Clinical trial NCT05120947: Hypofractionated Adjuvant Radiotherapy for Resected Head and Neck Cancers
Official title: A Phase I Study of Hypofractionated Adjuvant Radiotherapy for Resected Head and Neck Cancers (HART-HN)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Resectable Head and Neck Squamous Cell Carcinoma
Keywords: Head and Neck Squamous Cell Carcinoma
Hypofraction Adjuvant Radiation
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2021-11-16
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This study will use a time-to-event continual reassessment method (TITE-CRM) for assigning subjects to the radiation therapy dosages.
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to determine the safe reduction of the treatment fractions to 10, 8, or 5, that may be delivered safely in resected head and neck squamous cell carcinoma (HNSCC) patients with intermediate pathologic risk features.

Detailed description: RATIONALE: Postoperative hypofractionated radiation is well established in many malignancies, yielding benefits in compliance, access to care, convenience, and cost savings. In several solid tumor types, short-course high dose-per-fraction (hypofractionated) post-operative radiation has shown excellent tolerability, reduced healthcare costs, improved compliance, and at least equivalent cancer control compared to conventional post-operative radiation (long course, low dose-per-fraction).(1-3) Despite advances in other malignancies, hypofractionated post-operative radiation is not used in previously untreated mucosal HNSCCs, for which an extended course of conventional post-operative radiation (usually 60 Gy in 2 Gy fractions delivered over six weeks) remains the standard. Hypofractionation has been stymied in the post-operative setting for HNSCCs primarily due to concerns of toxicity in treating a large mucosal field and an inability to spare critical structures such as the brain and spinal cord. These concerns were well-founded in the 1970s during the era of 2-dimensional radiotherapy when conventional HNSCC radiotherapy regimens were developed.(4) But because radiotherapy can be delivered far more precisely using intensity modulated radiation therapy (IMRT), it is hypothesized that post-operative radiation for HNSCCs can now be delivered safely in only five fractions delivered over one week.(3, 5, 6)

Eligibility criteria: Inclusion Criteria:

1. Patients 18 years or older with gross totally resected (R0 resection) Human papillomavirus (HPV) -negative squamous cell carcinoma of the head and neck (squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, nasal cavity, paranasal sinuses or carcinoma of unknown head/neck primary) who have at least 1 of the following intermediate risk factors for adjuvant radiation:

   1. Pathologic Node Positive Disease
   2. Perineural Invasion
   3. Oral cavity cancer with depth of invasion of at least 5 mm
   4. Lymphovascular Space Invasion
   5. Pathologic T3 or T4 disease
2. Zubrod performance status 0-2.
3. Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
4. Inclusion of Covid-19 positive patients will be based on standard institutional protocol.
5. Female patients must meet one of the following:

   * Postmenopausal for at least one year before the screening visit, or
   * Surgically sterile (i.e. undergone a hysterectomy or bilateral oophorectomy), or
   * If subject is of childbearing potential (defined as not satisfying either of the above two criteria), agree to practice two acceptable methods of contraception (combination methods requires use of two of the following: diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male or female condom, hormonal contraceptive) from the time of signing of the informed consent form through 90 days after the last dose of study agent, AND o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptom-thermal, post ovulation methods\] and withdrawal are not acceptable contraception methods).
6. Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:

   * Practice effective barrier contraception during the entire study period and through 60 calendar days after the last dose of study agent, OR
   * Must also adhere to the guidelines of any study-specific pregnancy prevention program, if applicable, OR o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptom-thermal, post ovulation methods\] and withdrawal are not acceptable methods of contraception.)
7. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

1. Pathologic evidence of extranodal extension.
2. Pathologic evidence of a final positive margin (R1 resection) or gross residual disease (R2 resection).
3. HPV-positive squamous cell carcinoma.
4. Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer).
5. Life expectancy less than 12 months.
6. Performance status Zubrod ≥ 3.
7. Patients with prior radiation therapy to the head and neck Note: Prior external beam radiotherapy is excluded, but Iodine 131 is allowed.
8. Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer.
9. Body weight ≤ 30 kg.
10. Any of the following severe laboratory abnormalities within 14 days of registration, unless corrected prior to it: Sodium \< 130 mmol/L or \> 155 mmol/L; Potassium \< 3.5 mmol/L or \> 6 mmol/L; Fasting glucose \< 40 mg/dl or \> 400 mg/dl; Serum calcium (ionized or adjusted for albumin) \< 7 mg/dl or \> 12.5 mg/dl; Magnesium \< 0.9 mg/dl or \> 3 mg/dl.
11. Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to Step 1 registration.
12. Transmural myocardial infarction within three months prior to Step 1 registration.
13. Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements.
14. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after radiation, this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Women who are breastfeeding are also excluded.

Primary outcomes:
measure: Maximum-tolerated Radiation Dose
timeFrame: 12 months
measure: Incidence of Dose-Limiting Toxicities
timeFrame: 12 months
Secondary outcomes:
measure: Overall Survival
timeFrame: One year
measure: Locoregional progression
timeFrame: One year
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Froedtert & the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: Musaddiq Awan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Moran MS, Truong PT. Hypofractionated radiation treatment for breast cancer: The time is now. Breast J. 2020 Jan;26(1):47-54. doi: 10.1111/tbj.13724. Epub 2020 Jan 15.
citation: Benjamin LC, Tree AC, Dearnaley DP. The Role of Hypofractionated Radiotherapy in Prostate Cancer. Curr Oncol Rep. 2017 Apr;19(4):30. doi: 10.1007/s11912-017-0584-7.
citation: Stevens G, Thompson JF, Firth I, O'Brien CJ, McCarthy WH, Quinn MJ. Locally advanced melanoma: results of postoperative hypofractionated radiation therapy. Cancer. 2000 Jan 1;88(1):88-94. doi: 10.1002/(sici)1097-0142(20000101)88:13.0.co;2-k.
citation: Tupchong L, Scott CB, Blitzer PH, Marcial VA, Lowry LD, Jacobs JR, Stetz J, Davis LW, Snow JB, Chandler R, et al. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys. 1991 Jan;20(1):21-8. doi: 10.1016/0360-3016(91)90133-o.
citation: Kumar AMS, Miller J, Hoffer SA, Mansur DB, Coffey M, Lo SS, Sloan AE, Machtay M. Postoperative hypofractionated stereotactic brain radiation (HSRT) for resected brain metastases: improved local control with higher BED10. J Neurooncol. 2018 Sep;139(2):449-454. doi: 10.1007/s11060-018-2885-6. Epub 2018 May 10.
citation: Murray Brunt A, Haviland JS, Wheatley DA, Sydenham MA, Alhasso A, Bloomfield DJ, Chan C, Churn M, Cleator S, Coles CE, Goodman A, Harnett A, Hopwood P, Kirby AM, Kirwan CC, Morris C, Nabi Z, Sawyer E, Somaiah N, Stones L, Syndikus I, Bliss JM, Yarnold JR; FAST-Forward Trial Management Group. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet. 2020 May 23;395(10237):1613-1626. doi: 10.1016/S0140-6736(20)30932-6. Epub 2020 Apr 28.