Clinical Trials /

Hyperbaric Radiation Sensitization of Head and Neck Cancers

NCT03843671

Description:

There is reason to believe that hyperbaric oxygen administered immediately prior to radiotherapy will prove beneficial for this cancer type and stage. The basis for this hypothesis is a review of several decades of published work, the conclusion of a recent (2018) Cochrane Review, and results of a Phase I trial.

Related Conditions:
  • Laryngeal Squamous Cell Carcinoma
  • Oral Cavity Squamous Cell Carcinoma
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Hyperbaric Radiation Sensitization of Head and Neck Cancers
  • Official Title: A Phase II Randomized Sham-Controlled Trial With Allocation Concealment and Blinded Patients and Assessors, Investigating Hyperbaric Oxygen as a Radiation Sensitizer for Locally Advanced Squamous Cell Carcinoma of the Oropharynx and Larynx

Clinical Trial IDs

  • ORG STUDY ID: NBS2019-1
  • SECONDARY ID: 93840508
  • NCT ID: NCT03843671

Conditions

  • Squamous Cell Carcinoma of the Head and Neck

Interventions

DrugSynonymsArms
Hyperbaric oxygenHyperbaric chamberGroup 1

Purpose

There is reason to believe that hyperbaric oxygen administered immediately prior to radiotherapy will prove beneficial for this cancer type and stage. The basis for this hypothesis is a review of several decades of published work, the conclusion of a recent (2018) Cochrane Review, and results of a Phase I trial.

Detailed Description

      The goal of this research is to address the question:

      "Does the addition of hyperbaric oxygen to radiation and chemotherapy improve outcomes in
      locally advanced oropharyngeal or laryngeal squamous cell carcinoma?"

      There is reason to believe that hyperbaric oxygen administered immediately prior to
      radiotherapy will prove beneficial for this cancer type and stage. The basis for this
      hypothesis is a review of several decades of published work, the conclusion of a recent
      (2018) Cochrane Review, and results of a Phase I trial. A summary of this body of work
      follows.

      During the 1950's, several reports laid the groundwork for hyperbaric oxygen's potential as
      an effective radiation sensitizer. Gray and colleagues observed that curability of small
      animal tumors with radiotherapy was limited by the radio-resistance of the portion of cells
      that retain their reproductive integrity.(1) Tumor cell sensitivity to irradiation was seen
      to increase when tumor-bearing mice breathed oxygen under hyperbaric conditions. Gray's group
      further observed that radiobiological damage demonstrates dependence on the concentration of
      oxygen in the immediate vicinity of tumor cells at the time of radiation.( 2) It became
      evident that many solid tumor cell populations exist within a wide range of oxygen
      tensions.(3) These findings were sufficiently encouraging to warrant a small clinical study
      to determine if this anticipated radio-sensitization effect could be demonstrated
      histologically.(4) A small diver recompression chamber was acquired from the Royal Navy and
      modified to accommodate a recessed acrylic window.(5)

      The trial involved eight patients whose breast or lung tumor sites would lie directly below
      the window, above which a radiation delivery source was mounted. To assess any difference
      afforded by hyperbaric oxygen, tumors had to be large enough so they could addressed in two
      aspects. Irradiation of the inferior aspect occurred conventionally, with the superior aspect
      shielded. Shielding was then reversed and the superior aspect irradiated while patients
      breathed oxygen to 3.0 atmospheres absolute.(4) Preliminary findings of increased tumor
      destruction secondary to hyperbaric oxygen exposure promoted investigators to treat another
      35 patients in this manner. Despite their uniformly poor prognosis, the hyperbaric effect was
      again significant and outcomes were deemed "much better than anticipated".(6)

      On the strength of this preliminary data there was widespread interest in hyperbaric
      radiation sensitization.(7,8,9,10) However, frustration at the lack of 'visibility' for other
      anatomic sites with these chamber types initially limited wider application. Industry
      responded by manufacturing purpose-built chambers with increasing numbers of windows. By the
      early 1960's, a completely seamless acrylic hyperbaric chamber had been produced.

      It eventually became apparent that hyperbaric oxygen's effectiveness was inconsistent across
      all tumor types (the concept of varying tumor hypoxic fraction was in its infancy). Quite
      probably, many of these cancers had already metastasized. Along with suggestions of a higher
      incidence of new primary tumors and rates of metastasis in hyperbaric oxygen irradiated
      patients, (11, 12) the testing of alternative sensitizers, and a lack of uniformity in
      radiation dosing (making comparisons difficult), interest in hyperbaric sensitization
      eventually began to wane. By the early 1970's, the hyperbaric chamber as a sensitizing agent
      had largely been abandoned.

      Little more was heard of this sensitization technique until 1996, when Japanese neurosurgeons
      reported the results a small clinical trial investigating malignant gliomas.(13) Due to the
      evolution of targeted radiation delivery devices it was no longer possible to undertake
      concurrent hyperbaric oxygen and radiotherapy. This group, therefore, introduced a sequential
      approach, irradiating patients immediately upon exiting the chamber. They were encouraged
      enough by their findings to undertake, along with several other Japanese groups, additional
      brain tumor trials.

      In 1997, Machin et al. summarized 30 years of the U.K.'s Medical Research Council sponsored
      trials of solid tumors, using modern statistical methodology.(14) When the five trials
      involving hyperbaric sensitization were re-analyzed, a clear survival advantage was evident
      in each of the two head and neck cancer trials, with mixed results in cancers of the cervix.
      In 1999, oncologists from Yale reported the results of a head and neck squamous cell
      carcinoma trial, conducted 20 years earlier.(15) Patients were randomized to receive
      radiotherapy conventionally or during hyperbaric oxygenation. Significant improvement in
      local control, and relapse free survival at five years was evident in the hyperbaric group.

      In 2000, magnetic resonance imaging demonstrated hyperbaric oxygen's ability to elevate
      implanted tumor oxygen levels in mice. This effect remained for 20-30 minutes after chamber
      decompression.(16) Malignant glioma oxygen responses to various conditions were measured via
      stereotactic CT guided implanted oxygen electrodes in 18 patients.(17) Hyperbaric, but not
      normobaric, oxygen significantly increased tumor oxygen tension, and this effect likewise
      remained for more than 20 minutes following patient removal from the chamber. This study had
      involved pre- and post-hyperbaric recordings. Becker and colleagues took this one step
      further and measured tumor oxygen response prior to and during hyperbaric oxygen
      exposure.(18) In seven head and neck squamous cell carcinoma patients, mean baseline tumor
      oxygen pressure was 17 mmHg, increasing to 550 mmHg in a mean of 17 minutes of hyperbaric
      oxygen breathing.

      Four clinical trials have further evaluated the sensitization potential of hyperbaric oxygen
      in malignant gliomas. This technique was considered feasible, held promise,(19) and involved
      minimal toxicity,(20,21) and modestly extended overall survival.(19,20,21,22)

      A 2018 Cochrane Review concluded that 'given the findings of improved tumor control and
      mortality with the use of hyperbaric oxygen for patients with cancers of the head and neck…,
      there is a case for large randomized trials of high methodological vigor…'.(23)

      In contrast to earlier unsystematic reports, a 2003 meta-analysis failed to establish a
      causal relationship between hyperbaric oxygen therapy and de novo development of a tumor,
      established tumor growth, or an increase in the degree of metastases.(24)

      Key messages from this body of work:

      i. Radiation-resistance is largely a function of tumor tissue hypoxia ii. Hyperbaric oxygen
      elevates squamous cell carcinoma oxygen tension in animals and man.

      iii. In humans, squamous cell carcinoma oxygen tensions to peak at a mean of 17 minutes
      during hyperbaric oxygenation. They remain elevated for more than 15 minutes after exposure.

      iv. Provision of hyperbaric oxygen has proven feasible and safe as a radiation sensitizer for
      both malignant brain tumors and head and neck squamous cell carcinomas.

      In preparation for this Phase II trial, a Phase I 'dose escalation' study was undertaken.(25)
      Its purpose was to verify safety and tolerability of hyperbaric oxygen immediately prior to
      radiation therapy for oropharyngeal carcinoma. It also assessed the acute toxicity impact of
      hyperbaric oxygen delivered in different groups twice, three times, and five times weekly.
      With a mean follow-up of 19 months, five days per week hyperbaric dosing had not increased
      overall toxicity, and patient compliance was good. (25) Complete clinical response occurred
      in all patients who completed the protocol. One patient suffered bone and liver metastases.
      While this study was not designed to assess clinical outcomes, a subsequent report involving
      a minimum 61 months follow-up confirmed no late toxicities, with overall survival of 100%,
      zero local recurrence, and an 11% incidence of distant metastases.(26)

      Citations are listed in the Reference section
    

Trial Arms

NameTypeDescriptionInterventions
Group 1ExperimentalHyperbaric oxygen Hyperbaric chamber
  • Hyperbaric oxygen
Group 2Sham ComparatorSham for hyperbaric oxygen Hyperbaric chamber
  • Hyperbaric oxygen

Eligibility Criteria

        Inclusion Criteria:

          1. Patients with histological or microscopic proof (from the primary tumor and/or lymph
             nodes) of invasive squamous cell carcinoma of the oral cavity, oropharynx or larynx
             (World Health Organization type 1).

          2. Stage III or IV disease, M0

          3. Non-surgical candidate; for reasons of health or age (except biopsy)

          4. Human Papillomavirus (P16) negative

          5. Life expectancy of at least 6 months and a Karnofsky performance status of ≥ 70

          6. Age ≥ 18 years

          7. No distant metastatic disease

          8. No clinically significant heart disease:

             No significant ventricular arrhythmia requiring medication with antiarrhythmic. No
             symptomatic coronary artery disease (angina). No myocardial infarction within the last
             6 months. No second or third degree heart block or bundle branch block or clinically
             significant conduction system abnormality.

          9. Patients must sign a study-specific informed consent form

        Exclusion Criteria:

          1. Histology other than squamous cell carcinoma

          2. Evidence of metastasis (below the clavicle or distant) by clinical or radiographic
             means

          3. History of prior invasive malignancy, unless at least 5 years without evidence of
             recurrence (tumor-specific restaging)

          4. Prior resection of the primary tumor or lymph node, unless un-operated N2-N3 nodal
             disease or primary tumor remaining, respectively.

          5. Prior chemotherapy for head and neck cancer or radiotherapy to the head and neck

          6. Prior treatment with Bleomycin

          7. Creatinine clearance: measured or estimated Glomerular Filtration Rate <40 ml/min.

          8. Patients with simultaneous primaries

          9. Pregnancy

         10. Participating in a conflicting protocol

         11. Pulmonary pathologies (risk of decompression-induced pulmonary barotrauma)

             Current, untreated pneumothorax. Previous history of spontaneous pneumothorax.
             Previous history of intrathoracic surgery. History or evidence of pulmonary blebs or
             bullous lung disease. Clinically significant chronic obstructive pulmonary disease,
             associated with carbon dioxide retention, poorly controlled or associated with acute
             bronchospasm.

         12. Where the hyperbaric physician deems the patient to have an otherwise unacceptable
             risk for hyperbaric chamber exposure

         13. Claustrophobia
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival
Time Frame:Two years
Safety Issue:
Description:Per blinded radiotherapy assessor

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Two years
Safety Issue:
Description:Per blinded radiotherapy assessor
Measure:Incidence of acute hyperbaric complications; ear/sinus barotrauma, oxygen toxicity, myopia, confinement anxiety
Time Frame:At seven weeks from start of protocol, having completed 35 hyperbaric chamber exposures
Safety Issue:
Description:Clinical and study record assessment by hyperbaric physician
Measure:Incidence and degree of acute radiation toxicity
Time Frame:At seven weeks from start of protocol, having completed 35 radiotherapy treatments
Safety Issue:
Description:Common Terminology Criteria Adverse Events version 5.0
Measure:Incidence and degree of late radiation tissue injury
Time Frame:Two years
Safety Issue:
Description:Common Terminology Criteria Adverse Events version 5.0 and clinical assessment
Measure:Hyperbaric protocol and radiotherapy dosing protocol compliance
Time Frame:Approximately 45 days after initiation of protocol
Safety Issue:
Description:Assessed per Radiation Therapy Chair and hyperbaric oxygen physician per medical record review
Measure:Subject quality of life: Rating scale
Time Frame:Two week post RT, then 3, 6, 12 & 24 months post radiotherapy
Safety Issue:
Description:Functional Assessment of Cancer Therapy: Head and Neck version 4.0 $ Performance Status Scale for Head and Neck.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Baromedical Services

Trial Keywords

  • Hyperbaric oxygen; HNSCC; Radiotherapy; Chemotherapy

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