A personalized approach using hypoxia resolution to guide curative-intent radiation dose-reduction to 30 Gy: A novel de-escalation paradigm for HPV-associated oropharynx cancers (OPC).

Abstract

6076 Background: We conducted a pilot study using functional imaging to guide reduction in radiation (RT) to 30Gy with concurrent chemotherapy in patients with HPV+ OPC. Methods: 19 patients were enrolled prospectively from 7/2015-10/2016. Primary tumors were excised and analyzed for DNA repair foci ex-vivo. A pre-RT dynamic 18F-FMISO (fluoromisonidazole) PET was then used to assess tumor hypoxia (defined as > 1.2 tumor to muscle SUV ratio) in cervical lymph nodes. Patients without hypoxia on baseline or repeat scan done 5-10 days after initiation of chemoRT received 30Gy (57% reduction) over 3 weeks to the tumor bed and neck with 2 cycles of concurrent chemotherapy (high-dose cisplatin or carboplatin/5-FU). Patients with persistent hypoxia received the standard dose of 70Gy over 7 weeks with chemo. Neck dissection (ND) was done 4-months post chemoRT. Weekly DWI MRI, ctDNA, whole exome & RNA sequencing were performed. Results: 19 patients (11 tonsil, 5 BoT, 3 unknown primaries) were enrolled. Staging: 11 T1, 5 T2, 3 Tx; 5 N1, 3 N2a, 11 N2b; all M0. On pre-RT 18F-FMISO scans, 13 were positive and 6 were negative for hypoxia. Of the 12 intra-treatment 18F-FMISO scans (1 not done due to intermittent illness, this patient received 70Gy), 3 were positive and these patients received 70Gy chemoRT. 15 patients were de-escalated to 30Gy. To date, analysis showed complete pathologic response in 8 of 9 patients (all 15 expected to have ND by April 2017. The one positive case received only 1 cycle of cisplatin. To date, 18 of 19 patients (95%-6 pending ND) remain disease free. Correlative analysis with sequencing, DNA repair foci, ctDNA, and results from pathologic and intra-treatment imaging response will be presented. Conclusions: This is the first report of apersonalized approach to a major decrease in RT dosing for definitive treatment of HPV+ oropharyngeal carcinoma guided by patient-specific imaging-based treatment response. De-escalation to 30Gy informed by intra-treatment imaging for hypoxia appears feasible, safe and efficacious. A multi-center trial to validate these pilot results is planned. Clinical trial information: NCT00606294.

Predicting hypoxia status using a combination of contrast-enhanced computed tomography and [18F]-Fluorodeoxyglucose positron emission tomography radiomics features

“…We used TBR max to quantify hypoxia as it minimizes uptake normalization errors and is highly correlated with the tumor-to-muscle ratio that is commonly used in clinical trials [9, 13, 30]. It has been argued that for a more reliable determination of tumor hypoxia a kinetic analysis of dynamic PET data may be needed [31], as the raw 18 F-FMISO uptake is expected to be affected by factors such as the distribution volume [32].…”

“…This has motivated the development of HNSCC chemoradiotherapy protocols that stratify patients based on the assessment of tumor hypoxia [9, 10, 11]. Major alterations of the treatment are being tested in clinical trials, such as the reduction of the radiation dose to non-hypoxic lesions from the standard 70 Gy to 30 Gy, thereby significantly reducing the risk of normal tissue toxicity [12, 13].…”

Radiotherapy dose and survival outcomes in human papillomavirus positive oropharyngeal cancer

“…Preliminary results are promising, with a pathological complete response seen in 18 of 19 patients. 22…”