Hyperbaric Radiation Sensitization of Head and Neck Cancers

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

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