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An estimated 57 deaths per year in Ireland are from HPV-related oropharyngeal cancer
Clinicians are in the middle of a HPV pandemic with global hotspots in America, Europe and Australia, a head and neck cancer specialist told the recent Gathering around Cancer.
During an update on head and neck cancer at the meeting, Consultant Radiation Oncologist Dr Sinéad Brennan, who is the Principal Investigator of the Head and Neck Disease Specific Sub Group at Cancer Trials Ireland, said it is estimated that up to 70 per cent of all oropharyngeal cancer is HPV related.
“It is expected by 2030 that oropharyngeal cancers will constitute at least half of all head and neck cancers and will have surpassed the numbers of cervical cases per year,” she said.
“Head and neck cancer is often regarded as an orphan disease but it has had a bit more attention recently,” Dr Brennan added.
“In the new National Cancer Strategy it has been stressed that we need to pay more attention to the socio-economic inequalities in cancers such as head and neck cancer.”
A largely preventable cancer, the disease has received much media attention in Ireland due to the new Public Health (Alcohol) Bill, the recent introduction of plain cigarette packaging and the HPV vaccination saga.
Up until five or six years ago there were no clinical trials in head and neck cancer trials open in Ireland, said Dr Brennan, “but the cancer trials portfolio is looking a lot healthier these days”.
Citing a National Cancer Registry Ireland (NCRI) report released in May of this year, she noted HPV-related oropharyngeal cancer incidence rates are increasing by about 4 per cent per year.
“And on average each year we have 133 cases of HPV-related oropharyngeal cancer, 100 of which are in men. These cancers are predominantly treated with radiation treatment with approximately half of them getting recombinant chemotherapy and smaller numbers having surgery.”
The NCRI research found that between 2010 and 2014 there were an estimated 57 deaths per year from HPV-related oropharyngeal cancer. The majority, 44, were men.
“There is an increasing recognition that HPV is a sex neutral problem. However the vaccination rate in girls has dropped to less than 50 per cent so we can no longer rely on herd immunity and we need to give consideration to vaccinating boys,” Dr Brennan outlined.
There is an ongoing health technology assessment looking into providing the HPV vaccine for boys in Ireland, which is already in place in Canada and Australia.
Discussing HPV-positive patients, Dr Brennan said this cohort is younger, fitter and from a higher socio-economic class. They also have an increased number of sexual partners and a reduced smoking history.
“They have increased survival,” she pointed out.
“It is a very bulky disease but they respond better to radiation treatment and there is a high rate of complete response. Many of these patients are long-time survivors.”
She explained that this cohort has a higher radio-sensitivity and have intact p53-mediated apoptotic response. They also have a reduced lifetime exposure to cigarettes, have an absence of field cancerisation and some studies have indicated reduced second primary tumours.
However, HPV-negative disease has a poor prognosis and Dr Brennan stressed the need to intensify treatment above and beyond recombinant cisplatin radiation treatment, and to look at hypoxia-targeting agents and also immunotherapy.
As there is an excellent prognosis for HPV-positive disease, “the question is can we leave out the chemo, can we change the radiation?”, asked Dr Brennan, who is the Principal Investigator for several international trials in head and neck cancer.
“Are all HPV-positive tumours the same?” she asked.
“We all know from our clinical practice that some of these patients still do very, very badly despite the standard treatment so we need to identify sub-groups where it is safe to de-intensify treatment.”
She added that it is established that smoking can alter the behaviour of these tumours and responses to treatment
There have been a number of recent interesting studies looking into oropharyngeal cancer, including the UK-based De-ESCALaTE HPV. This study, which was examining whether the side effects of treating patients with oropharyngeal cancers with cetuximab chemoradiation are better than treating them with cisplatin chemoradiation, closed last year and the results are awaited.
“The next option is to look at the role of induction chemotherapy,” said Dr Brennan.
“The rationale behind this is we can use chemotherapy to select out patients that are going to respond well to treatment.”
Traditional surgery has not been used in treatment of oropharyngeal cancer due to the poor outcomes for speech and swallowing, however, with the advent of robotic surgery there could be a re-emerging role, Dr Brennan noted.
“There are lots of studies going on. The rationale behind the use of surgery in cases of oropharyngeal cancer is we can reduce the dose of radiation from 70 grade to 66, maybe even 60 grade, which would be adequate in the management of microscopic disease.
“And we can also use the pathological findings to decide on who may be suitable to select patients better for chemotherapy.”
The CompARE study is looking at different treatments for intermediate and high-risk oropharyngeal cancers.
A large study with multi-stage design trial, it has five arms: Standard chemo radiation; induction followed by chemo radiation; dose-escalated radiation; surgery; and immune therapy.
She also highlighted new American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guidelines for oropharyngeal squamous cell carcinoma (OPSCC).
Among the recommendations is that concurrent cetuximab or carboplatin-fluorouracil should be delivered to patients with stage IVA-B OPSCC receiving definitive radiation therapy who are not medically fit for high-dose cisplatin. This, Dr Brennan commented, is interesting.
“Standardly here in Ireland if patients aren’t suitable for cisplatin we tend to give them carboplatin alone,” she said.
“That doesn’t appear on the guideline at all.”
Concluding, she said for low-risk HPV-related oropharyngeal disease there is emerging evidence that there may be risk-adaptive approaches for using chemotherapy and surgery for deciding who may be suitable for lower-dose chemotherapy
Furthermore, concomitant chemotherapy cisplatin should be the standard of care, but she acknowledged that performance status is the main reason that prevents clinicians from doing this. Patients who are suitable could be offered other treatments such as carbo 5FU alone.
“We need to take smoking status into account as all HPV disease is not the same. It is very exciting time to be involved in head and neck trials,” Dr Brennan concluded.
There has been rapid progress in bladder cancer treatment over the last two years, Prof Ray McDermott, Consultant Medical Oncologist, St Vincent’s University Hospital, Dublin, outlined at the recent Gathering around Cancer.
“This progress is good news for patients and clinicians,” Prof McDermott, who was appointed Clinical Professor in Medical Oncology by UCD in 2016, told the meeting.
Citing the seminal study by von der Maase et al, ‘Gemcitabine and cisplatin vs methotrexate, vinblastine, doxorubicin and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomised, multinational, multicenter, phase III study’, which was published in the Journal of Clinical Oncology in 2010, Prof McDermott said that approximately 15 per cent of patients with metastatic disease are long-term survivors.
“These are survivors who live for a number of years on cisplatin-based chemotherapy,” he said, adding that if patients are suitable, they should receive cisplatin.
In terms of general principles, neo adjuvant is better than adjuvant and he reiterated that cisplatin-based treatment should be given where possible. Second-line therapy options have traditionally been poor, he added, and performance status and co-morbidities must dictate the disease’s management.
Regarding immunotherapy for urothelial carcinoma, Prof McDermott said it was not a new idea, citing the bacillus Calmette-Guérin (BCG) vaccine.
While the exact mechanism of action of BCG was unclear, three key steps were recognised: The internalisation of BCG into urothelial cells and cancer cells; the induction of immune reaction via cytokine release with increased APC; and the induction of anti-tumour effects.
“BCG has been around for years but it does work,” the Professor outlined. However, he acknowledged that there were limitations to BCG. There was limited efficacy and it was best in carcinoma in situ, with a ~50 per cent recurrence after induction and fewer effects on reduction.
Adverse events were also common, although usually mild, and the role for combination with interferon was not definite, Prof McDermott noted.
He also told the meeting that a number of drugs are being developed to treat this condition; ie, atezolizumab, pembrolizumab, durvalumab, nivolumab and avelumab, and these drugs represent a “game changer” in bladder cancer.
While Prof McDermott said it is currently unclear which drug might be superior, it is an exciting time in bladder cancer, he added.
“We’re seeing real differences,” he said. “We just want to use these drugs for our patients and the sooner we can do that the better.”
The successful fifth annual two-day Gathering around Cancer conference, which was attended by more than 300 delegates, was held in the Croke Park Conference Centre, Dublin, on 12-13 October, and attracted a host of leading international and national oncology experts.
Breast cancer screening must target high-risk groups as an age-alone selection criteria is no longer appropriate, the recent Gathering Around Cancer heard.
During the closing talk of the conference, Prof Maccon Keane, Consultant Medical Oncologist at Galway University Hospital, asked his colleagues to consider the cost of progress in breast cancer.
“Progress is difficult to define sometimes, but from my standpoint as a medical oncologist, real progress is reducing the death rate in this disease. That’s really what we’re about. Ultimately it is about ensuring that women don’t die from this disease,” he said.
However, breast cancer mortality has largely remained unchanged over the last 10 to 15 years despite what many people think of as progress, he added.
Data from the National Cancer Registry Ireland (NCRI), published this year, revealed that there has been a significant uplift in female breast cancer incidence for both invasive disease and in situ disease.
“Much of it is driven probably around the screening programme,” he said. “When you look at mortality, which has gone down somewhat, particularly from the late 1990s, between 2004 and 2013 these confidence intervals overlap and there hasn’t been a whole lot of change.”
Looking at the annual percentage increase, there has been a significant increase in the diagnosis of in situ disease, while invasive disease has also increased, but not as much.
“Mortality rates have gone down a little, about 2 per cent,” Prof Keane said. “I would suggest that an awful lot of what we have been doing has not had a real impact in what we would consider to be really progress.”
In terms of reducing breast cancer mortality, there are a number of things clinicians can do: Preventing the disease; diagnosing an incurable disease at a curable stage; converting an incurable disease to a curable one; and converting an incurable disease to a chronic illness.
Diagnosing an incurable disease at a curable stage is the goal of the screening service, he said “but if we take a look at screening and what it actually does, what I am suggesting is it doesn’t do this particularly well and the data very clearly demonstrates that”.
In terms of converting an incurable disease to a chronic illness, Prof Keane gave the example of HIV.
“In breast cancer where does that tipping point happen? It really happens when you go from localised disease to metastatic disease. So what you want to do is prevent this, or get it before it becomes incurable, or convert it to a chronic disease. And we’re really not there at all on any level.”
In terms of value versus cost, the health system wants high value for low cost, if possible, he stated.
“What we don’t want, and what we seem to do an awful lot, particularly in breast cancer treatment, is get low value for a very high price,” Prof Keane said.
Screening, when it started in the 1970s when there was little available therapeutically, was obstinately a really good thing to do, the meeting heard. The Irish biannual BreastCheck screening programme, which was established in 2000, has been extended to include women aged 65 to 69 years. It is based on mammography and attempts to identify tumours at a point they can be cured.
However, international data suggests that screening can lead to over diagnosis, Prof Keane said. According to Welch HG et al writing in the New England Journal of Medicine in 2016, since the introduction of widespread screening mammography in the US in the early 1980s, there has been an approximately 30 per cent increase in the incidence of all invasive breast cancers.
“And simultaneously in this, you had absolutely little or no change in the incidence of metastatic breast cancer,” said Prof Keane. Examining the data in detail, Welch et al revealed that the increase in incidence of small tumours exceeded the decline in incidence of large tumours by 132 per 100,000, suggesting over-diagnosis.
“When it comes to the effect of that screening in terms of mortality, they (the authors) took the same group of patients and looked at the case fatality reports. The mortality reduction due to treatment was 17 per 100,000, while the mortality reduction due to screening was about eight per 100,000, so it’s about half.
“So, in fact, screening did have a little benefit in terms of mortality but significantly less than therapeutics. And we have now committed a whole cohort of women to a diagnosis of breast cancer that they would never have had.
“The effect of this ultimately is that per case of breast cancer prevented by screening, appropriately 600 women will have a false-positive mammogram, 70 to 100 women will have an unnecessary biopsy and between three and 13 will be over-diagnosed with breast cancer that they didn’t need to have diagnosed at all.”
In the Irish context, BreastCheck is planning to screen approximately 108,000 women between 2017 to 2021. This expansion will see 72 WTE posts employed to roll out the plan. Prof Keane said it is important to note there is a benefit from this, but it may not be significant.
“Staging is an issue of real consequence to all of us every day in our clinics and there is a significant amount of staging that occurs all around the world in patients that really don’t need it. For a staging test to be of benefit, the consensus is that the pre-test for the positive predictive value needs to be in the order of about 1 per cent.”
In other words, about one in a hundred scans should identify an asymptomatic woman who has metastatic disease. “That becomes a reasonable cut off point at which to do any studies, otherwise your false-positive rate goes up, your unnecessary investigation rates go up and it’s really not worthwhile.”
Follow-up is a massive cost, the meeting was told and Prof Keane questioned its benefit.
“A patient comes to my clinic for two reasons – can I diagnose her relapse early and secondly, does she have a new breast cancer. When you examine it, there is no survival benefit to that woman arriving in my clinic asymptomatic. So if she is feeling perfectly well, other than a mammogram to identify if a new cancer has arisen, there is no benefit in terms of her long-term survival for anything that I do.”
The goal for follow-up should be access to very prompt investigations for new symptoms and that will significantly reduce the anxiety, cost and the number of non-beneficial investigations that are currently being done. In terms of who should be carrying out the follow-ups, there is no difference between specialist versus primary care in terms of outcome, Prof Keane said.
“So an enormous amount of what we are currently spending on follow-up really isn’t necessary at all,” he said.
Ductal carcinoma in situ (DCIS) has escalated dramatically in terms of the number of patients affected, Prof Keane highlighted. The standard of care for this disease currently is surgery followed typically by radiation therapy, the Professor said. However, he added that the benefit of radiation in DCIS is exceptionally small.
“The benefit of surgery in DCIS is a whole other question,” he commented.
He referenced a 2015 study published in the Journal of Clinical Oncology, entitled ‘Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study’. This study by Solin LJ et al looked at two cohorts of patients, those with low or intermediate grade DCIS with a tumour size of 2.5cm or smaller (cohort one), and those with high-grade DCIS with a tumour size of 1cm or smaller (cohort two).
The authors found that the 12-year rate for an ipsilateral breast event (IBE) in cohort one was 14.4 per cent and for invasive IBE 7.5 per cent. In cohort two for IBE the rate was 24.6 per cent and for invasive IBE it was was 13.4 per cent.
Prof Keane said that the results of the LORIS (the low-risk DCIS) trial will be very interesting. Its objective is to assess whether active monitoring is non-inferior to surgery, in terms of ipsilateral invasive breast cancer-free survival time. This study will see women who have low or intermediate grade DCIS on a biopsy being randomising to monitoring versus surgery.
In conclusion, Prof Keane said that while there are many women who believe that they have been cured of breast cancer, they may have received medical interventions for a condition that they may never have needed to be diagnosed with.
“The evidence for this is that the five-year survival rate of this disease has flatlined overall, over the last decade,” he said.
The need to screen high-risk groups is evident, he added, but it is very clear that screening by age alone is no longer appropriate.
“We need to screen for lethal disease. The disease that kills most women with breast cancer is HER-2 positive disease and triple negative disease. Our current screening tool is so out-of-date, that all it picks up is pre-malignant conditions and conditions that are actually not relevant in the long-term survival. Certainly this tool needs to be replaced.”
When it comes to the treatment of women with metastatic disease, the focus must be on reducing the death rate.
“We certainly need to be targeting the high-risk trials in the adjuvant setting,” he said. “We also need to be focusing on the cured adjuvant patients….There has been very little work done identifying the factors that make those women survive having got chemo or any other intervention.”
In conclusion, Prof Keane called on his colleagues to always question the “dogma” of guidelines and look at primary level one data.
We need to follow the evidence regardless, he said, and called for appropriate education of clinicians and patients on the benefits of available treatments.
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