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11th September 2023
Two genes appear to be responsible for conferring chemoresistance in the majority of drug-resistant cell strains of patients with head and neck cancers, and silencing either gene leads to a complete reversal of drug resistance, researchers at Queen Mary University of London (QMUL) have found.
In the study, published in the journal Molecular Cancer, the team used transcriptome data-mining to identify potential genes that may be affecting tumour responsiveness to drug therapy. They identified a total of 28 genes in 12 strains of chemoresistant cell lines each against cisplatin, 5-fluorouracil, paclitaxel and docetaxel chemotherapies.
A total of 10 multi-drug chemoresistance genes were identified, four of which – TOP2A, DNMT1, INHBA and NEK2 – were up-regulated in a cohort of 221 head and neck cancer patients.
The INHBA and NEK2 genes appeared to be pan-cancer prognostic markers for predicting poor survival outcome in the majority of cancer types. But the team also identified two compounds – sirodesmin A and carfilzomib – from drug library screens, which were able to target both INHBA and NEK2 and re-sensitise cisplatin-resistant cells.
Dr Muy-Teck Teh, senior author of the study from QMUL, said: ‘These results are a promising step towards cancer patients in the future receiving personalised treatment based on their genes and tumour type that give them a better survival rate and treatment outcome.
‘Unfortunately, there are lots of people out there who do not respond to chemotherapy or radiation. But our study has shown that in head and neck cancers at least it is these two particular genes that could be behind this, which can then be targeted to fight against chemoresistance.‘
In Europe, head and neck cancers affect around 22 people per 100,000. While the cure rate is high for early-stage disease, around two-thirds of patients present with advanced-stage disease with a poor survival outcome. An additional and important cause of treatment failure leading to a poor survival, is the development of resistance to chemo and/or radiotherapy, although the underlying genes responsible for chemoresistance have previously been unclear.
31st October 2022
A deep learning algorithm (DLA) has been found able to better predict pathologic microscopic and macroscopic extranodal extension (ENE), indicative of cancer spread, than radiologists according to the findings of a study presented at the World Cancer Congress, 2022.
Worldwide, head and neck cancers account for approximately 900,000 cases and over 400,000 deaths annually. Typically, treatment strategies consist of radiation with or without chemotherapy or upfront surgery followed by adjuvant radiation with chemotherapy. ENE, and which is also referred to extracapsular extension or extracapsular spread, occurs when metastatic tumour cells within the lymph node break through the nodal capsule into surrounding tissues. Moreover, in locally advanced head and neck cancer, extracapsular spread of the tumour from neck nodes is a significant prognostic factor associated with a poor outcome. A further problem is that ENE can only be reliably diagnosed from postoperative pathology and if present, warrants adjuvant treatment intensification with the addition of chemotherapy to radiation therapy. The presence of ENE can be determined from CT scans although the method is not very accurate. Nevertheless, in a previous study, the same researchers developed a deep learning algorithm that enabled the prediction of ENE with an area under the receiver operating characteristic curve (AUC) of 0.91, prompting the authors to conclude that such a model has the potential for use as a clinical decision-making tool to help guide head and neck cancer patient management.
But could this same deep learning-based model be generalisable to more high-risk patients, was the question addressed in the present study. The team turned to data collected as part of the E3311 trial, which was a phase II randomised trial of reduced- or standard-dose postoperative radiotherapy for high-risk patients with resected stage III-IVa, human papillomavirus associated (HPV+), oropharynx cancer (OPC). Using pre-treatment CT scan information and corresponding surgical pathology reports from E3311 patients, researchers designated patients as being at high-risk if there was ≥1 mm ENE and such individuals were assigned to chemotherapy and high-dose radiation following transoral surgery. The predictive ability of the model was assessed using the area under the curve (AUC) and four head and neck radiologists were used for comparative purposes.
Deep learning algorithm and prediction of ENE
From a total of 177 scans, 311 lymph nodes were annotated and of which, 23% had ENE and 13% had ENE >1 mm.
The deep learning algorithm accurately classified 85% (95% CI 80 – 89%) of the nodes as having ENE whereas the highest AUC for a radiologist was 70% (64 – 76%). The model was also better than all four radiologists for the detection of ENE >1 mm (model AUC = 85% vs a mean of 68% for the radiologists, p < 0.001).
The authors concluded that their model showed a high performance for predicting pathologic microscopic and macroscopic ENE in a cohort of patients with HPV-OPC from a prospective clinical trial, substantially outperforming expert head and neck radiologists. They added that the model should be evaluated in a clinical trial with the goal of reducing tri-modality (i.e., surgery, radiation, or chemotherapy) therapy.
Citation
Kann BH et al. Screening for Extranodal Extension with Deep Learning: Evaluation in ECOG-ACRIN E3311, a Randomized De-Escalation Trial for HPV-Associated Oropharyngeal Carcinoma. No 141. World Cancer Congress, 2022
18th October 2022
Irma Verdonck-de Leeuw originally graduated as a psychologist, speech pathologist and linguist and is now Professor of Psychosocial Oncology at the University Medical Centre Amsterdam. She spoke with Hospital Healthcare Europe about head and neck cancer and, in particular, the recently published European Head and Neck Society recommendations for head and neck cancer survivorship care.
Professor Verdonck-de Leeuw leads the head and neck team at the University Medical Centre Amsterdam, which has seven surgeons, three radiologists dedicated to head and neck cancers and two medical oncologists. There’s also a multi-disciplinary team that includes speech pathologists, physiotherapists, dieticians, psychologists and social workers. It is a busy department that sees around ‘500 new head and neck cancer diagnoses every year’. However, the caseload comprises a mix of new and returning patients and at a weekly outpatient clinic, staff can see ’40-50 patients for their follow-up care on a clinic day’.
According to Professor Verdonck-de Leeuw, there are approximately ‘3,200 new head and neck cancers diagnosed every year in the Netherlands and the care is centralised in the university medical centres and the cancer centre.’ Across the whole of Europe, she says the incidence of head and neck cancers is around 22 per 100,000 and believes that globally, such cancers are the fifth or sixth most common.
The high incidence is a likely reflection of the heterogenous nature of the cancers in the head and neck area, such as those originating in mucosa of the oral cavity, throat, nose or larynx, which are distinct and relatively rare types of cancer.
She described how smoking and excessive alcohol use are important lifestyle causative factors adding that infection with the human papilloma virus (HPV) has, over the last 15 years or so, also become a recognised risk factor for throat cancer. She mentioned how head and neck cancers, particularly among those who smoke or misuse alcohol are more common in those belonging to a lower sociodemographic group. In contrast, those infected with HPV tend to be younger and more educated. Interestingly, she noted that in this latter group ‘their tumours often respond better to the treatment and the side effects are often less in this population.’
Professor Verdonck-de Leeuw described how typically, ‘patients present with a complaint of a sore tongue, pain in the throat, a hoarse voice, a blocked nose, a lump in the neck or a problem with swallowing.’ While these symptoms might have other potential causes, she added that it was more likely to be a cancer, particularly where the duration of symptoms exceeded three weeks. In fact, she says that such symptoms should be considered red flags and a prompt to both patients and clinicians of a potential problem that warrants referral to a specialist.
Although patients are usually referred by their GP, an alternative route is via a dentist, who, after an oral examination, might spot something unusual and have a suspicion about cancer. She also mentioned that head and neck cancers are very rare below the age of 40 and that the mean age of affected patients is about 61 years of age.
Overall survival rates for head and neck cancer, she says, are between 55% and 60%. However, this is highly dependent upon the stage at which the cancer is detected and this is largely driven by patients’ symptoms. For instance, a cancer of the vocal cords is more likely to be picked up at an earlier stage, simply because patients seek medical advice over the continued presence of hoarseness, such that the survival rate can be as high as 90%.
In contrast, patients with a cancer in the hypopharynx or the oral cavity are often asymptomatic and once symptoms occur, the cancer is more likely to be at an advanced stage, such as 3 or 4, and thereby having a worse prognosis.
Professor Verdonck-de Leeuw described that once a patient receives a cancer diagnosis and begins a course of treatment, there are inevitably a number of concerns, including an initial ‘uncertainty over whether the treatment is going to work, together with the burden of side effects from therapy.’
She explained how adverse effects are particularly burdensome because the cancer might affect an individual’s ability to speak or swallow. This has a potentially huge impact not only upon the patient but also on other family members or carers, especially if the patient is unable to communicate their feeling or concerns. Such cancers also negatively impact a patient’s social life, as meeting friends for drinks or meals can create difficulties.
Professor Verdonck-de Leeuw noted that prior to developing the new guideline, the only other available was published in 2018 and was US-based. As there are inherent differences between the US and European healthcare systems, the US guidelines seem inappropriate for European clinicians and hence required an update. She added that ‘in the US, most aftercare is provided within primary care whereas centralised care, as in Europe, seems better.’
The drive to develop the new guidelines came from the European Head and Neck Society and a steering committee within the society that organises the ‘Make Sense’ campaign. The focus of the campaign is not only to increase awareness of head and neck cancers but also to improve clinical practice. Consequently, the working group performed a literature review and produced the new guideline. Professor Verdonck-de Leeuw explained that the literature review had identified a growing body of work on supportive care for patients, which was subsequently incorporated into the new guideline.
While the guideline contains a large number of recommendations, such as an emphasis on the importance of patient surveillance to ensure that the cancer had either not undergone metastases or returned, equally relevant is an emphasis on the physical and pysycho-social aspects of care. As she explained, ‘the care of cancer patients is so complicated and there are so many things that require attention.’
Professor Verdonck-de Leeuw considers one of reasons why patients with head and neck cancers still have so many unmet needs is related to supportive care, ‘because not all of these topics can be addressed during visits to the clinic’. It was necessary for clinicians to remain cognisant of the fact that patients are unique and the supportive care offered needs to be tailored to the individual.
A key recommendation is the importance of providing more tailored psycho-social support to patients, which prompts an enhanced ability to cope and to live their lives again after treatment. As she said, ‘patients may continue to experience many difficulties such as swallowing problems, speech problems, fatigue, pain, or whatever, and it’s vital to address these symptoms.’
Furthermore, it is equally important to ‘consider the psychological problems, as sometimes patients can become depressed and very anxious that the tumour might return.’ Whilst psycho-social care was designed to be supportive, a further aspect was to increase patient resilience using various evidence-based interventions.
Another component of aftercare that is often not acknowledged and absent she feels, is encouraging patients to adopt a more healthy lifestyle by, for example, stopping smoking or reducing alcohol intake.
Continued support is also needed for those who might have had a complete removal of the larynx and are unable to speak. Despite improvements in voice prostheses that create a voice to the patient, the new voice will be different and this, too, can become a problem for patients and requires some degree of ongoing support.
Professor Verdonck-de Leeuw strongly believes that given differences in the level of care provided across Europe, the new guideline will ultimately allow clinicians to improve their practice. She saw it was necessary for the guideline group to include clinicians from across Europe to enable the collation and sharing of best practice. Whilst the importance of interventions such as smoking cessation being incorporated into aftercare were accepted, identifying the source of funding for these services was a potential barrier.
Professor Verdonck-de Leeuw recognised that there may be economic consequences associated with implementing the new guideline. As she explained, ‘in the short-term the cost for head and neck cancer care may increase and the question is whether the increased costs will occur at the hospital or can we refer patients to healthcare professionals outside of the hospital’.
A further uncertainty was ‘whether the investment in optimal supportive care for cancer patients can decrease clinical costs such as a reduction in hospitalisation or GP visits’. Nevertheless, she was hopeful that ‘the investment in clinical care may well have a social impact, in that patients can return to work much earlier and achieve greater benefits in their social life’. Despite the possible economic effects, she does believe that adherence to the new guideline will help to meet the majority of patients’ needs.
The guideline recommends that patients are seen approximately every two months in the first year after therapy, reducing to half yearly or annually later, although this schedule is somewhat dependent on the individual patient. She feels that one of the more positive effects of the Covid-19 pandemic was that we learned that much of the workload of clinical staff could be undertaken remotely.
She added that although there was an initial reluctance on the part of clinicians to make greater use of digital technology, the pandemic meant that it was effectively non-negotiable. But, with hindsight, it seemed that the process worked well. Moving forwards, she feels that ‘we can use digital care to improve, tailor and personalise the care that people need and will lead to much less unmet needs’.
Professor Verdonck-de Leeuw mentioned how her own centre is actively looking at the guideline recommendations to explore if the level of patient care can be improved, in particular, through greater use of digital care.
Another aspect and which forms part of her current research, is if greater self-management enables patients to better manage themselves. Although peer support is often vital for some patients, for others, the input of psychologists is unnecessary provided they have access to the necessary tools to self-manage more effectively.
Professor Verdonck-de Leeuw imagines that the first step is to learn about the impact of the guideline throughout Europe. Equally important is an assessment of the economic impact, as she explained ‘we know that the healthcare resources will decrease and that the number of patients will increase and, while there is already a problem, this will be much bigger in the future. We really need other kinds of support such as digital care, peer-support and self-management to improve so that in the future, head and neck cancer care can be sustainable.’
A further anticipated difficulty is that there is a lack of healthcare professionals required to deal with the likely increase in the number of patients requiring treatment and support. She believes sustainability will also be compromised by a higher number of patients visiting clinics, but this can be mitigated to some extent through more remote care. She also sees a benefit from tele-consultations in that they allows psychologists to see how and where people live, providing greater insight into patients’ social circumstances.
Professor Verdonck-de Leeuw feels that the purpose of the guideline was to outline best practice care and to ensure that sufficient psycho-social support is in place. She also believes that immediate introduction of all the recommendations would be a daunting, possibly unnecessary, task for clinicians. A more pragmatic approach would be for centres to initially incorporate those recommendations that are easily achievable, building upon current practice, and assessing the impact and progressing gradually but with the ultimate goal of achieving full implementation in the future.
29th March 2022
Matching cancer patients to treatment based on their levels of a key immune protein may allow clinicians to select those who would benefit most from the combination of immunotherapy and chemotherapy, according to research among patients with head and neck cancer.
The study found patients benefited from different treatments depending on the results of a test measuring levels of the protein PD-L1 in tumours and on surrounding cells. The researchers hope use of the test will be adopted in guidelines as a way to personalise patients’ treatment by selecting immunotherapy, chemotherapy or the combination of the two depending on PD-L1 levels.
Immunotherapy has transformed treatment of head and neck cancer and several other cancer types – but there are still major difficulties in predicting who will respond best and so personalising treatment effectively.
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust analysed data from the major KEYNOTE-048 trial to assess whether they should be treated with a combination of the immunotherapy pembrolizumab and chemotherapy.
Out of the 882 people involved in the trial, 373 had a moderate PD-L1 score between 1 and 19. Among people in this group, pembrolizumab on its own or with chemotherapy was able to stop tumour growth in many patients.
However, it was the pembrolizumab-chemotherapy combination that led to a longer overall survival – 12.7 months, compared with 9.9 months for the comparator of cetuximab plus chemotherapy. The latest results, together with previous findings from the trial, suggest that three different approaches to treatment should be considered, depending on PD-L1 levels.
Patients with low levels of PD-L1 are highly unlikely to benefit from pembrolizumab alone, and should receive chemotherapy alone or chemotherapy plus cetuximab. Patients with moderate levels of PD-L1 may benefit most from a pembrolizumab and chemotherapy combination, and those with high levels of PD-L1 may benefit most from pembrolizumab alone.
This led to differing regulatory approvals of pembrolizumab across the globe as a first-line treatment for patients with relapsed head and neck cancer, based on a PD-L1 scoring system. In England, NICE recommended pembrolizumab alone for patients with moderate or high levels of PD-L1.
But the new findings suggest patients with moderate levels of PD-L1 may have better outcomes if they also receive chemotherapy. Overall, they support use of the PD-L1 test, which is cheap and reliable, to target pembrolizumab’s use more precisely than before in relapsed head and neck cancer.
Researchers cautioned that some of the results should be interpreted carefully, given the small number of participants with a PD-L1 score of less than 1, and that additional biomarkers are needed to further select patients who could benefit from pembrolizumab.
Study leader Professor Kevin Harrington, Professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“We have found that patients with head and neck cancer benefit from different approaches to treatment depending on the levels of a key immune protein in the tumour and among the surrounding cells. This new, more refined interpretation of the PD-L1 test should give clinicians a much clearer indication of which patients are most likely to benefit from immunotherapy alone and who should be considered for immunotherapy in combination with chemotherapy.
“Our new findings suggest people with a moderate PD-L1 score would benefit more from a combination of pembrolizumab plus chemotherapy. Currently, NICE has only recommended pembrolizumab on its own for this group of people, so I hope our new evidence will be taken into account and potentially change care for people in England and Wales.”
Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:
“Smarter tests to identify patients who are most likely to respond to treatment are a key aspect of precision medicine and are urgently needed for immunotherapies. Tests like these can help improve outcomes for patients and make sure we don’t subject people who are unlikely to respond to treatments that won’t benefit them.
I hope our new study can improve care for patients with head and neck cancer by helping to optimise treatment depending on test results.”
Mr Richard John, a head and neck cancer patient at The Royal Marsden with high levels of PD-L1, said:
“My PD-L1 test was over 20, which meant I was treated with pembrolizumab, a form of immunotherapy, on its own. I am now in complete remission and so grateful to have benefitted from this study at The Royal Marsden and the ICR. It is such a relief that I didn’t have to undergo any additional treatments, such as chemotherapy, which wouldn’t have done any more for me than having immunotherapy on its own.
The understanding about what treatments are best suited to each individual is transformative for patients like me, meaning we do not have to spend any more time in hospital or dealing with side effects of treatment than is necessary.”
The research which is published in the Journal of Clinical Oncology was funded by the drug’s manufacturer, Merck & Co., Inc., known as MSD outside the US and Canada.
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