Tumor hypoxia on 18F-fluoromisonidazole (FMISO) positron emission tomography (PET) may serve as a reliable clinical biomarker of distant metastasis risk for patients with head and neck squamous cell carcinoma (HNSCC) after chemoradiotherapy (CRT), according to a study by MSK researchers.
The study, published recently in JAMA Network Open, found that persistent intratreatment hypoxia was associated with a 3.5-fold increased risk of distant metastasis and worse overall survival (OS) after CRT. Conversely, no patients with hypoxia-negative disease before CRT developed distant metastasis. (1)
“Our study is the largest analysis to date of tumor hypoxia on FMISO PET,” said radiation oncologist and early drug development specialist Nancy Lee, MD, FASTRO, service chief of Head and Neck Radiation Oncology at MSK and Multimodality Section Head of the Early Drug Development Service.
“Using tumor hypoxia as a biomarker of distant metastasis risk for this patient population will improve our ability to identify those requiring escalated or de-escalated therapeutic strategies.”
Head and Neck Squamous Cell Carcinoma and Tumor Hypoxia
Long-term survival for HNSCC is about 50% to 60% across subsites and more than 75% for human papillomavirus (HPV)-positive disease. (2)(3) CRT improves locoregional control, (4) but distant metastasis occurs in 10% to 15% of patients and confers a poor prognosis. (2)(3)
Hypoxia is a common feature of all solid tumors that arises as the demand for oxygen by rapidly growing cancer cells outstrips the available supply, leaving oxygen levels at less than 1%. (5) Preclinical evidence shows that hypoxia promotes virtually every step of the metastatic cascade. (6)(7) With localized disease, a hypoxic tumor environment promotes known precursors for metastasis, including immune evasion and epithelial-mesenchymal transition.
MSK has been using FMISO PET to assess tumor hypoxia for selecting patients with HNSCC that may safely receive CRT de-escalation without jeopardizing oncologic outcomes since well before 2016. (8)
Despite the underlying biological rationale linking tumor hypoxia with distant metastasis, it has been challenging to accumulate a sufficient sample size to investigate the relationship in HNSCC since distant metastasis is a rare event in this cancer type. Most prospective clinical trial series evaluating the role of FMISO PET in HNSCC have been small, ranging from 15 to 53 patients. (8)(9)(10)(11)(12)(13)
Study Design
Dr. Lee and colleagues complied a prospective series of 281 patients with nonmetastatic HNSCC preparing to undergo CRT as part of definitive treatment plans within two prospective phase 2 trials that incorporated FMISO PET that took place at MSK from 2004 to 2021. Nuclear medicine physicians evaluated tumor hypoxia status in FMISO PET scans before and one to two weeks after starting CRT. (1)
The primary outcome was distant metastasis, defined as biopsy-proven HNSCC outside the primary site and regional lymph nodes after CRT completion. The secondary outcome was OS. (1)
Study Results
Among 281 patients included in the study, 251 or 89% were male. Most had primary oropharyngeal tumors (242 or 86%), and HPV-positive disease confirmed by p16 immunohistochemistry or RNA in situ hybridization (266 or 95%). Also, most patients had early-stage disease, including 217 (77%) with T stage 1 or 2 and 231 (82%) with N stage 2b or less. (1)
About half of all patients underwent primary tumor resection before CRT. Approximately half received 30 Gray (Gy) de-escalated CRT, and the remainder received the standard of 70 Gy CRT. Most patients (239 or 85%) had received cisplatin-based chemotherapy. (1)
FMISO PET results showed that 73 patients (23%) had hypoxia-negative disease, 138 patients (49%) had hypoxia-positive disease before CRT and then hypoxia-negative disease during CRT, and 70 patients (25%) had persistent hypoxia-positive disease before and during CRT. N stage 2c or greater HNSCC was associated with persistent intratreatment hypoxia, with an odds ratio of 2.4 (p = 0.01). (1)
Among 12 patients who experienced distant metastasis, 4 experienced locoregional recurrence before distant metastasis. Metastasis occurred in the lungs, bone, and liver. The cumulative incidence of distant metastasis at two years was estimated to be 10.2 % for patients with persistent intratreatment hypoxia and 2.4% for those without. HPV-positive disease was associated with a lower distant metastasis risk (hazard ratio, 0.13). (1)
Six of 22 deaths in the patient study cohort were related to metastatic HNSCC progression. Five-year OS estimates were 89% for patients with persistent intratreatment hypoxia and 96% for those without (hazard ratio, 2.66). Advanced age and T stage 3 or greater disease were associated with worse OS, whereas HPV-positive disease and receipt of cisplatin-based CRT were associated with improved OS. (1)
“Poorer OS was associated with persistent intratreatment hypoxia, but not with pretreatment hypoxia, suggesting that intratreatment hypoxia is clinically important for optimizing treatment,” said Dr. Lee.
Main Implications
“Both the presence and absence of tumor hypoxia may serve as biomarkers to guide personalized treatment plans for patients with HNSCC,” said Dr. Lee. “Patients with a higher distant metastasis risk may benefit from escalated therapeutic strategies, including novel systemic targeted therapies and immunotherapies. Patients with no tumor hypoxia on FMISO PET may benefit from treatment de-escalation.”
Learn more about MSK clinical trials for patients with head and neck cancer.
This study was funded by the National Institutes of Health (grant Nos. R01 CA238392-02A1 and R01 CA157770-01A1), the National Cancer Institute Cancer Center (support grant No. P30 CA008), and numerous patient philanthropic funds. Access disclosures for Dr. Lee.
