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Purpose To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. Materials and Methods Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with Results Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2–69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. Conclusion The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

Background and Scientific Rationale Solitary plasmacytoma of the bone (SPB) is a rare entity representing 5% of all plasma cell dyscrasias. SPB treated with radiation therapy (RT) has a 10% risk of progression to multiple myeloma (MM) over 3 years if there is no marrow involvement, whereas there is a 60% chance of progression over 3 years in patients with minimal marrow involvement. Median time to progression in the latter group is 26 months. Presently, despite mounting evidence of a significant risk of progression to MM, there is no FDA-approved therapy and patients are usually treated with localized RT. This is an area of unmet need. A similar opportunity exists in the setting of MM patients relapsing with localized disease amenable to RT. This group of patients may not immediately require long-term systemic therapy especially if RT combined with epigenetic modulation and lenalidomide results in therapeutically relevant immune responses. A few studies combining lenalidomide and azacitidine have shown responses even in a lenalidomide refractory population with upregulation of cancer testis antigen (CTA) as well as CTA specific T cell responses (Table 1). These synergistic mechanisms focus on: 1) manipulating antigen expression and enhancing antigen presentation (both neoantigens and cancer testis antigens) with oral azacitidine (CC-486), and 2) augmentation of antigen specific immune responses via increased IL2 production leading to an increase in the proliferation of T cells with lenalidomide. This combination with RT would serve to inflame the tumor microenvironment and potentially lead to therapeutically active systemic immune responses via an abscopal effect. Study Design and Methods This is an open-label, single center, single-arm study of CC-486, lenalidomide plus RT, which will enroll a total of 20 patients in two cohorts. Clinical trial registry number NCT04174196, actively recruiting. Study population and inclusion criteria Each cohort will enroll ten patients - Cohort 1: i) Histologically confirmed newly diagnosed solitary plasmacytoma of the bone or lytic bone lesion ii) Minimal marrow involvement (Detectable clonal bone marrow (BM) plasma cells by multicolor flow cytometry and ≤ 10% clonal plasma cells in a BM biopsy by immunohistochemistry, morphology, or flow cytometry) iii) Secretory M protein < 3 g/dL Cohort 2: i) Relapsed multiple myeloma with plasmacytomas appropriate for RT on imaging ii) Relapsed (reappearance of M-spike/serum FLC) or progressive myeloma defined by a 25% increase from nadir in M-spike or involved serum FLC on 2 separate measurements; or with BM involvement by clonal plasma cells detectable by IHC iii) Any prior number of therapies is permitted, including prior RT iv) Allogeneic transplant patients are permitted Statistical methods We estimate the historical rate of stringent complete response (sCR) is approximately 5% (based on the rate for newly diagnosed myeloma with lenalidomide and dexamethasone on the MAIA study of 7.3% and for relapsed myeloma with Rd based on the POLLUX study of 4.6%). The primary endpoint of the study will be reported separately for the two cohorts. With 10 patients in each cohort, the maximum half-width of the exact 95% confidence interval for the response rate is +/- 0.31. A sCR rate of ≥20% would be considered promising for either cohort. Study treatment In the study, patients will be treated with CC-486 100 mg on day 1-21 and lenalidomide 25 mg on day 1-21 for 6 cycles. RT to the plasmacytoma will be initiated after cycle 2. Total dose may vary between 30-50 Gy (45-50 Gy for cohort 1) based on clinical judgement. (Figure 1) Endpoints Primary To provide preliminary efficacy data based on the rate of sCR by 2016 IMWG Criteria on post-treatment BM biopsy and aspirate specimens with no new lesions by PET. Secondary - To assess the safety of this combination. - To estimate the progression free survival and overall survival Exploratory - To evaluate antigen expression at the tumor site pre and post RT - To further characterize the antigen specific T cell response pre and post RT at the tumor site - To assess changes in epigenetic marks - To assess changes in the tumor microenvironment Disclosures Shah: Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Mailankody:Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding; Allogene Therapeutics: Research Funding; Janssen Oncology: Research Funding; Takeda Oncology: Research Funding; PleXus Communications: Honoraria; Physician Education Resource: Honoraria. Korde:Astra Zeneca: Other: Advisory Board; Amgen: Research Funding. Hultcrantz:GSK: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding; Intellisphere LLC: Consultancy. Smith:Precision Biosciences: Consultancy; Fate Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Dahi:Kite: Consultancy. Chung:Genentech: Research Funding. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Barker:Elekta: Research Funding; Amgen: Research Funding; Alpha Tau Medical: Other: Travel expenses, Research Funding; Merck: Research Funding. Giralt:KITE: Consultancy; MILTENYI: Consultancy, Research Funding; OMEROS: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other; Glenmark: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Lesokhin:Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Serametrix Inc.: Patents & Royalties. OffLabel Disclosure: CC-486 is an is an oral hypomethylating agent that has been studied in acute myeloid leukemia. This study combines CC-486 with lenalidomide and radiation therapy in plasma cell disorders.

Purpose To update the guideline recommendations on the use of larynx-preservation strategies in the treatment of laryngeal cancer. Methods An Expert Panel updated the systematic review of the literature for the period from January 2005 to May 2017. Results The panel confirmed that the use of a larynx-preservation approach for appropriately selected patients does not compromise survival. No larynx-preservation approach offered a survival advantage compared with total laryngectomy and adjuvant therapy as indicated. Changes were supported for the use of endoscopic surgical resection in patients with limited disease (T1, T2) and for initial total laryngectomy in patients with T4a disease or with severe pretreatment laryngeal dysfunction. New recommendations for positron emission tomography imaging for the evaluation of regional nodes after treatment and best measures for evaluating voice and swallowing function were added. Recommendations Patients with T1, T2 laryngeal cancer should be treated initially with intent to preserve the larynx by using endoscopic resection or radiation therapy, with either leading to similar outcomes. For patients with locally advanced (T3, T4) disease, organ-preservation surgery, combined chemotherapy and radiation, or radiation alone offer the potential for larynx preservation without compromising overall survival. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy. Patients with clinically involved regional cervical nodes (N+) who have a complete clinical and radiologic imaging response after chemoradiation do not require elective neck dissection. All patients should undergo a pretreatment baseline assessment of voice and swallowing function and receive counseling with regard to the potential impact of treatment options on voice, swallowing, and quality of life. Additional information is available at www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .

Purpose To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials. Methods A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors. Results Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated. Recommendations All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

Diffuse pontine tumors are highly lethal and conventional therapy with irradiation provides long-term survival to a very small proportion of the patients. We have reported promising results using high-dose chemotherapy with autologous stem cell rescue in patients with recurrent high-grade astrocytomas in other anatomic locations, but our results and those of others have been very discouraging in children with brain stem tumors. Alternative strategies need to be developed for this highly lethal disease.