data from Refinitiv.

Keytruda brought in revenue of $7.17 billion for Merck in 2018, while Bristol’s Opdivo earned $6.74 billion.

How do speech-language pathologists support cancer patients?

Source: syvnews.com
Author: Aundie Werner

Question: What are speech-language pathologists and how do they support cancer patients?

It is estimated that about 100,000 people will be diagnosed with a head, neck or thyroid cancer this year.

Although this does not grab headlines as often as many other cancers, for those affected the disease and treatment can have a significant impact on their lives. In general, most people survive head and neck cancer; however, side effects of treatment can sometimes be a long-term problem.

The support and guidance of a speech-language pathologist (SLP) can do much to help promote recovery and cope with the difficult symptoms of treatment. Ideally, the SLP becomes involved when the patient has been identified as having head and neck cancer before their surgery or before their chemotherapy/radiation protocol. Counseling and education are provided as to the functions of voice, speech and swallowing. Assessment is made to determine the patient’s baseline and to provide guidance as to the patient’s role in their rehabilitation.

Frequently, the SLP works with patients who have difficulty eating and drinking. Treatment is based on the cause of the problem: anatomical changes from surgery, decreased saliva, changes in taste, difficulty opening the mouth due to trismus, and problems protecting the airway, which can result in coughing and choking during meals.

Maintaining nutrition after surgery and during treatment is necessary to help the body heal. At times, the patient may need to have a feeding tube to help with nutrition when it becomes too difficult to swallow. The SLP assesses the patient’s current needs, instructs the patient in specific swallowing exercises, compensatory swallowing strategies or diet modification recommendations. The goal is for patients to continue to eat and drink during and after treatment.

Following radiation therapy, patients may experience lymphedema and/or fibrosis of the radiated tissue. These effects can persist long after the treatment concludes. Difficulties can include problems opening the mouth to eat from a spoon or fork, or decreased ability of the throat muscles to protect the airway while eating or drinking. In these cases, specific testing and exercises are instructed by the SLP.

Voice changes may also occur after surgery or radiation. The SLP instructs patients how to use their voice efficiently so as not to strain the muscles. Patients who have had their voice box removed are instructed in alternative methods to produce voicing to communicate.

Additionally, articulation and resonance changes can occur from surgery and/or radiation. Patients who have had sinus, palatal, jaw or tongue cancer are instructed how to articulate more clearly through customized treatment or prosthetic devices, if needed.

Each patient’s cancer is unique, as is the plan of care developed by the SLP. The Central Coast has excellent speech-language pathologists who are trained to provide their expertise to facilitate your road to recovery.

March, 2019|Oral Cancer News|

Immunotherapy extends the life of head and neck cancer patients

Source: Pharmatimes.com
Date: 12/3/18
Author: Anna Smith

A new immunotherapy can greatly extend the lives of a proportion of people with advanced head and neck cancer, with some living for three years or more, reports a major new clinical trial.

The study, by The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, found that the drug – MSD’s Keytruda (pembrolizumab) – has been shown to have significant benefits for patients, with 37% of those who received it surviving for a year or more, compared with only 26.5% of those on standard care.

The drug was evaluated in a trial of nearly 500 patients with very advanced head and neck cancer that had spread around the body and already become resistant to platinum chemotherapy, the first-line treatment for the disease.

Some 247 patients were randomised to receive Keytruda and 248 to standard of care – chemotherapy or the targeted agent Erbitux (cetuximab).

When chemotherapy or targeted therapies stop working, treatment options for people with advanced head and neck cancer are limited, and they are normally expected to survive for less than six months.

Patients in the Keytruda arm survived for a median of 8.4 months, compared to 6.9 months with standard treatment. However, a minority of patients responded extremely well to Keytruda – 36 patients saw their cancer partially or completely disappear, and some are still cancer free three years after first receiving the drug.

“Our findings show that the immunotherapy pembrolizumab extends the life of people with advanced head and neck cancer overall, and in a group of patients has really dramatic benefits. It is also a much kinder treatment than those currently approved,” said Professor Kevin Harrington, professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and consultant at The Royal Marsden NHS Foundation Trust.

“I would like to see pembrolizumab approved for use in the clinic, so that people with advanced head and neck cancer can be offered the chance of a longer life and improved quality of life.

“There is also an urgent need to work out how we can identify in advance which patients are likely to benefit, given that some of these people may do much better than they do on standard treatment.”

The trial was sponsored and funded by MSD, and the results are published in The Lancet.

December, 2018|Oral Cancer News|

Standard chemotherapy treatment for HPV-positive throat cancer remains the most effective, study finds

Source: www.eurekalert.org
Author: press release, University of Birmingham

A new study funded by Cancer Research UK and led by the University of Birmingham has found that the standard chemotherapy used to treat a specific type of throat cancer remains the most effective.

The findings of the trial, which aimed to compare for the first time the outcomes of using two different kinds of treatment for patients with Human papillomavirus (HPV)-positive throat cancer, are published today (November 15th) in The Lancet.

Throat cancer is one of the fastest rising cancers in Western countries. In the UK, incidence was unchanged between 1970 and 1995, then doubled between 1996 and 2006, and doubled again between 2006 and 2010. The rise has been attributed to HPV, which is often a sexually transmitted infection. Most throat cancers were previously caused by smoking and alcohol and affected 65 to 70 year old working class men. Today, HPV is the main cause of throat cancer and patients are middle class, working, have young children and are aged around 55.

HPV-positive throat cancer responds well to a combination of cisplatin chemotherapy and radiotherapy, and patients can survive for 30 to 40 years, but the treatment causes lifelong side effects including dry mouth, difficulty swallowing, and loss of taste.

The De-ESCALaTE HPV study, which was sponsored by the University of Warwick, compared the side effects and survival of 164 patients who were treated with radiotherapy and cisplatin, and 162 who were given radiotherapy and cetuximab. The patients were enrolled between 2012 and 2016 at 32 centres in the UK, Ireland, and the Netherlands. Patients were randomly allocated to be treated with radiotherapy and either cisplatin or cetuximab. Eight in ten patients were male and the average age was 57 years.

Importantly, the results found that there was very little difference between the two drugs in terms of toxicity in patients and side effects such as dry mouth, however, there was a significant difference in the survival rates and recurrences of cancer in patients taking part in the trial.

They found that the patients who received the current standard chemotherapy cisplatin had a significantly higher two-year overall survival rate (97.5%) than those on cetuximab (89.4%). During the six-year study, there were 29 recurrences and 20 deaths with cetuximab, compared to 10 recurrences of cancer and six deaths in patients who were treated with the current standard chemotherapy cisplatin.

And cancer was three times more likely to recur in two years following treatment with cetuximab compared to cisplatin, with recurrence rates of 16.1 per cent versus six per cent, respectively.

Study lead Professor Hisham Mehanna, Director of the University of Birmingham’s Institute of Head and Neck Studies and Education, said: “Many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as cisplatin chemotherapy with radiotherapy and caused fewer side effects but there has been no head-to-head comparison of the two treatments.

“Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin.

“This was a surprise – we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV positive should be given cisplatin, and not cetuximab, where possible.”

Dr Emma King, Cancer Research UK Associate Professor in head and neck surgery at the University of Southampton, said: “Studies like this are essential for us to optimise treatments for patients. We now know that for HPV-positive throat cancer, the standard chemotherapy treatment remains the most effective option.

“However, we must keep testing new alternatives to ensure patients always have access to cutting-edge and kinder treatments. Chemotherapy and radiotherapy can leave head and neck cancer patients with long term pain and difficulties swallowing, so we should always strive to minimise side effects.”

Professor Janet Dunn from the University of Warwick, whose team ran the De-ESCALaTE HPV trial, said: “In the current trend for de-escalation of treatment, the results of the De-ESCALaTE HPV trial are very important as they were not as we expected. They do highlight the need for academic clinical trials and are an acknowledgement of the key role played by Warwick Clinical Trials Unit at the University of Warwick as the co-ordination and analysis centre for this important international trial.”

The patients on the De-ESCALaTE trial Steering Committee endorsed the importance of research findings.

Malcom Babb, who is also President of the National Association of Laryngectomee Clubs, said: “From a patient perspective, De-ESCALaTE has been a success by providing definitive information about the comparative effectiveness of treatment choices.”

November, 2018|Oral Cancer News|

A Look at Therapy Toxicities & Biology in Head & Neck Cancers

Source: journals.lww.com
Author: Valerie Neff Newitt

A measure of intrigue and discovery pertaining to head and neck cancer, spiked with compassion for patients struggling against treatment toxicities, helps quench the intellectual thirst of Yvonne Mowery, MD, PhD, Butler Harris Assistant Professor of Radiation Oncology at Duke University Medical Center, Durham, N.C.

Splitting time between the clinic and laboratory, Mowery is actively engaged in patient care as well as preclinical, translational, and clinical research. “I hope to get a better understanding of the biology of head and neck cancer and determine pathways that we can target to reduce metastatic spread of the disease and improve responsiveness to available treatments,” she told Oncology Times.

Long before reaching her current status as an award-winning investigator, Mowery grew up in Richmond, Va., in the midst of a “completely non-scientific” family. “I was an oddball,” she joked, while recalling her parents’ patience with her backyard composting experiments that became so foul-smelling that the health department was contacted. As a kid, her idea of a great present was an encyclopedia of science, and the thing that caught her eye at the toy store was a junior chemistry set.

Science was clearly her path when she headed to the University of Virginia. In her sophomore year, Mowery began working in a genetics lab. That’s where the lure of fruit flies took hold. “I looked at the development of their reproductive system and found that very interesting,” she recalled.

Nearing the completion of her undergraduate education, Mowery debated between attending medical school or graduate school. The eventual winner? Both. “I investigated physician-scientist training programs and arrived at Duke in 2004 to do a combined MD/PhD.” Today, Mowery spends 1 day a week in clinic where she sees patients, then moves to the lab for the remainder of the week to find strategies to improve patient care and develop therapies to deliver better outcomes for patients, both present and future.

Clinical Challenges
“I treat cancers primarily of the head and neck—such as oral cavity, larynx, tonsils, base of tongue, sinuses—with radiation therapy. I think of head and neck cancers as being in a ‘very high-stakes real estate’ area,” she said, “because they are often close to saliva glands, vocal cords, etc. This requires intricate planning for radiation treatment. Visualization of the tumor through fiberoptic laryngoscopy allows me to see a tumor responding to radiation and chemotherapy during the weeks of treatment; it is gratifying to watch it happen with your own eyes.”

Mowery said toxicity associated with treatment of this area of the body can be severe, partially due to the fact that it is typically “…one of the longer courses of radiation that we do—about 7 weeks, 5 days a week,” she explained. “Patients typically require pain medicine to eat and drink a soft diet, lose their sense of taste, and experience very dry mouth, sometimes requiring a feeding tube for nutrition. In addition, the skin on their neck often falls off.” Comparing it to severe sunburn, Mowery said skin typically blisters and peels off, leaving behind a neck that is “red, angry, and very uncomfortable. It just comes with the territory.”

In addition to these side effects, Mowery said there is also an unusual biological aspect to head and neck cancers which figures largely in her work. “Something very interesting scientifically drew me to these cancers,” she informed. “There are two main causes of cancer in this area: tobacco use and human papillomavirus (HPV). Outcomes for patients with HPV-positive oropharynx cancers are excellent; even when the cancer is locally advanced about 80-90 percent of patients are cured. But the tobacco-induced cancers, by contrast, do much worse (about 60% or less survival rate for locally advanced disease). Even if the tumor size is the same and the number of involved lymph nodes are the same, the biology is completely different for the HPV-related and the HPV-unrelated disease.”

In fact, the staging system was changed at the beginning of this year so that HPV-related cancers and HPV-negative cancers are staged differently. “HPV-positive cancers that used to be staged at IVA may now be staged at I or II, but they remain at stage IVA if the cancer is HPV-negative,” Mowery detailed.

Asked why tobacco-related cancer behaves so badly, Mowery answered, “We do not have a good understanding of that; it is something I am studying. We do know, however, that HPV-negative tumors exhibit a loss of function of the p53 gene, [which] is really the king of all tumor suppressors. In HPV-related tumors, p53 is usually genetically still intact but its activity is affected by HPV.”

She also commented that people still actively smoking during treatment tend to do much worse, likely due in part to having lower oxygen levels in the tumor, which in turn causes the radiation to work less effectively. “If we can figure out ways to make HPV-negative tumors behave more like HPV-positive tumors, outcomes would improve.”

From Clinic to Research
These realities on the clinical side have informed and inspired some of Mowery’s research efforts. One of her projects aims at reducing the toxicity of treatment while maintaining good outcomes in patients.

“A clinical trial that I am about to start will use PET/CT, a type of metabolic imaging, as an early litmus test to evaluate how patients are responding during treatment. If we find they are responding well, we will de-intensify and back off on the chemotherapy and radiation dose while still trying to achieve good outcomes,” Mowery explained.

She noted that because HPV-positive and HPV-negative cancers are still treated exactly the same way when not on a clinical trial, investigators also hope to find out if treatment can be de-intensified for the HPV-positive patients who tend to have more successful outcomes by virtue of their cancer type, thus allowing them to avoid some of the severe side effects.

“Of course, even in HPV-positive cancers, not every patient is cured,” cautioned Mowery, “so we want to see if we can identify, early on, who is going to do well and who, in contrast, still needs that full 7-week intensive course of radiation therapy and chemotherapy.”

Another clinical trial ongoing at Duke in which Mowery is involved is testing a drug called BMX-001 given to patients through a subcutaneous injection during radiation. “We hope the drug will reduce the—the inflammation and irritation of the lining of the mouth and throat during radiation—and dry mouth,” she said.

Mowery is also busy in lab with intensive work in developing new mouse models of both HPV-related and HPV-unrelated squamous cell carcinoma of the head and neck. “My objective is to develop a platform in which I can develop radiation with immunotherapy, as well as with chemotherapy and various novel systemic agents, to try to improve outcomes particularly for HPV-negative disease,” noted Mowery, also the winner of a 2017 Conquer Cancer Young Investigator Award. “I want to discover if there are ways that we can make our bodies and our immune system realize that these cells are not ‘self’ and activate the immune system to attack and eliminate them.”

Tobacco-related cancer is induced in mice by giving them a carcinogen present in tobacco, “… causing them to become like a tobacco chewer or smoker,” Mowery explained. “Having that exposure causes mutations in cells in the lining of their mouth.”

Mowery further said her research is taking advantage of large sequencing projects in which various head and neck tumors have been sequenced. These data are publicly available and published primarily by The Cancer Genome Atlas organization. “I have been able to see which genes are most commonly mutated and then can genetically engineer mice to have those mutations. In other words, I can specifically knock out certain genes in the head and neck to model the cancer in mice.”

This is extremely important because it allows Mowery and team to interrogate the biology of the mutations, and determine which genetic changes and pathways lead to the cancer spreading from its site of origin to the lymph nodes or the lungs. “It helps us to develop therapies to block the cancer and keep it at bay, and to determine if there are better ways to sensitize the cancer to radiation and chemotherapy,” she detailed. “And we have an opportunity to test drugs that we hope will help with side effects of radiation. We must make sure that drugs protecting normal tissue are not also protecting the tumor. Having great animal models of human cancer is really important to making progress.”

As if her work in head and neck cancer were not enough, Mowery is continuing an earlier effort begun in the lab of her research mentor David G. Kirsch, MD, PhD, by acting as radiation oncology principal investigator for a multi-site, international prospective randomized clinical trial investigating the combination of the immune checkpoint inhibitor pembrolizumab (anti-PD-1 antibody) and radiation therapy for patients with high-risk soft tissue sarcoma of the extremities. The researchers are also examining the biology behind the effects of radiation combined with pembrolizumab in a co-clinical trial using primary mouse models of sarcoma.

“We saw promising results combining them in this model. Our hope is by using this combination during the early stage of disease we may be able to eliminate those cells that have escaped the primary tumor before they cause a problem.”

Who Has Time for Hobbies?
Asked about her life outside of the clinic and lab, Mowery admitted that little time is left for hobbies. “I used to play tennis, but now I just enjoy watching it,” she said through a chuckle. “I splurged on a Labor Day vacation to the U.S. Open in New York. In my off time, I mostly read and spend time with my family. I am married; my wife is a nurse at Duke working in bone marrow transplant. We have no children.”

But the couple does have the patter of little feet in their midst. “We have two small dogs, Heidi and Cassie, a Maltese and a Maltese Shih Tzu mix—both less than 10 lbs.,” Mowery offered. “We live in downtown Durham, N.C., which is a burgeoning area. It’s kind of cool, and a little bit grungy—but in a good way. I love going for walks and checking out new restaurants. And I love food,” she added brightly.

After a brief pause, Mowery turned her thoughts again to patients. “There is one other clinical trial we’ve recently opened in the head and neck space. We are looking at financial toxicity of patients,” she said. “We are very concerned about the bills patients incur for cancer care and how that affects their quality of life.

“Unfortunately, some people just can’t afford to fill their whole prescription. Some take their drugs every other day because they are worried about cost. Some patients just do not follow through on therapy. We need to get a better sense of how much of that is going on and if there are early warning signs we can detect allowing us to intervene.”

Mowery added that better communications between health care providers and patients are needed to help patients better understand costs they face and identify resources that can help them.

“We just opened this survey-based pilot trial in June. We hope to have data next year and be able to develop a follow-up plan to employ the strategies that we find,” said Mowery. “There are a lot of ways we can try to help our patients.”

November, 2018|Oral Cancer News|