J.B. Vermorken MD, PhD

Immune-modulating antibodies in head and neck cancer: past, present, and future

Squamous cell carcinoma of the head and neck (SCCHN) has recently expanded the growing range of oncologic diseases successfully treated with immune-modulating agents. With the origins dating back to the nineteenth century, the concept of immunotherapy was repeatedly revisited and refined but also rejected and criticized. Currently, its armamentarium comprises tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating antibodies. Among these approaches it has been the latter one drawing major attention from healthcare professionals. Nivolumab and pembrolizumab are monoclonal immunoglobulins directed against programmed cell death protein-1 (PD-1), an immune-checkpoint negatively regulating T-cells. In second-line recurrent and/or metastatic SCCHN, two phase III studies demonstrated meaningful clinical benefit achieved by these drugs, dubbed checkpoint inhibitors, compared with standard monotherapy (methotrexate, docetaxel, or cetuximab). In the CheckMate-141 trial, nivolumab significantly improved median overall survival (OS) from 5.1 to 7.5 months. A similar benefit achieved by pembrolizumab in KEYNOTE-040 fell short of statistical significance (8.4 vs. 6.9 months), probably due to post-study immune-checkpoint therapy leading to a better-than-expected survival in the control arm. However, the classical outcome measures do not fully capture the exceptional activity of these agents. Apart from low frequency of severe adverse events (13% vs. 35% with standard therapy), these antibodies can induce durable tumour responses and retain activity even after several previous chemotherapy lines. With their advent in first-line palliative regimens and protocols for locally advanced disease, further progress is expected. Reliable predictive biomarkers are urgently needed, and several candidates are being evaluated. Among them, tumour mutational burden and gut microbiota offer an innovative approach to biomarker-enrichment strategies.

The role of chemoradiotherapy in elderly patients with locoregionally advanced head and neck cancer

Paralleled by rising cancer burden, recent global demographic changes have been marked by a constantly growing number of people aged 65 or more. In the United States, presently 54% of malignant head and neck cancer cases occur in the geriatric population, and by 2030, this proportion is expected to attain 66%. Despite the obvious importance of addressing specific needs of elderly patients, these individuals have often been undertreated and refrained from geriatric assessment in clinical practices and underrepresented in prospective trials. Unfortunately, many health care professionals still believe that older patients cannot tolerate intensified treatment regimens. In this paper, we focused on concurrent chemoradiation as definitive or post-operative treatment in locoregionally advanced squamous cell carcinoma of the head and neck. Although confirmatory data from large randomised phase III trials conducted in the elderly are lacking, available evidence from meta-analyses of prospective trials and retrospective reviews of population-based cross-sectional registries indirectly support this approach, primarily in the definitive treatment setting. However, irrespective of calendar age, distinction between fit and frail senior patients is of paramount priority. In this respect, several geriatric screening tools have been developed for use by practicing physicians to help select which patients need a comprehensive geriatric assessment, who requires a specific examination only (e.g. focused on certain comorbid conditions, cognition, nutritional status, social support, or psychological state), and where no further testing is warranted.

(BELG J MED ONCOL 2018;12(3):110–117)

Locally advanced cancer of the uterine cervix: Diagnosis and multidisciplinary treatment

Patients treated for locally advanced cancer of the uterine cervix, FIGO stages IB2 to IVA, may expect a 5-year survival varying from 75% to 16%, respectively. Even though screening programs in Latin America and the Caribbean were established since the 1960´s, advanced stages continue to impact mortality in these countries. Morbidity and quality-of-life are compromised because most of the patients present with symptoms in these later stages. It is crucial to accurately determine tumour size and extension to surrounding organs, not only to establish prognosis, but also for therapy planning. Positron emission tomography combined with computed tomography is the preferred imaging modality but magnetic resonance imaging has high accuracy characterising the primary lesion. Concurrent cisplatin-based chemoradiotherapy is the standard nonsurgical approach, with a relative risk of death of 0.81 compared to the same radiation therapy alone, showing an absolute survival benefit at five years of 6%. Before or after chemoradiation, additional systemic therapy could be used to improve outcomes in patients with locally advanced cancer of the uterine cervix.

(BELG J MED ONCOL 2018:12(3):118–124)

Immune-modulating antibodies in head and neck cancer: past, present, and future

Squamous cell carcinoma of the head and neck (SCCHN) has recently expanded the growing range of oncologic diseases successfully treated with immune-modulating agents. With the origins dating back to the nineteenth century, the concept of immunotherapy was repeatedly revisited and refined but also rejected and criticized. Currently, its armamentarium comprises tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating antibodies. Among these approaches it has been the latter one drawing major attention from healthcare professionals. Nivolumab and pembrolizumab are monoclonal immunoglobulins directed against programmed cell death protein-1 (PD-1), an immune-checkpoint negatively regulating T-cells. In second-line recurrent and/or metastatic SCCHN, two phase III studies demonstrated meaningful clinical benefit achieved by these drugs, dubbed checkpoint inhibitors, compared with standard monotherapy (methotrexate, docetaxel, or cetuximab). In the CheckMate-141 trial, nivolumab significantly improved median overall survival (OS) from 5.1 to 7.5 months. A similar benefit achieved by pembrolizumab in KEYNOTE-040 fell short of statistical significance (8.4 vs. 6.9 months), probably due to post-study immune-checkpoint therapy leading to a better-than-expected survival in the control arm. However, the classical outcome measures do not fully capture the exceptional activity of these agents. Apart from low frequency of severe adverse events (13% vs. 35% with standard therapy), these antibodies can induce durable tumour responses and retain activity even after several previous chemotherapy lines. With their advent in first-line palliative regimens and protocols for locally advanced disease, further progress is expected. Reliable predictive biomarkers are urgently needed, and several candidates are being evaluated. Among them, tumour mutational burden and gut microbiota offer an innovative approach to biomarker-enrichment strategies.

TPFE (docetaxel, cisplatin, 5-FU and cetuximab) for recurrent mucoepidermoid carcinoma of the parotid gland: an aggressive strategy for an aggressive disease

SUMMARY

The prognosis of patients with advanced malignant salivary gland cancer is usually poor. Systemic therapy combined with best supportive care is recommended for patients with metastatic or recurrent advanced salivary gland cancer ineligible for surgery or radiotherapy. Sensitivity to chemotherapy is thought to be histotype specific. However, to date, none of the systemic therapies, whether cytotoxic or non cytotoxic, can be considered standard for these tumours.

We report the case of a 43 year-old male patient with a third (loco)regional recurrence and metastases in lymph nodes below the clavicles of a mucoepidermoid carcinoma of the right parotid gland. He participated in a feasibility study and was treated with 3-weekly cycles of docetaxel, cisplatin, 5-fluorouracil plus weekly cetuximab (TPFE). After four TPFE cycles, additional radiation was given to the left neck. A complete response was reached which is ongoing for ten years. TPFE induced acute toxicities: skin rash grade 3, hypotension grade 3, neutropenia grade 3, anaemia grade 2 and alopecia grade 2. This observation underlines the importance of offering patients the possibility to participate in clinical trials. International collaboration for rare head and neck cancers, such as mucoepidermoid carcinoma, is urgently needed.

(BELG J MED ONCOL 2017;11(8):386-392)

Recurrent and metastatic non-nasopharyngeal head and neck cancer: state of the art of systemic treatment

Summary

The majority of patients diagnosed with recurrent and/or metastatic squamous cell carcinoma of the head and neck are deemed ineligible for surgery or irradiation. Their management prioritise symptom control and quality-of-life improvement. According to patient’s performance status, medical comorbidities and symptoms, recommended treatment options include supportive care only, mono- or multi-drug chemotherapy or cetuximab (epidermal growth factor receptor inhibitor) either alone or as an adjunct to cytotoxic drugs. Despite achieving response rates superior to single-agents, doublet and triplet regimens incorporating cisplatin and/or taxanes did not increase overall survival and were often difficult to tolerate. The platinum (cisplatin or carboplatin)/5-fluorouracil/cetuximab regimen is the only regimen showing significant survival improvement over PF alone in a large randomised trial, and therefore is the only approved new standard systemic treatment today. However, the very poor overall survival of six to ten months expected in this patient population, remains a continuous challenge and novel anticancer therapies are urgently needed. The potential to induce durable responses with manageable toxicity has propelled immunotherapy to the forefront of cancer research, yet its validation in phase III clinical trials is pending. Another crucial task is the identification of reliable, prospectively confirmed prognostic and predictive biomarkers. Mounting evidence from retrospective analyses suggests that human papillomavirus status with p16 immunohistochemical positivity as its surrogate represent promising candidates for this role.

(BELG J MED ONCOL 2016;10(6):207–214)

Targeted therapy for the treatment of head and neck squamous cell carcinomas: hopes and pitfalls

Targeted therapy is a promising strategy for the treatment of head and neck squamous cell carcinoma and other cancers, which has been developed as a result of breakthroughs in molecular characterisation of carcinogenesis. It is thought to offer a higher therapeutic index and, therefore, to be associated with less toxicity than cytotoxic drugs. Unfortunately this kind of therapy also has weaknesses; in particular the long-term response rate is disappointing. This review will not only focus on the benefits of EGFR targeted agents in head and neck squamous cell carcinoma, but will also summarise its weaknesses.

(BELG J MED ONCOL 2015;9(5):175–78)