oropharyngeal cancer

An Occult HPV-Driven Oropharyngeal Squamous Cell Carcinoma Discovered Through a Saliva Test

Source: Frontiers in Oncology
Date: March 31st, 2020
Authors: Kai Dun Tang, Sarju Vasani, Touraj Taheri, Laurence J. Walsh, Brett G. M. Hughes, Lizbeth Kenny, and Chamindie Punyadeera

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.

Introduction

The incidence of high-risk human papillomavirus (HR-HPV−16,-18,-33) driven oropharyngeal cancer (OPC) is rapidly increasing in developed countries (13). HPV-driven OPCs have surpassed cervical cancer as the most common HPV-driven cancer in the USA. The prevalence of HR-HPV has been reported as 3.7% of the USA population, with a bimodal age distribution of incidence (4). It remains unclear why some individuals go on to develop OPC, while others clear the initial HPV infection (5). The strong association between HR-HPV infection and cervical cancer has led to screening programmes in primary healthcare settings, resulting in earlier diagnosis and a reduction in cancer deaths (6). Unlike cervical cancer, no screening test is available for OPC and current HPV vaccines have yet to demonstrate any reduction in future OPC development (7). Here, we report the first ever case of occult OPC detected as a direct result of a theoretical screening test—in this case HPV-16 DNA analysis in salivary oral rinse samples. Our clinical and pathological findings increase our understanding of both the natural history of the disease and the potential for wider screening to identify early stage OPC, facilitating less morbid treatments.

Cases Presentation

An ongoing HPV-16 DNA prevalence study was approved by institutional ethics committees from the University of Queensland; Queensland University of Technology and the Royal Brisbane and Women’s Hospital. A total of 665 cancer-free healthy individuals from Queensland Region, Australia between May 2016 and October 2017 were recruited. All participants gave written informed consent prior to sample collection.

Six hundred and fifty cancer-free healthy individuals with sufficient amount of DNA were tested for oral HPV-16 DNA. Of these 3 have been identified to have persistent oral HPV-16 DNA infection. Following discussion with our ethics team we have approached these three participants and offered them consultation with an Ear, Nose, and Throat (ENT) surgeon. A 63-year-old caucasian male was assessed as part of this consultation process. He had consistently been HPV-16 DNA positive for a period of 36 months, with a steadily rising HPV-16 viral load in his salivary oral rinse samples (Figure 1A). He was invited to attend the ENT clinic for assessment and discussion.

FIGURE 1
www.frontiersin.orgFigure 1. Occult oropharyngeal microcarcinoma detected based on a screening test through the serial measurements of salivary HPV-16 DNA. (A) HPV-16 DNA viral load in salivary oral rinse samples over time. B (Baseline); F1 (6 month follow-up); F2 (12 month follow-up); F3 (36 month follow-up); PT (2-week post-tonsillectomy). (B) Sections of the left tonsillar tissue found a 2 mm non-keratinising squamous cell carcinoma, with focal stromal invasion <1 mm, excised with clear margins. The remainder of the left tonsil showed follicular lymphoid hyperplasia. Hematoxylin-eosin (H&E x200) (C) HPV-16 DNA was only positive in left tonsillar tissue. (D) p16INK4a immunohistochemistry staining (IHC) x20: Diffuse positive brown staining for p16INK4a in tumor region comparing non-affected area in the left tonsil.

He is an ex-smoker, having quit 15 years ago, with a 45 pack year history of smoking. He drinks two standard drinks (2.5 units of alcohol) per day. He is heterosexual, and his social history includes multiple oral sex partners in the past (>5), followed by a long term monogamous relationship. Initial clinical examination of the oropharynx including palpation and white light revealed no significant abnormalities. Both tonsils were irregular due to mucous retention cysts and there was slight tonsillar asymmetry (Left < Right) but no evidence of any malignant lesions. Narrow band imaging (NBI) showed some mild vascular changes at the left glosso-tonsillar sulcus. There were no palpable lymph nodes in the neck. An MRI examination of the oropharynx and neck demonstrated no occult lesions of the tonsils or the base of tongue and no cervical lymphadenopathy.

He was offered continued surveillance, or a biopsy of the area of NBI change with bilateral tonsillectomy. The patient elected for bilateral tonsillectomy and biopsy of the base of tongue with NBI guidance under general anesthetic and informed consent was obtained. The surgical specimens were sent for histology and tissue HPV-16 DNA testing. The patient was discharged from hospital the same day. He had a routine postoperative course with a sore throat for 1 week and recovered fully. An ultrasound scan of his neck was performed 2 months post-surgery which showed no cervical lymphadenopathy. He is currently under routine oncological surveillance. The patient has a very high likelihood of cure with minimal morbidity from single modality treatment.

Clinical Specimens’ Collection and Processing

Salivary oral rinse samples of this individual were collected at baseline, 6, 12, 36 month, and 2 weeks after his bilateral tonsillectomy using previously published method (810). Briefly, participants were asked to swish and gargle for 1–2 min with 2 × 10 mL volumes of 0.9% saline, prior to expectorating the rinse sample into a 50 mL falcon tube. Tissue biopsies from the tonsil and base of tongue were obtained after surgical resection. All samples were immediately frozen on dry ice upon collection and transported back to the laboratory for subsequent processing.

HPV-16 DNA QPCR Analysis

Total DNA was extracted from salivary oral rinse and tonsillar tissue samples using the QIAmp DNA Mini Kit (Qiagen, Germantown, MD, USA) as per manufacturer’s protocol. For detection of HPV-16 genotyping, the qPCR assay targeting the opening reading frame (ORF) region of HPV16 E6/7 was carried out with the QuantStudio™ 7 Flex Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) as described previously (11, 12). For quantification of HPV-16 DNA viral copies in salivary oral rinse and tissue samples, a standard calibration curve was generated using qPCR by plotting threshold cycle (Ct values) against the logarithm of the copy number of 8-fold serially diluted (1 × 101-1 × 108 copies) of pHPV-16 plasmid DNA [American Type Culture Collection (ATCC)® 45113™].

Immunohistochemistry

H&E (Haemotoxylin and Eosin stains) staining on formalin-fixed paraffin-embedded (FFPE) slide was performed to investigate the cellular and tissue structure/morphology. HPV status was evaluated using CINtec® p16INK4a Histology Kit (E6H4 clone) (Roche MTM Laboratories, Heidelberg, Germany) according to manufacturer’s instructions. p16INK4a was considered positive by two independent pathologists when there was a strong, diffuse nuclear and cytoplasmic staining pattern in the majority (>70%) of tumor cells.

Salivary HPV-16 DNA as a Biomarker-Based Tool for HPV-Driven OPC Screening

Salivary oral rinse samples from this individual had been collected at baseline, 6, 12, and 36 month follow-up as well as 2 weeks after his bilateral tonsillectomy. HPV-16 DNA genotyping and viral loads in all samples were analyzed using an in-house developed qPCR assay. HPV-16 DNA viral load in saliva increased exponentially across the 36 month follow-up period (from 3.43 to 1,281.69 copies/50 ng) and subsequently declined to undetectable levels post-tonsillectomy (Figure 1A).

Histologically Confirmed Diagnosis of an Occult P16INK4A Positive OPC

This individual was diagnosed as having a 2 mm squamous cell carcinoma (T1N0M0) in the left tonsil (Figure 1B) using Haemotoxylin and Eosin (H&E) staining. He had only foci of stromal invasion with a depth of <1 mm. The remainder of the left tonsil showed follicular lymphoid hyperplasia. Further, HPV-16 DNA was only positive in left tonsillar tissue (Figure 1C). Immunohistochemistry (IHC) staining for p16INK4a demonstrated diffuse and strong staining in more than 70% of tumor cells (Figure 1D). However, the non-affected remainder of the left tonsil as well as the right tonsil were negative for p16INK4a with usual mosaic pattern of staining. The excision margins of the left tonsillar malignancy were widely clear. No atypia or malignancy could be identified in the right tonsil and bilateral tongue base specimens all of which were negative for HPV-16 DNA.

Discussion

Long-term persistence of HPV-16 infection is likely to be a prerequisite for the development of malignancy (13, 14). Women with persistent HPV-16 infection in the cervix for <1 year have a 40% risk of developing cervical intraepithelial neoplasia grade 2 or more within 3 years (13). Indeed, the natural history of HPV in the oropharynx from initial infection to carcinogenesis is not known with many questions remaining unanswered. Several studies have evaluated the prevalence of HPV-16 DNA in saliva (1518) without clinical assessment of positive individuals. Studies aimed at clinical assessment of those with persistence for premalignancy or microscopic carcinoma have failed to detect significant abnormalities (19). This has led to the assertion that screening for early occult or premalignant oropharyngeal lesions is not feasible. Here, we report the first ever histologically confirmed diagnosis of an asymptomatic occult OPC (T1N0M0) discovered by a theoretical screening test through the serial measurements of HPV-16 DNA in salivary oral rinse samples.

The impact of the pattern of salivary HPV persistence including changes in the absolute HPV viral DNA copies over time has never been investigated. The pattern of salivary HPV-DNA detection in this case demonstrates an exponential upward trend with the titer at first sample being 3.43 copies per 50 ng and the final titer before surgery of 1281.7 viral copies per 50 ng. This may represent progression of the lesion with subsequent shedding of increasing levels of HPV-16 DNA into the saliva. In future cases the presence of this pattern should be evaluated, as it may provide a critical marker for the progression of disease and hence a signal for intervention; indeed the pattern of viral copies in serial measurement may have more importance than the persistence itself.

This case also has important implications with regards to the natural history of the disease. The left tonsil was strongly positive for HPV 16 DNA outside the region of malignancy and as anticipated was p16INK4a positive only within carcinoma. This implies that the malignancy is likely to have developed in a wider field of HPV infection with only a component undergoing malignant change. The existence of a precursor lesion to OPC has long been doubted and is cited as one of the obstacles to OPC screening (16). This case demonstrates that very early lesions can be found in asymptomatic individual, and that they can potentially be eradicated with minimal morbidity.

The quest for a sensitive and specific screening test for HPV-driven OPC is of great importance. The uptake of HPV immunization in developed countries is variable and the developing world remains largely unimmunised. As sexual habits change in the developing world (20, 21) there is likely to be the same rapid expansion in this disease that we have witnessed in the United States and Europe and global burden will continue to rise. As the first singular case, this report does not act as direct evidence of the value of screening in a general population, however, it demonstrates a possible salivary screening test and pathway for the detection of microscopic OPC. It demonstrates that a screened individual can receive significantly less morbid treatment than would be required for the standard presentation at a more advanced stage. This report and previous studies (8, 11, 12, 22), support the value of a salivary oral rinse test as a potential screening tool. Unlike previously published work, our study is the first to demonstrate that continuous monitoring of HPV-16 DNA in salivary oral rinse samples can detect occult OPC.

Data Availability Statement

All datasets generated for this study are included in the article.

Ethics Statement

This study was approved by institutional ethics committees from the University of Queensland (UQ) [HREC No: 2014000679 and 2014000862]; Queensland University of Technology [HREC No: 1400000617 and 1400000641]; and the Royal Brisbane and Women’s Hospital (RBWH) [HREC/16/QRBW/447]. Written informed consent was obtained from this participant for publication of this case report.

Author Contributions

All authors have read and agree to the published version of the manuscript. KT and CP: conceptualization. All authors: methodology, validation, formal analysis, data curation, investigation, and writing—review and editing. KT, SV, and CP: writing—original draft preparation. CP: funding acquisition.

Funding

The prevalence study was funded by Janssen Biotech Inc.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Dr. Gert Scheper from Janssen Vaccines & Prevention B.V. We would also like to thank Lilian Menezes for her assistance in the recruitment of study patient and collection of clinical samples.

 

May, 2020|Oral Cancer News|

Blood Test Spot On for HPV Cancer Recurrence

Source: MedPage Today
Date: April 1st, 2020
Author: Charles Bankhead

 

A blood test for tumor-associated human papillomavirus (HPV)-DNA had near-perfect accuracy for identifying oropharyngeal cancer patients at high risk of recurrence after treatment, a prospective study showed.

Overall, 28 patients tested positive for circulating tumor (ct) HPV-DNA, including 16 patients who had two consecutive positive tests. All but one of the 16 patients subsequently had biopsy-proven disease recurrence. No patient who had only negative tests developed recurrent disease.

The findings have clear and immediate implications for clinical practice, including earlier initiation of salvage therapy for patients with recurrent disease, reported Bhisham S. Chera, MD, of the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, and colleagues in the Journal of Clinical Oncology.

“With regard to how this is applicable to clinical practice, I think it improves the effectiveness, it improves the efficiency, and it reduces the cost and financial toxicity to patients,” Chera told MedPage Today. “This blood test’s performance is really good: Negative predictive value (NPV) 100%, two consecutive positive tests, 94% positive predictive value (PPV). This performs better than any physical examination, PET/CT, or fiberoptic re-examination in identifying cancer recurrence. Right now, I think this is the best surveillance tool we have.”

The findings extended those of a previous report, which showed that a persistently negative ctHPV-DNA test ruled out disease recurrence.

HPV infection accounts for a majority of new cases of oropharyngeal cancer in the U.S. After years of rapid increases in prevalence and incidence, oropharyngeal squamous cell carcinoma (OPSCC) has become the most common HPV-associated cancer, surpassing HPV-associated cervical cancer.

In general, HPV-positive OPSCC has a favorable prognosis as compared with HPV-negative disease, which has supported efforts to de-intensify treatment regimens to reduce exposure to potentially toxic therapies. Nonetheless, as many as a fourth of patiens will develop recurrences, the authors noted.

Most recurrences occur within the first 2 years after treatment, but some patients remain at risk of recurrence for as long as 5 years, or even longer in rare cases. Salvage therapy for recurrent HPV-positive OPSCC leads to better outcomes as compared with salvage therapy for recurrent HPV-negative disease.

PET/CT imaging 3 months after definitive treatment is standard for response assessment in many cases, the authors continued. National Comprehensive Cancer Network guidelines recommend surveillance visits at increasing time intervals through 5 years. During the visits, patients often undergo fiberoptic nasopharyngolaryngoscopy, although a recent report showed that routine surveillance rarely identifies recurrent disease.

A blood-based surveillance test based on detection of ctHPV-DNA offers potential for early detection of recurrent disease and has precedents in bladder, breast, and colorectal cancer. Chera and colleagues prospectively evaluated a ctHPV-DNA liquid biopsy in 115 patients who had completed definitive chemoradiotherapy for HPV-positive OPSCC. Each patient had PET/CT imaging 3 months after finishing treatment. Investigators tested patients for ctHPV-DNA at 6- to 9-month intervals.

During a median follow-up of 23 months, 28 patients tested positive for ctHPV-DNA, including 16 patients who had two consecutive positive tests. Also during follow-up, 15 patients developed biopsy-proven recurrence of OPSCC; all 15 had two consecutive positive tests for ctHPV-DNA. The median time from ctHPV-DNA positivity to recurrence was 3.9 months.

Consecutive positive tests had a PPV of 94%. The previous report from the study showed that a negative test had a NPV of 100%.

“The way I see this working in the clinic is that if you have a negative test, we don’t do a fiberoptic exam, we don’t order any imaging,” said Chera. “If you have a patient whose surveillance test is positive, we would bring the patient back 2 or 3 months later and repeat the blood test. If it’s positive again, then we would do an in-depth physical examination; we would do a fiberoptic exam and order a total-body PET/CT scan. This test can help us better identify which patients we can omit imaging in and those patients we can do imaging in.”

The test very well could have value in the management of patients with other types of HPV-related cancers, he said. Investigators have already examined the rate of ctHPV-DNA clearance as a biomarker for response to treatment and a possible decision-making tool for treatment de-escalation.

The testing technology has been licensed to Naveris for commercial development, and multiple medical centers have already partnered with the company to conduct studies across a variety of HPV-related diseases, said Chera.

April, 2020|Oral Cancer News|

Prevalence of Oral HPV Infection Declines in Unvaccinated Individuals

Source: Infectious Disease Advisor
Date: September 30th, 2019
Author: Zahra Masoud

Oral human papillomavirus (HPV) prevalence has decreased in unvaccinated men, possibly as a result of herd protection, but the incidence of such infection has remained unchanged in unvaccinated women from 2009 to 2016 in the United States, according to a study published in the Journal of the American Medical Association.

Since 2011 for women and 2006 for men, prophylactic HPV vaccination for prevention of anogenital HPV infection has been recommended for routine use in the United States. Previous studies have demonstrated that this vaccine has high efficacy in reducing the prevalence of oral HPV infection. However, the vaccine is not indicated to prevent oral HPV infection or oropharyngeal cancers because there are few results from randomized trials. Further, there has been a lack of surveillance studies reporting on herd protection against oral HPV infection, which is defined as a form of indirect protection from infectious diseases that occurs when a large percentage of the population has become immune/vaccinated, thereby providing protection for individuals who are not immune/not vaccinated. Therefore, this study investigated evidence for herd protection against oral HPV infection in unvaccinated men and women in the United States using temporal comparisons of oral HPV prevalence for 4 vaccine types and 33 non-vaccine types.

This study was conducted across 4 cycles (from 2009 to 2016) of the National Health and Nutrition Examination Survey (NHANES), using a cross-sectional, stratified, multistage probability sample of the civilian population in the United States. For the examination component, response rates were 68.5% in the 2009 to 2010 period, 69.5% in the 2011 to 2012 period, 68.5% in 2013 to 2014, and 58.7% in 2015 to 2016. In total, 13,676 participants were included, which represented 174,333,042 individuals in the US population aged 18 to 59 years. The 4 vaccine-type oral HPV were HPV-16, -18, -6, and -11. DNA was collected from oral rinses and was evaluated using PGMY09/11 polymerase chain reaction and linear array genotyping for 37 types of HPV presence. In unvaccinated individuals, sex-stratified analyses were performed along with multivariable logistic regression analyses adjusted for other variables.

From 2009 to 2016, HPV vaccination rates increased from 0% to 5.8% in men and from 7.3% to 15.1% in women. From 2009 to 2010 to 2015 to 2016, vaccine-type oral HPV prevalence declined from 2.7% to 1.6% (P =.009) in unvaccinated men; however, this decline was not heterogenous by age (P =.41 for interaction). During this period, non-vaccine-type oral HPV prevalence remained unchanged (P =.66) among unvaccinated men. From 2009 to 2010 to 2015 to 2016 in unvaccinated women, both vaccine-type and non-vaccine-type oral HPV prevalence remained unchanged (P =.79 and P =.58, respectively).

The 37% decline in vaccine-type oral HPV among unvaccinated men from 2009 to 2016 suggests herd protection against oral HPV infections. This herd protection may arise from the increased rate of HPV vaccination among women and is consistent with herd protection studies against genital HPV infections in unvaccinated women in the United States. The unchanged prevalence of oral HPV among unvaccinated women from 2009 to 2016 does not suggest herd protection; this may reflect low statistical power because of a low prevalence in women.

Overall, the study authors concluded that, “The estimated herd protection should be incorporated into evaluations of cost-effectiveness of HPV vaccination of men older than 26 years. Vaccine trials of oral HPV incidence and persistence in men should inflate sample sizes to account for herd protection.”

Reference

Chaturvedi AK, Graubard BI, Broutian T, Xiao W, Pickard RK, Kahle L, Gillison ML. Prevalence of oral HPV infection in unvaccinated men and women in the United States, 2009-2016. JAMA. 2019;322(10):977-979.

October, 2019|OCF In The News|

Robotic surgery for oropharyngeal cancer not better than radiation therapy, study finds

Source: News Medical
Date: June 7, 2019
Author: Reviewed by James Ives, M.Psych (Editor)

In 2012, scientists at Lawson Health Research Institute launched the world’s first clinical trial comparing robotic surgery to radiation therapy for the treatment of oropharyngeal cancer (cancer at the back of the throat). The team is now reporting findings from the seven-year study which challenges beliefs that surgery leads to better swallowing outcomes, suggesting instead that radiation results in better quality of life for patients.

For Betty Ostrander, an operating room nurse from Tillsonburg, Ontario, a throat cancer diagnosis was life-changing. Betty was 59 when she discovered a small lump on the right side of her neck. After seeking medical care and testing, she was told she had oropharyngeal cancer.

“I remember thinking ‘I’m healthy, I eat right and I exercise; this can’t be happening to me.’ But it was, and it was scary,” recalls Betty. “One of the first questions I asked was whether there were any clinical trials available.”

Betty was one of 68 research participants in the ORATOR trial. The study included six centres from across Canada and Australia, including London Health Sciences Centre’s (LHSC) London Regional Cancer Program. Participants were randomized to receive either precision radiation therapy, often combined with chemotherapy, or transoral robotic surgery (TORS).

TORS is a surgical method for treating throat cancer which uses a small 3D camera and miniature robotic instruments to remove tumors. LHSC was the first center in Canada to offer TORS in 2011.

“Early studies suggested TORS might reduce the risk of swallowing problems historically associated with radiation and it therefore rose quickly in popularity,” explains Dr. Anthony Nichols, Associate Scientist at Lawson and Head and Neck Cancer Surgeon at LHSC. “But there was no randomized trial to compare patients’ swallowing outcomes. As the first center in Canada to offer TORS, we decided to tackle this problem through the ORATOR trial.”

The research team found no difference in survival between the two groups but, surprisingly, participants in the radiation group experienced better swallowing outcomes. A mild decline in swallowing function was observed in 40 per cent of the surgery participants compared to 26 per cent of radiation participants. All participants were able eat a full diet after treatment but 16 per cent from the surgery group said they needed to specially prepare their food.

Our findings challenge the notion that TORS leads to better swallowing outcomes. While radiation was previously associated with poor swallowing outcomes, treatments have advanced considerably and are now much more precise, which may be leading to better patient outcomes.”

Dr. David Palma, Associate Scientist at Lawson and Radiation Oncologist at LHSC

Patients in the surgery group were also at risk for dangerous bleeding during surgery. One year after treatment, patients in the surgery group were more likely to experience pain (22 per cent versus eight per cent in the radiation group), use painkillers (45 per cent versus 15 per cent), have issues with their teeth (12 per cent versus one per cent), and experience shoulder impairment.

The team found that patients in the radiation group experienced more short-term constipation and a temporary drop in blood counts. They also experienced an increased risk of tinnitus (ringing in the ears) and high frequency hearing loss when receiving chemotherapy, with some needing hearing aids.

“Each therapy has its different potential side effects but our findings suggest that TORS is not superior to modern radiation,” says Dr. Nichols. “We hope this research can be used by patients and their oncologists to help inform treatment decisions.”

Cases of oropharyngeal cancer have more than doubled since the 1990s. While throat cancer was more common in elderly patients with a history of heavy smoking or drinking, physicians have seen a dramatic rise in cases caused by human papilloma virus (HPV).

There is fortunately a high survival rate in patients with HPV-related throat cancer, leading researchers to study quality of life after treatment.

Drs. Nichols and Palma recently launched the ORATOR 2 trial which will further compare TORS against radiation and chemotherapy. The goal is to reduce the intensity of radiation and chemotherapy to improve quality of life while maintaining survival rates. The team aims to recruit 140 participants.

Results from the ORATOR trial were shared by Dr. Nichols at the American Society of Clinical Oncology’s Annual Meeting on May 31, 2019. The study was funded by the Canadian Cancer Society.

June, 2019|Oral Cancer News|

Queensland scientist develops new HPV cancer vaccine

Source: 9News
Date: May 22, 2019
Author: 9News Staff

*click Source to view video*

Former Australian of the Year Professor Ian Frazer has developed a vaccine aimed at treating HPV-related cancers of the head, neck, throat and tongue.

While funding is still being finalised, a trial of the vaccine is being prepared for people with incurable oropharyngeal cancers.

Professor Frazer, the Scottish-born immunologist who developed and patented the vaccine against HPV-related cervical cancer, has been working on this vaccine for nearly 15 years.

While the cervical cancer vaccine works as a preventative, this new vaccine is a treatment therapy.

It works by teaching the patient’s immune system to target the cancer cells containing HPV. The patient will then be given immunotherapy drugs that supercharge the immune system.

“This is all about a new way to treat cancer using the body’s defence against infection,” Professor Frazer said.

“This might give a second chance at life.”

HPV-related throat cancer kills three Australians every day.

“It’s going to become a major problem in Australia, in fact in the US we’ve seen an increase in HPV-related throat cancers by 225 per cent,” head and neck radiation oncologist Sandro Porceddu said.

Professor Porceddu will conduct the trial at the Princess Alexandra Hospital. It should begin towards the end of this year if a further $700,000 in necessary funding is found.

© Nine Digital Pty Ltd 2019
May, 2019|Oral Cancer News|

Lowering Radiation Dose Could Improve QoL, Cut Costs in Oral Ca

Source: MedPage Today, Medpage.com
Date: October 25th, 2018
Author: Elizabeth Hlavinka

SAN ANTONIO — Radiation de-intensification was tied to a quicker rebound in a number of quality of life (QoL) measures and reduced costs for patients with HPV-associated oropharyngeal cancer, a pair of studies found.

With lower doses of radiotherapy (RT), QoL measures including speech, pain, and socialization still generally worsened after treatment, but returned to baseline within 3 to 6 months, reported Kevin Pearlstein, MD, of the University of North Carolina in Chapel Hill.

And more aggressive de-intensification led to a 22% cost reduction for treatment overall ($45,884 versus $57,845 with standard care), with 33% lower costs for RT itself and 50% lower costs for post-treatment care (P=0.01), according to findings presented by Mark Waddle, MD, of the Mayo Clinic in Jacksonville, Florida.

The studies were presented here at the American Society for Radiation Oncology (ASTRO) meeting during a session on improving outcomes while minimizing toxicity in oropharyngeal cancer.

In the research from Pearlstein’s group, patients reported global QoL scores of 81 at baseline (using the 100-point EORTC QLQ-C30 questionnaire, where higher scores connote better health), which dipped to 69 at 3 months post-treatment, then rose to 75 at 6 months. Global QoL scores increased to 82 and 84 by months 12 and 24, respectively.

Common long-term side effects such as sticky saliva, taste, and ability to swallow did not return to baseline within months 3 to 6, but continued to improve between months 12 and 24. Pearlstein noted that swallowing took longer to return to baseline, typically between 1 to 3 years.

“This highlights the possibility that there can be improvement in these symptoms with longer-term follow-up,” he said.

Although oropharynx cancers associated with HPV generally have a more favorable prognosis compared with those that are not, the treatment is similar for both. As a result, these lower-risk patients still typically experience symptoms of dysphagia, dry mouth, and taste changes for upwards of 1 year after treatment, Pearlstein said.

While standard treatments typically include 70 Gy RT along with 100 mg/m2cisplatin, this study investigated whether patients given 60 Gy RT along with weekly 30 mg/m2 doses of cisplatin would result in improved QoL. Cisplatin-intolerant patients were treated with cetuximab, and patients who could not tolerate either did not receive chemotherapy.

The authors also conducted a multivariate analysis that controlled for type of chemotherapy, gender, and age. Those with with worse baseline symptoms of dry mouth, taste, and sticky saliva were more likely to return to baseline function at 12 months (ORs of 1.06, 1.09, and 1.02, respectively). Similar associations for sticky saliva and swallowing were found among patients who underwent unilateral neck RT.

“One obvious limitation is that we don’t have a direct comparison with standard intensity chemotherapy/radiotherapy,” Pearlstein said. “However, when we view these findings in the context of what we already know for patients with head and neck cancer, we do feel our findings suggest that patients who receive de-intensified chemotherapy/radiotherapy may benefit from faster return to baseline quality of life, continue improvement in symptoms over time, and less long-term morbidity.”

To conduct the study, the researchers collected data from two de-intensification phase II trials that took place from 2012 to 2017. A total of 126 patients were included, a majority of which were ages 60 and over (53%) and were non-smokers (63%). Patients were followed for an average of 25 months.

Cost of Treatment

De-intensification of radiation may also benefit these patients by decreasing total treatment costs, according to an analysis of a prospective phase II study.

“Several studies have or are investigating de-escalation of treatment to reduce toxicity while maintaining outcomes,” Waddle said during his presentation. “However, those studies haven’t investigated the cost of care that may be associated with de-escalation of treatment.”

He reported that the median cost was $17,309 for RT among those who received de-escalated doses compared with $28,161 with standard treatment (P<0.0001). The per-patient costs were $797 versus $933 per month, respectively, in the first 6 months after treatment and $518 versus $611 in the 16 to 24 months after treatment.

Among the post-treatment savings, gastrointestinal-related costs were 79% lower (P<0.01), hospitalization costs were 40% lower, and emergency department visit costs were 90% lower.

This study obtained data from the MC1273 trial, in which 68 patients received aggressive de-escalated doses of RT (30-36 Gy), and then compared the costs to 84 patients treated with standard of care (60-66 Gy). The average patient age was 58.5 years and the majority of them were white men.

October, 2018|Oral Cancer News|

HPV Vaccination Linked to Decreased Oral HPV Infections

Author: NCI Staff
Date: June 5th, 2017
Source: www.cancer.org

New study results suggest that vaccination against the human papillomavirus (HPV) may sharply reduce oral HPV infections that are a major risk factor for oropharyngeal cancer, a type of head and neck cancer.

The study of more than 2,600 young adults in the United States found that the prevalence of oral infection with four HPV types, including two high-risk, or cancer-causing, types, was 88% lower in those who reported receiving at least one dose of an HPV vaccine than in those who said they were not vaccinated.

About 70% of oropharyngeal cancers are caused by high-risk HPV infection, and the incidence of HPV-positive oropharyngeal cancer has been increasing in the United States in recent decades. In the United States, more than half of oropharyngeal cancers are linked to a single high-risk HPV type, HPV 16, which is one of the types covered by Food and Drug Administration (FDA)-approved HPV vaccines.

“In an unvaccinated population, we would estimate that about a million young adults would have an oral HPV infection by one of these vaccine HPV types. If they had all been vaccinated, we could have prevented almost 900,000 of those infections,” said senior study author Maura Gillison, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center.

Dr. Gillison presented the new findings at a May 17 press briefing ahead of the 2017 annual American Society of Clinical Oncology (ASCO) meeting, held June 2–6 in Chicago.

A Rapidly Rising Cancer

Oropharyngeal cancer “is the fastest-rising cancer among young white men in the United States,” said Dr. Gillison, who was at Ohio State University when she conducted the study.

“The HPV types that cause oropharyngeal cancers are primarily transmitted through sexual contact,” explained lead study author Anil Chaturvedi, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics. The increased incidence of oropharyngeal cancers in white men has been linked to changes in sexual behaviors from the 1950s through the 1970s, he said. The exact reasons for the greater increase in oropharynx cancer incidence in men versus women are still unclear, Dr. Chaturvedi added.

Clinical trials have shown that FDA-approved HPV vaccines can prevent anogenital HPV infections and precancerous lesions that lead to HPV-associated cancers, including cervical and anal cancer. However, Dr. Gillison said, the potential impact of current HPV vaccines on oral HPV infections that lead to cancer has not yet been rigorously tested in clinical trials, and thus the vaccines are not specifically approved for preventing cancers of the oropharynx.

From 2006 through 2014, most HPV-vaccinated individuals in the United States received Gardasil®, an HPV vaccine that protects against infection with HPV types 6, 11, 16, and 18. In January 2015, FDA approved an updated HPV vaccine, Gardasil 9®, that protects against five additional HPV types.

Looking for a Link

To investigate the relationship between HPV vaccination and oral HPV infection, the researchers analyzed data for 2,627 young adults who participated in NHANES, a national survey that assesses the health of a representative slice of the US population.

Drs. Gillison, Chaturvedi, and their colleagues restricted their analysis to NHANES data from 2011 to 2014, focusing on 18- to 33-year-old men and women “because they were the first group [in the United States] to receive the vaccine,” Dr. Gillison said.

In the United States, routine vaccination against HPV, which causes nearly all cervical cancers, has been recommended since mid-2006 for 11- to 12-year-old girls and for females up to age 26 who have not previously been vaccinated. HPV vaccination has been recommended for males ages 9–26 since 2009.

The researchers analyzed mouth rinse samples (containing oral cells) from all study participants for the presence of 37 HPV types, including types 6, 11, 16, and 18, which are covered by Gardasil, Dr. Gillison said.

The prevalence of oral infections with these four HPV types was 1.61% in unvaccinated young adults versus 0.11% in vaccinated young adults—an 88% reduction in HPV prevalence with vaccination. Among men, the prevalence of oral infection with the four HPV types was 2.1% in unvaccinated individuals and 0.0% in vaccinated individuals.

By contrast, the prevalence of oral infection with 33 HPV types not covered by the vaccine was 4.0% in vaccinated groups and 4.7% in non-vaccinated groups, the researchers found, a difference that was not considered to be statistically meaningful.

Vaccination rates were low overall, with only 29.2% of women and 6.9% of men in the study population reporting having received at least one dose of an HPV vaccine before age 26.

Prevention Potential

Although the self-reported vaccination rates in this study were low, Dr. Gillison said, “there is considerable optimism because more recent data indicate that [roughly] 60% of girls and 50% of boys under age 18 have received more than one HPV vaccine dose.”

“HPV vaccines are already strongly recommended for cancer prevention,” Dr. Gillison continued. “Parents who choose to have their children vaccinated against HPV should realize that the vaccine may provide additional benefits, such as preventing oral HPV infections linked to oral cancers.”

However, she and Dr. Chaturvedi noted, only a randomized clinical trial that follows people over time could definitively show a cause and effect relationship between HPV vaccination and a lasting reduction of high-risk oral HPV infections, which experts agree is a more meaningful indicator of vaccine effectiveness.

In July 2013, NCI researchers and their collaborators reported findings from the NCI-sponsored HPV Vaccine Trial in Costa Rica that suggested that HPV vaccination can reduce oral HPV infections in women.

“Our study builds on those results by showing a reduction in oral HPV prevalence in vaccinated men, the group that bears the greatest burden of HPV-associated oropharynx cancers,” Dr. Chaturvedi said.

June, 2017|Oral Cancer News|

Smokeless Tobacco Use and the Risk of Head and Neck Cancer: Pooled Analysis of US Studies in the INHANCE Consortium.

Source: www.pubmed.gov
Author: Wyss AB, Gillison ML, Olshan AF

Abstract

Previous studies on smokeless tobacco use and head and neck cancer (HNC) have found inconsistent and often imprecise estimates, with limited control for cigarette smoking. Using pooled data from 11 US case-control studies (1981-2006) of oral, pharyngeal, and laryngeal cancers (6,772 cases and 8,375 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, we applied hierarchical logistic regression to estimate odds ratios and 95% confidence intervals for ever use, frequency of use, and duration of use of snuff and chewing tobacco separately for never and ever cigarette smokers. Ever use (versus never use) of snuff was strongly associated with HNC among never cigarette smokers (odds ratio (OR) = 1.71, 95% confidence interval (CI): 1.08, 2.70), particularly for oral cavity cancers (OR = 3.01, 95% CI: 1.63, 5.55). Although ever (versus never) tobacco chewing was weakly associated with HNC among never cigarette smokers (OR = 1.20, 95% CI: 0.81, 1.77), analyses restricted to cancers of the oral cavity showed a stronger association (OR = 1.81, 95% CI: 1.04, 3.17). Few or no associations between each type of smokeless tobacco and HNC were observed among ever cigarette smokers, possibly reflecting residual confounding by smoking. Smokeless tobacco use appears to be associated with HNC, especially oral cancers, with snuff being more strongly associated than chewing tobacco.

© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.  

October, 2016|Oral Cancer News|

America’s Most Popular ‘Legal’ Drug is Responsible for 25% of ALL Cancer

Source: www.thefreethoughtproject.com
Author: John Vibes

There are many factors contributing to the massive rise in cancer cases in the US, but according to a new study from the American Cancer Society, cigarette smoke is by far the leading cause. The study found that roughly 25% of all cancer deaths could be attributed to cigarette smoking.

Although cigarette smoking has waned somewhat in recent years, nearly 40 million adults in the U.S. currently smoke cigarettes. The CDC says cigarette smoking is the leading cause of preventable disease and death in the U.S., responsible for more than 480,000 deaths annually.

According to the study:

We estimate that at least 167133 cancer deaths in the United States in 2014 (28.6% of all cancer deaths; 95% CI, 28.2%-28.8%) were attributable to cigarette smoking. Among men, the proportion of cancer deaths attributable to smoking ranged from a low of 21.8% in Utah (95% CI, 19.9%-23.5%) to a high of 39.5% in Arkansas (95% CI, 36.9%-41.7%), but was at least 30% in every state except Utah. Among women, the proportion ranged from 11.1% in Utah (95% CI, 9.6%-12.3%) to 29.0% in Kentucky (95% CI, 27.2%-30.7%) and was at least 20% in all states except Utah, California, and Hawaii. Nine of the top 10 ranked states for men and 6 of the top 10 ranked states for women were located in the South. In men, smoking explained nearly 40% of cancer deaths in the top 5 ranked states (Arkansas, Louisiana, Tennessee, West Virginia, and Kentucky). In women, smoking explained more than 26% of all cancer deaths in the top 5 ranked states, which included 3 Southern states (Kentucky, Arkansas, and Tennessee), and 2 Western states (Alaska and Nevada).

Smoking is one of the leading causes of illness and death in the world. The use of tobacco has become more widespread than ever and the substance itself is far more dangerous than it has ever been before.

Today, cigarettes are mass produced and treated with thousands of additives and chemicals. Carcinogenic, poisonous chemicals and toxic metals can all be found in modern tobacco products. These chemicals are present for many reasons ranging from taste and preservation to being purposely addictive. There are over 4000 of these chemicals in cigarettes and all of them are not revealed to the public. They are protected under law as “trade secrets” — meaning they can add anything they want in there without our knowledge.

The financial advantage alone should be enough of an argument to quit smoking. In most states, cigarettes are now over 6 dollars a pack, more than half of which is taxes. So people are literally paying the government and rich multinational corporations an average of 10 dollars every day, for a product that destroys their bodies. It is true that there are addictive chemicals in cigarettes but their strength and power has been blown way out of proportion.

The psychological addiction is always much stronger than the physical addiction even with harsh narcotics like heroin and especially with nicotine. All you have to do is stop and get through a few days without it. Soon enough the smell and taste will no longer be desirable to you and you will be happy to have that extra 6 dollars a pack in your pocket. It will be easier to breathe, you won’t get sick as often and you will overall be in better spirits. Quitting cigarettes is one decision that you can make that will drastically improve your life in a number of ways and it will give the elite less control of your money and your health.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

October, 2016|Oral Cancer News|

Can your own immune system kill cancer?

Source: www.cnn.com
Author: Jacqueline Howard

screen-shot-2016-10-26-at-9-38-07-am

There was another big win in the advancement of immunotherapy treatments for cancer this week.

The Food and Drug Administration approved an immunotherapy drug called Keytruda, which stimulates the body’s immune system, for the first-line treatment of patients with metastatic non-small-cell lung cancer.

In other words, the drug could be the very first treatment a patient receives for the disease, instead of chemotherapy. Keytruda is the only immunotherapy drug approved for first-line treatment for these patients.

So it seems, the future of cancer care may be in our own immune systems, but how exactly does it work, and what are its pros and cons?

“It’s certainly going to become an independent way of treating cancers,” said Dr. Philip Greenberg, head of immunology at the Fred Hutchinson Cancer Research Center in Seattle, during a Q&A session at the International Cancer Immunotherapy Conference in New York in September.

“We always talk about the three pillars of cancer therapy — radiation therapy, chemotherapy and surgery — and it’s become quite clear now that there’s going to be a fourth pillar, which is immunotherapy,” he said. “There are times where it will be used alone, and there will be times that it will be used in conjunction with the other therapies, but there’s very little to question that this is going to be a major part of the way cancers are treated from now on, going forward.”

Here’s a look at the past, present and future of cancer immunotherapy.

It began with Bessie

In the summer of 1890, 17-year-old Elizabeth Dashiell, affectionately called “Bessie,” caught her hand between two seats on a passenger train and later noticed a painful lump in the area that got caught, according to the Cancer Research Institute.

She met with a 28-year-old physician named Dr. William Coley in New York to address the injury. He performed a biopsy, expecting to find pus in the lump, probably from an infection. But what he found was more disturbing: a small gray mass on the bone. It was a malignant tumor from a type of cancer called sarcoma.

Dashiell had her arm amputated to treat the cancer, but the disease quickly spread to the rest of her body. She died in January 1891. A devastated Coley went on to devote his medical career to cancer research.

Coley is sometimes referred to as the “father of cancer immunotherapy,” according to the Memorial Sloan Kettering Cancer Center.

During his career, he noticed that infections in cancer patients were sometimes associated with the disease regressing. The surprising discovery prompted him to speculate that intentionally producing an infection in a patient could help treat cancer.

To test the idea, Coley created a mixture of bacteria and used that cocktail to create infections in cancer patients in 1893. The bacteria would sometimes spur a patient’s immune system to attack not only the infection but also anything else in the body that appeared “foreign,” including a tumor. In one case, when Coley injected streptococcal bacteria into a cancer patient to cause erysipelas, a bacterial infection in the skin, the patient’s tumor vanished — presumably because it was attacked by the immune system.

Coley’s idea was occasionally studied by various researchers in the 1900s but was not widely accepted as a cancer treatment approach until more recently.

“Immunotherapy has essentially undergone a sort of revolution in the last decade in the sense that something that was experimental — and there were still questions about what role it would have in the way cancer is treated — is completely turned around, and now it’s clear it’s effective,” Greenberg said.

German physician Dr. Paul Ehrlich, who won the Nobel Prize in physiology or medicine in 1908, proposed using the immune system to suppress tumor formation in the “immune surveillance” hypothesis — an idea that seems to follow Coley’s.

Yet it wasn’t until the early 2000s that the hypothesis became more widely accepted, according to the Cancer Research Institute. A landmark review published in the journal Nature Immunology in 2002 supported the validity of cancer immunosurveillance.

“Cancer immunotherapy really refers to treatments that use your own immune system to recognize, control and hopefully ultimately cure cancers,” said Jill O’Donnell-Tormey, CEO of the Cancer Research Institute, during the conference in New York last month.

“Many people for many years didn’t think the immune system was really going to have a role in any treatment for cancer,” she said, “but I think the entire medical community (and) oncologists now agree that immunotherapy’s here to stay.”

‘Turning oncology on its head’

One of the most famous cancer patients to have received a form of immunotherapy is former President Jimmy Carter, who had a deadly form of skin cancer called melanoma. Last year, he announced that he was cancer-free after undergoing a combination of surgery, radiation and immunotherapy.

Carter was taking Keytruda. It’s approved to treat melanoma, non-small-cell lung cancer, and head and neck cancer. However, it’s not the only approved immunotherapy option out there.

“The advances and the results we’ve seen with using the immune system to treat cancer in the last five years or so are turning the practice of oncology on its head,” said Dr. Crystal Mackall, a professor at the Stanford University School of Medicine and expert on cancer immunotherapy.

You don’t want to overstate it. As an immunotherapist, I see things from my vantage point, which is biased, but my clinical colleagues use words like ‘revolution,’ ” she said. “When I hear them say that, I think, ‘Wow, this really is a paradigm shifting for how we think about treating cancer.’ ”

Immunotherapy comes in many forms — treatment vaccines, antibody therapies and drugs — and can be received through an injection, a pill or capsule, a topical ointment or cream, or a catheter.

The FDA approved the first treatment vaccine for cancer, called sipuleucel-T or Provenge, in 2010. It stimulates an immune system response to prostate cancer cells and was found in clinical trials to increase the survival of men with a certain type of prostate cancer by about four months.

Another treatment vaccine, called T-VEC or Imlygic, was approved by the FDA in 2015 to treat some patients with metastatic melanoma.

Some antibody therapies have been approved, as well. Antibodies, a blood protein, play a key role in the immune system and can be produced in a lab to help the immune system attack cancer cells.

The FDA has approved several antibody-drug conjugates, including Kadcyla for the treatment of some breast cancers, Adcetris for Hodgkin lymphoma and a type of non-Hodgkin T-cell lymphoma, and Zevalin for a type of non-Hodgkin B-cell lymphoma.

The FDA also has approved some immunotherapy drugs known as immune checkpoint inhibitors. They block some of the harm that cancer cells can cause to weaken the immune system.

Keytruda, which Carter took, is a checkpoint inhibitor drug. Other such drugs include Opdivo to treat Hodgkin lymphoma, advanced melanoma, a form of kidney cancer and advanced lung cancer. Tecentriq is used to treat bladder cancer, and Yervoy is used for late-stage melanoma.

Additionally, there are many immunotherapy treatments in clinical trials, such as CAR T-cell therapy. The cutting-edge therapy involves removing T-cells from a patient’s immune system, engineering those cells in a lab to target specific cancer cells and then infusing the engineered cells back into the patient. The treatment is being tested to treat leukemia and lymphoma.

“The real excitement now in cellular therapy, in T-cell therapies, is it reflects the developments in an area that we call synthetic biology, which is that you can add genes to cells and you can change what they do, how they behave, how they function, what they recognize,” Greenberg said.

The high price of new immunotherapy drugs has also garnered attention in the field, according to the Fred Hutchinson Cancer Research Center. For instance, some estimates suggest that checkpoint inhibitor treatments could cost as much as $1 million per patient.

As approvals continue, many scientists caution that doctors and patients alike should prepare for potential severe side effects and downsides.

Boosting the immune system with such therapies may cause skin reactions, flu-like symptoms, heart palpitations, diarrhea and a risk of infection. New cancer immunotherapy drugs have even been linked to arthritis in some patients.

A clinical trial conducted by Juno Therapeutics to test the effectiveness of an experimental immunotherapy treatment for lymphoblastic leukemia was halted after three patients died. They suffered cerebral edema or brain swelling.

Greenberg is a scientific co-founder of Juno Therapeutics.

However, “one of the best attributes of immunotherapy and the future of medicine is that it’s very precise in the way that it kills tissue and spares normal tissue, so in some way, immunotherapy is less toxic (than other therapies). There are patients who are treated with checkpoint inhibitors who have essentially no side effects,” Mackall said. “That would never happen with chemotherapy. They would always have side effects.

“Still, you know, the fact remains that probably nothing is perfect, and there are likely to be some side effects, but as far as we know now, they are less likely to be as severe or prevalent.”

As immunotherapy continues to develop as an option for cancer treatment, experts plan to be realistic about forthcoming challenges.

The challenges of immunotherapy

Experts say they hope to better understand why some patients may have different responses to immunotherapy treatments than others — and why some treatments may result in remissions instead of relapses, or vice versa.

“There’s this whole problem of, you give people an immunotherapy, it looks like it’s working, and then it stops working. We get recurrences or progression after some period, and the question is, why did that happen? How can you change it?” Greenberg said.

“This is where the science has come to play an important part: Is it because the immune response was working and somehow the tumor turned it off? And if that’s the case, then we have to look at ways in which we can reactivate the immune system,” he said. “Or is it not that, is it just that the immune system did what it’s supposed to do, but now a variant grew out, now a tumor grew out that’s no longer recognized by the immune response you are enforcing? If that’s the case, then we need ways to build subsequent immune responses to tackle that.”

Therefore, researchers have to better understand the behavior of not only the immune system but also cancerous tumors — and it’s no simple task.

“If there’s a perception that it’s easy, that’s a mistake. I think our lab has spent decades trying to figure out how to manipulate the immune response,” Greenberg said.

“Some patients are anticipating things to change overnight and be immediately available as a therapy. It takes quite a while,” he said, “but I’m quite certain immunotherapy is going to be enormously useful. It’s just, right now, we are limited in what can be done.”

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy

October, 2016|Oral Cancer News|