Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide ...per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.
Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether ...reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.
In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).
Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% (
= .04). For IMRT, 2-year PFS was 87.6% (
= .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6%
52.4%;
< .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% (
= .56).
The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.
Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. Although human papillomavirus (HPV)-associated HNSCCs have better overall ...survival compared with HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however, multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016, the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum-based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immunomodulation in HNSCC pathogenesis, response to treatment, and disease control. However, although immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.
Although the number of cancer survivors has increased substantially over the past several decades, the composition of survivors treated with radiotherapy is not well defined. Radiotherapy carries ...unique long-term toxicity risks for cancer survivors. This study describes the current estimates and future projections of the epidemiology of 5-year cancer survivors who receive radiation therapy.
We used cancer incidence and survival data from the Surveillance, Epidemiology, and End-Results (SEER) database linked to U.S. Census data to estimate the number of 5-year cancer survivors treated with radiation between 2000 and 2030. Future projections assumed continuing incidence and survival trends based on historical rates.
In 2016, there were an estimated 3.05 million cancer survivors treated with radiation, accounting for 29% of all cancer survivors. The number of radiation-treated cancer survivors is projected to reach 3.38 million by 2020 and 4.17 million by 2030. In 2016, breast (40%) and prostate cancer (23%) composed the majority of radiation-treated survivors, followed by head and neck cancer (5.8%), lymphoma (5.6%), uterine (3.9%), and rectal cancer (3.8%). The percentage of 70 years or older radiation-treated survivors steadily increased between 2000 and 2030.
The next several years are projected to see a large increase in the number of cancer survivors treated with radiation.
This group of cancer survivors has unique needs given the long-term risks of radiation, and increased research and awareness are required to optimize health of this growing population.
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Summary Despite recent advances in novel therapies, the prognosis for patients with squamous cell carcinoma of the head and neck (SCCHN) remains poor. Progress in understanding the biology of cancer ...has led to the development of personalized therapy targeted at blocking defective signaling pathways of cancer cells. These drugs aim to act selectively to reduce the adverse effects associated with systemic therapy. Cetuximab (Erbitux®), an anti-epidermal growth factor receptor gene ( EGFR )-targeted agent, is the only approved targeted therapy for patients with SCCHN. However, resistance to EGFR therapy remains a major obstacle to achieving a positive clinical outcome with cetuximab. Other therapies that offer better clinical outcomes in patients with advanced SCCHN are urgently needed. The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway, which is downstream of EGFR, has also been implicated in SCCHN development and progression, and therefore, targeting this pathway offers another rational treatment approach. This review discusses the potential role of PI3K pathway inhibitors in the treatment of patients with advanced SCCHN, both alone and in combination with other therapies.
To demonstrate an efficient method for training and validation of a knowledge-based planning (KBP) system as a radiation therapy clinical trial plan quality-control system.
We analyzed 86 patients ...with stage IB through IVA cervical cancer treated with intensity modulated radiation therapy at 2 institutions according to the standards of the INTERTECC (International Evaluation of Radiotherapy Technology Effectiveness in Cervical Cancer, National Clinical Trials Network identifier: 01554397) protocol. The protocol used a planning target volume and 2 primary organs at risk: pelvic bone marrow (PBM) and bowel. Secondary organs at risk were rectum and bladder. Initial unfiltered dose-volume histogram (DVH) estimation models were trained using all 86 plans. Refined training sets were created by removing sub-optimal plans from the unfiltered sample, and DVH estimation models… and DVH estimation models were constructed by identifying 30 of 86 plans emphasizing PBM sparing (comparing protocol-specified dosimetric cutpoints V
(percentage volume of PBM receiving at least 10 Gy dose) and V
(percentage volume of PBM receiving at least 20 Gy dose) with unfiltered predictions) and another 30 of 86 plans emphasizing bowel sparing (comparing V
(absolute volume of bowel receiving at least 40 Gy dose) and V
(absolute volume of bowel receiving at least 45 Gy dose), 9 in common with the PBM set). To obtain deliverable KBP plans, refined models must inform patient-specific optimization objectives and/or priorities (an auto-planning "routine"). Four candidate routines emphasizing different tradeoffs were composed, and a script was developed to automatically re-plan multiple patients with each routine. After selection of the routine that best met protocol objectives in the 51-patient training sample (KBP
), protocol-specific DVH metrics and normal tissue complication probability were compared for original versus KBP
plans across the 35-patient validation set. Paired t tests were used to test differences between planning sets.
KBP
plans outperformed manual planning across the validation set in all protocol-specific DVH cutpoints. The mean normal tissue complication probability for gastrointestinal toxicity was lower for KBP
versus validation-set plans (48.7% vs 53.8%, P<.001). Similarly, the estimated mean white blood cell count nadir was higher (2.77 vs 2.49 k/mL, P<.001) with KBP
plans, indicating lowered probability of hematologic toxicity.
This work demonstrates that a KBP system can be efficiently trained and refined for use in radiation therapy clinical trials with minimal effort. This patient-specific plan quality control resulted in improvements on protocol-specific dosimetric endpoints.
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