Efficacy of Ketamine Mouthwash in the Management of Oral and Pharyngeal Toxicity
Trial Snapshot
- Phase
- Phase 2
- Status
- Withdrawn
- Sponsor
- Northwell Health
- Locations
- 1
- Primary Endpoint
- Assessing Pain Response
Study Overview
Brief Summary
Patients with head and neck cancer generally receive a standard of care of 7 weeks of daily radiation therapy given alongside an aggressive chemotherapy drug called cisplatin. While rates of cure are often strong for patients who are able to complete treatment without any unscheduled breaks, the rates of high grade toxicity associated with this treatment are high even with the use of the most modern techniques of treatment. Pain, swallowing dysfunction, loss of taste sensation, and ulceration of the mouth and throat are ubiquitous and often contribute to a nutritional breakdown requiring feeding tube placement. Unfortunately, even with aggressive use of opioids and other conventional palliation methods, breakthrough pain and other toxicities are very common. In addition to the quality of life burdens of these side effects, patients who are unable to complete treatment on schedule have worse control of their cancer and worse overall survival.
Clearly, there is a clinical need for better management of these toxicities. The investigators hypothesize that ketamine mouthwash may effectively reduce both pain and the need for opioid drugs in this patient population. There is a large body of literature supporting the use of ketamine for pain control in diseases other than cancer, and a smaller but growing body of literature showing the effectiveness of ketamine for control of cancer-associated pain. Additionally, by providing ketamine in mouthwash form, the evidence shows that one can avoid the side effects associated with giving ketamine throughout the body, and in fact no significant side effects have been reported so far with this treatment.
In this study, the investigators will provide ketamine mouthwash to patients undergoing the standard treatment for this disease over a two week period, and measure their response in terms of both pain and need for opioids, as well as other measurements of quality of life. The investigators will also measure unscheduled interruptions in treatment. In years to come, the data from this study may show an impact on cancer control and survival.
Detailed Description
There is an unmet need for improvement in pain control among patients with cancer and undergoing anti-neoplastic therapies, with by one recent estimate 59% of patients on treatment and 33% of patients who completed curative treatment reporting inadequate pain control (1).
This burden is especially grave in the setting of curative treatment for head and neck cancer, in which rates of severe acute pain and other toxicities with major impact on quality of life are known to be high among radiotherapy and chemoradiotherapy patients.
In RTOG 9003, a randomized controlled trial evaluating altered fractionation in the setting of definitive radiotherapy in locally advanced head and neck cancer, acute grade 3-4 oral mucositis was seen in 25% of standard fractionation and 41% of hyperfractionation patients, and acute grade 3-4 pharyngeal/esophageal toxicity was seen in 11% of standard fractionation and 26% of hyperfractionation patients. In RTOG 0129, a randomized controlled trial evaluating accelerated fractionation in the setting of definitive cisplatin-based chemotherapy concurrent with radiotherapy in stage III-IV head and neck cancer, acute grade 3-4 dysphagia was seen in 23% of standard fractionation and 21% of accelerated fractionation patients, and acute grade 3-4 oral/pharyngeal mucositis was seen in 39% of standard fractionation and 33% of accelerated fractionation patients. Additionally, in RTOG 0129, 69% of standard and 67% of accelerated fractionation patients received nutritional support via feeding tube by treatment end (2,3).
The above landmark RTOG studies did not use modern intensity-modulated radiation therapy (IMRT) techniques which have since become standard in head and neck radiotherapy, and data do exist suggesting reduced acute toxicities through the use of IMRT such as in RTOG 0022 (4). Nevertheless, the burden is still significant, particularly when concurrent cisplatin is given. For example, in RTOG 1016, a randomized controlled trial which demonstrated the inferiority of cetuximab given concurrently with IMRT vs. concurrent cisplatin and IMRT in HPV-positive oropharyngeal cancers, the IMRT plus cisplatin arm showed an acute grade 3-4 dysphagia rate of 37.4%, an acute grade 3-4 oral mucositis rate of 41.5%, an acute grade 3-4 pharyngeal mucositis rate of 13.6%, an acute grade 3-4 anorexia rate (which is likely due at least in part to pain and swallowing dysfunction) of 22.4%, and a rate of feeding tube nutritional support at treatment end of 62% (5).
As a result of the above and other randomized studies, IMRT with concurrent cisplatin-based chemotherapy, with its high rates of expected high grade toxicities, is the standard of care for head and neck cancers except for those that are potentially operative and those that are very early stage.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Sequential
- Primary Purpose
- Supportive Care
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Adults aged 18-70
- •Pathologically proven squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx, larynx, or hypopharynx, with the exception of stages I-II glottic cancer
- •Prescribed a curative regimen of definitive radiotherapy to with concurrent cisplatin-based chemotherapy, administered in standard fractionated doses to 70 Gy in 35 Fx
- •CTCAE v 5.0 grade 3 or greater oral cavity or pharyngeal mucositis documented to have developed subsequent to initiation of radiation therapy, defined as severe pain limiting oral intake, with at least 14 remaining days on treatment with radiation therapy
Exclusion Criteria
- •Unable to render informed consent
- •Prior history of radiation therapy
- •Any other malignancy diagnosed or treated within 10 years prior to enrollment
- •Feeding tube placement or tracheostomy prior to initiation of radiation therapy
- •Deemed by attending radiation oncologist to be unlikely to adhere to the QID study intervention and daily outcomes reporting as described below
- •Any of the following contraindications for ketamine use: high risk for complications due to blood pressure elevation, documented hypersensitivity to ketamine, history of illicit drug use disorder, history of psychotic disorder, or any other medical contraindication attested to by the attending radiation oncologist
- •Pregnant or breastfeeding at the time of screening visit
Arms & Interventions
Ketamine Mouthwash
Enrolled patients with histologically confirmed squamous cell carcinoma of the head and neck undergoing definitive radiation therapy to 70Gy with concurrent cisplatin chemotherapy who develop grade 3+ toxicity will be prescribed ketamine mouthwash at a strength of 20mg/5mL in NovaFilm suspension with OraSweet flavoring agent via "swish and spit" route of administration. They will take the investigational drug four times daily.
Intervention: Ketamine Topical (Drug)
Outcomes
Primary Outcomes
Assessing Pain Response
Time Frame: 14 days
Pain response, defined by international consensus criteria as a combination of pain score per visual analogue scale (0-10) and opioid analgesic use (morphine-equivalent dose), through which the combination of the two measures are unified into a single evaluation of complete response (CR), partial response (PR), indeterminate response (IR), or pain progression (PP), depending upon the dynamics of VAS and MED taken separately
Secondary Outcomes
- Assessing Dysphagia(Baseline and repeated at 14 days)
- Assessing Sleep Quality(Nightly for 14 days)
- Assessing unscheduled treatment breaks(Categorical (yes/no) measurement at any time after start of ketamine therapy and prior to completion of cancer-directed therapy, a maximum 14 day period)
- Measuring opioid analgesic burden(Daily for 14 days)
- Assessing Patient-reported pain score(Daily for 14 days)
- Evaluating the placement of a feeding tube(Categorical (yes/no) measurement at any time after start of ketamine therapy and prior to completion of cancer-directed therapy, a maximum 14 day period)
- Assessing premature treatment termination(Categorical (yes/no) measurement at any time after start of ketamine therapy and prior to completion of cancer-directed therapy, i.e. the time of completion of 35 fractions of radiation therapy, which may occur later than completion of the trial protocol)
- Adverse events(Daily during each of the 14 days on trial protocol)