Cytoreductive surgery for head and neck squamous cell carcinoma in the new age of immunotherapy
Introduction
Patients with head and neck squamous cell carcinomas (HNSCC) have a relatively poor prognosis, which despite 5 decades of advancements in surgery, radiation therapy and chemotherapy, has not significantly improved. Recurrent/metastatic (R/M) HNSCC is especially challenging, regardless of HPV-status, and has few effective treatment options. HPV-negative HNSCC is associated with a local-regional relapse rate of between 19% and 35% and a distant metastatic rate of 14–22% following standard of care, compared to rates of 9–18% and 5–12% respectively for HPV-positive HNSCC [1], [2], [3]. The median overall survival for patients with R/M disease is 10–13 months in the setting of first line chemotherapy and 6 months in the second line setting. The current standard of care is platinum-based doublet chemotherapy with or without cetuximab. Second-line standard of care options include cetuximab, methotrexate, and taxanes. All of these chemotherapeutic agents are associated with significant side effects and only 10–13% of patients respond to treatment. HNSCC regressions from existing systemic therapies are transient, do not add significantly increased longevity, and virtually all patients succumb to their malignancy. Clinical trials should be a priority for these high-risk patients.
Complicating this situation in the head and neck region is that many patients with metastatic HNSCC suffer significant morbidity following treatment failure. Patients who develop local-regional disease progression in conjunction with distant metastasis have usually already received full course radiation therapy and therefore have few good palliative options available to achieve local tumor control and/or relieve symptoms other than surgery or re-irradiation. Surgical resection for previously untreated locally advanced disease offers benefit in terms of overall and disease free survival [4], [5], but is palliative in the setting of carotid artery involvement [5], [6], [7] or distant metastasis [8], [9], [10], with median survival of 3.6–13.5 months. Because of these discouraging statistics, surgeons have been reluctant to offer even palliative resections in the context of distant metastasis due to the ineffectiveness of systemic therapies. Therefore, patients with local recurrence often experience severe pain, bleeding, airway compromise, speech/swallowing dysfunction and death within one year of diagnosis, even though they may have low volume disease distantly.
Recent advances in immunotherapy are poised to transform the practice of oncology. In particular, adoptive cell transfer with tumor infiltrating lymphocytes [11], [12] or receptor-engineered T cells [13], [14], [15], [16], [17], [18], as well as checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte-associated protein-4 (anti CTLA-4) anti-programmed death-1 (anti PD-1), are resulting in durable responses in patients with numerous types of cancer [19], [20], [21], [22], [23], [24], [25], [26]. Two anti-PD-1 antibodies, nivolumab and pembrolizumab, have shown efficacy in clinical trials for R/M HNSCC and are poised for approval by the Federal Drug Administration (FDA) [27], [28]. These findings have ushered in a new era in the treatment of HNSCC and give cause to re-assess therapeutic approaches, as anti-PD-1 and other immunotherapies are integrated into standard of care (Table 1).
Section snippets
Cytoreductive surgery
Surgery remains the primary mode of treatment for most patients with HNSCC. In many oncologic settings, surgery is not attempted unless there is potential for complete removal of all cancer cells (an “R-0” resection). Nevertheless, many surgical approaches are accompanied by radiation therapy with or without chemotherapy to minimize the chance of local or distant recurrence from microscopic disease. By contrast, the goal of cytoreductive surgery is to minimize tumor-induced immune suppression
Summary
Cytoreductive surgery is an approach to cancer treatment that aims to reduce the number of cancer cells via resection of primary tumor or metastatic deposits, in an effort to minimize a potentially immunosuppressive tumor burden, palliate symptoms, and prevent complications. Furthermore, it provides a platform for investigation of biomarkers with the goal of optimizing immunotherapy to reverse the immunosuppressive tumor microenvironment and enhance adaptive immune responses. The utility of
Conflict of interest statement
The authors declare the following potential conflicts of interest:
Dr. Bell: Advisory Board: Janssen Research and Development, LLC; Consultant: Stryker CMF
Dr. Leidner: none
Dr. Crittenden: Consultant: Regeneron
Dr. Curti: Consultant: Prometheus
Dr. Jutric: none
Dr. Gough: none
Dr. Seung: none
Dr. Fox: Consultant/Advisory boards: MicroMet, MannKind, BioSante, Immunophotonics, Ventana/Roche, Dendreon, Perkin-Elmer, Definiens, Janssen Research and Development, LLC; Research support: Perkin-Elmer,
Acknowledgements
Funding sources: Oral and Maxillofacial Surgery Foundation Research Support Grant, Robert W. and Elsie Franz, Wes and Nancy Lematta, Lynn and Jack Loacker, and The Chiles foundation.
References (132)
- et al.
Neoadjuvant chemotherapy followed by surgery in very locally advanced technically unresectable oral cavity cancers
Oral Oncol
(2014) - et al.
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
Lancet
(2015) - et al.
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial
Lancet
(2014) - et al.
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, muticentre, phase 1b trial
Lancet Oncol
(2016) - et al.
Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: a randomized trial
Eur J Cancer
(2016) - et al.
Hyperthermic intraperitoneal chemotherapy and cytoreductive surgery in ovarian cancer: a systematic review and meta-analysis
Eur J Surg Onc
(2015) - et al.
European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon alfa-based immunotherapy compared with interferon alfa alone in metastatic renal cell carcinoma: a randomised trial
Lancet
(2001) - et al.
Population-based assessment of survival after cytoreductive nephrectomy versus no surgery in patients with metastatic renal cell carcinoma
Urology
(2009) - et al.
Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastatic renal cell carcinoma
J Urology
(1997) - et al.
The value of cytoreductive nephrectomy for metastatic renal cell carcinoma in the era of targeted therapy
J Urol
(2011)
The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy
J Urol
Tumor infiltrating lymphocytes and prognosis in oral cavity squamous cell carcinoma: a preliminary study
Oral Oncol
Out of sequence signal 3 paralyzes primary CD4(+) T-cell dependent immunity
Immunity
Downregulation of T helper type 1 immune response and altered pro-inflammatory and anti-inflammatory T cell cytokine balance following conventional but not laparoscopic surgery
Am J Surg
Surgical stress induces a shift in the type-1/type-2 T-helper cell balance, suggesting down-regulation of cell-mediated immunity commensurate to the trauma
Surgery
Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous cell carcinoma of the head and neck
N Eng J Med
Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer
N Eng J Med
Human papillomavirus and survival of patients with oropharyngeal cancer
N Eng J Med
Impact of surgical resection on survival in patients with advanced head and neck cancer involving the carotid artery
JAMA Otolaryngol Head Neck Surg
The impact of surgery in the management of head and neck carcinoma involving the carotid artery
Laryngoscope
Palliative surgery for head and neck cancer with extensive skin involvement
Laryngoscope
Survival after distant metastasis in head and neck cancer
Anticancer Res
Surgical palliation for malignant disease requiring locoregional control
Ann Palliat Med
Quality of dying in head and neck cancer patients
Eur Arch Otorhinolaryngol
Adoptive cell transfer as personalized immunotherapy for human cancer
Science
Prospects for gene-engineered T cell immunotherapy for solid cancers
Nat Med
A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response
Clin Cancer Res
Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma
Clin Cancer Res
Chimeric antigen receptor T Cells against CD19 for multiple myeloma
N Engl J Med
Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma
J Clin Oncol
Chimeric antigen receptor T cells for sustained remissions in leukemia
N Engl J Med
Improved survival with ipilimumab in patients with metastatic melanoma
N Engl J Med
Pembrolizumab for the treatment of non-small cell lung cancer
N Engl J Med
Nivolumab in previously untreated melanoma without BRAF mutation
N Engl J Med
Combined nivolumab and ipilimumab or monotherapy in untreated melanoma
N Engl J Med
Nivolumab versus docetaxel in advanced nonsquamous non-small cell lung cancer
N Engl J Med
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma
N Engl J Med
Nivolumab plus ipilimumab in advanced melanoma
N Engl J Med
Nivolumab vs investigator’s choice for recurrent or metastatic head and neck squamous cell carcinoma: CheckMate-141
Immunity to methylcholanthrene-induced sarcomas
J Natl Cancer Inst
Cytoredutive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma
Cancer J Clin
The role of surgery in metastatic gastrointestinal stromal tumors
Curr Treat Options Oncol
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with liver involvement
J Surg Oncol
Role of aggressive surgical cytoreduction in advanced ovarian cancer
J Gynecol Oncol
The role of cytoreductive surgery in the era of targeted agents
Curr Opin Urol
Cytoreductive surgery for pancreatic cancer improves overall outcome of gemcitabine based chemotherapy
Pancreas
Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma
J Clin Oncol
Sunitinib versus interferon alfa in metastatic renal-cell carcinoma
N Engl J Med
Sorafenib in advanced clear-cell renal-cell carcinoma
N Engl J Med
Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial
J Clin Oncol
Cited by (11)
Tumor microenvironment and immune-related therapies of head and neck squamous cell carcinoma
2021, Molecular Therapy OncolyticsCitation Excerpt :To solve this problem, there is a need to explore additional novel treatment strategies and identify potential treatment targets that can generate effective treatment options for HNSCC patients to improve outcomes and overall survival rates. To date, numerous studies have reviewed the use of different approaches to treat HNSCC, including the combination of surgery and immunotherapy,82 radioimmunotherapy,83 and a combination of chemotherapy and immunotherapy.84 In this review, we introduce classical immunotherapy and PD-1/PD-L1-related combination therapy, as well as molecules that regulate immunosuppressive cells.
Immunotherapy for Head and Neck Cancer
2019, Hematology/Oncology Clinics of North AmericaCitation Excerpt :Cytoreductive surgery aims to reduce the number of cancer cells via resection of primary tumor or metastatic deposits, in an effort to minimize a potentially immunosuppressive tumor burden, palliate symptoms, and prevent complications. Furthermore, specimens provide a platform for investigation of biomarkers to optimize immunotherapy, to reverse the immunosuppressive TME, and to enhance adaptive immune response.73 In mice models, Gough and colleagues51 have shown that surgical removal of a large primary sarcoma results in local recurrence in approximately 50% of animals.
Immunotherapy for Head and Neck Cancer
2019, Oral and Maxillofacial Surgery Clinics of North AmericaCitation Excerpt :Cytoreductive surgery aims to reduce the number of cancer cells via resection of primary tumor or metastatic deposits, in an effort to minimize a potentially immunosuppressive tumor burden, palliate symptoms, and prevent complications. Furthermore, specimens provide a platform for investigation of biomarkers to optimize immunotherapy, to reverse the immunosuppressive TME, and to enhance adaptive immune response.73 In mice models, Gough and colleagues51 have shown that surgical removal of a large primary sarcoma results in local recurrence in approximately 50% of animals.
Margin Analysis: Squamous Cell Carcinoma of the Oropharynx
2017, Oral and Maxillofacial Surgery Clinics of North AmericaCitation Excerpt :The favorable outcome may be contributed by a combination of the degree of surgical cytoreduction and the inflamed tumor microenvironment, thereby placing cytoreductive surgery as a viable surgical option to reduce tumor burden and decrease the burden of tumor-derived immunosuppression. It is feasible that surgical resection can be combined with immunotherapy to induce an effective immune response and overcome immunosuppression in the tumor microenvironment.64 Future directions will allow for a reliable and more accurate assessment of margins on a molecular level to guide precise excision.
Head and neck surgeons at the vanguard of immunotherapy
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