Relevance to inform research, policies, and/or programs
Oral mucositis is a significant toxicity of cytotoxic chemotherapy for which cryotherapy has using ice chips has benefit but is logistically and functionally challenging for patients and providers. A self-contained, reusable cryotherapy device was tested for efficacy and tolerability in a randomized, controlled trial in a patients receiving two cycles of treatment. Compared to controls, device users had significantly less pain and less analgesic use.
Introduction
Oral mucositis (OM) is an untoward side effect of many forms of cytotoxic chemotherapy [ 1 ]. OM risk is associated with the cancer regimen used, the dose and sequence of treatment, and a range of patient-associated variables including genomics, age, and gender [ 2 ]. While chemotherapy regimens are not as stomatotoxic as focal radiation-based therapies, they are associated with mucosal injury of such severity as to necessitate pain management, and which can disrupt planned anti-cancer treatment. Although the literature reports an aggregate mucositis (any severity) incidence of about 40% in patients being treated with standard chemotherapy regimens, real world data suggests this figure underestimates OM’s true incidence [ 3 ]. Additionally, patients who develop OM in the first cycle of chemotherapy appear to have a higher risk of recurrence in subsequent cycles [ 4 , 5 ].
Treatment options for OM are limited. Palifermin use is restricted to patients receiving conditioning regimens prior to stem cell transplant for the treatment of hematologic malignancies [ 6 ]. No other drugs or biologicals were approved in the USA to prevent or treat OM. A number of gels and rinses, classified as devices, are marketed as palliating agents for mucositis symptoms including barrier strategies (GelClair®, MuGard®) and remineralizing rinses (Caphosol). Data supporting the effectiveness of these agents is minimal or negative, [ 7 – 10 ].
The efficacy of cryotherapy in managing OM has been well studied for well over a decade [ 11 – 13 ]. In a recent critical review, its effectiveness in reducing mucositis associated with bolus 5-FU or melphalan was confirmed. The same review suggested that additional studies with drugs with short half-lives would be of value [ 14 ]. It is presumed that cryotherapy’s efficacy is based on cold-initiated local vasoconstriction reducing mucosal levels of the cytotoxic agent.
While cryotherapy has been “suggested” as a component of the current Mucositis Management Guidelines of the Multinational Association of Supportive Care in Cancer [ 15 ], its use can be logistically challenging for patients and clinic staff as melting ice, management of patient secretions, nausea, drooling, and need for constant replenishment are common [ 16 ]. The device assessed in this trial was developed as an alternative to ice-chips for the delivery of cryotherapy to the oral cavity.
This study was performed to evaluate the efficacy of a self-contained, patient-administered cryotherapy device in mitigating patient-reported symptoms associated with OM secondary to standard stomatotoxic chemotherapy regimens, and in reducing the need for analgesics in response to oral pain. Efficacy was based on the overall incidence of OM symptoms defined as the number of patient-reported episodes of pain observed during a 14-day period from the day of infusion for the first two chemotherapy cycles (up to 28 days total). Similarly, analgesic use was assessed based on the frequency (by day) of medication use or not.
Methods
Overall study design
This was a randomized, prospective, multi-center ( n = 16) study in which the efficacy of a novel oral cryotherapy delivery device to mitigate OM symptoms was compared to best supportive care (BSC) in patients being treated with standard chemotherapy regimens. The trial was reviewed and approved by institutional IRBs and registered on ClinicalTrials.gov ( NCT04595838 ). Written informed consent was obtained from all study participants.
The study was performed for each patient in two phases: a screening phase (within 30 days prior to the start of chemotherapy cycle 1) and an active assessment phase beginning the first day of chemotherapy cycle 1 and continuing until the first day of cycle 3.
Prior to randomization, during the screening phase, patient tolerability of the device was evaluated. Potential patients placed the device in their mouths to assess fit. For the first 30 patients enrolled in the trial, the device was offered in one size (57.65 mm × 53.34 mm). However, given the rate of screen failures in this group because of device discomfort, it became clear that a smaller option was desirable, and one was made available. Subsequently, patients who did not tolerate the first version of the device then evaluated the fit and comfort of a smaller version (oral piece dimensions of 45.97 mm × 42.42 mm). Patients who could not tolerate either sized device comfortably were designated as screen failures and did not proceed to randomization. Of 210 patients screened, 17 of 46 screen failures were associated with device intolerance. Notably, the rate of screen failures dropped from 35.6% (16/45) to 18.2% (30/165) with the introduction of a small sized device option.
One-hundred and sixty-four patients (between the ages of 18 and 80) were randomized in a 2:1 ratio to 1 of 2 arms: arm A, cryotherapy device + BSC, or arm B (Controls), BSC only. BSC was based on recommendations from the National Institute of Dental and Craniofacial Research and the Centers for Disease Control and Prevention. Patients in arm A used the device beginning 10 min before the start of the first chemotherapy infusion in cycles 1 and 2 and then throughout the duration of the infusion. A new frozen device was substituted every 30–45 min. Patients were allowed a 5–10-min break between device changes. Additionally, 5-min breaks in device use every 15 min were permitted in cases where a patient could not tolerate the device in their mouth for the entire 30–45 min. Usage time was recorded. Following infusion, patients used the device at home for a minimum of two 30–45-min periods for 5 days.
Patients were offered the option of a device size change if they were having difficulty tolerating the original size.
Patients
Study patients (ages 18–80 years) planned to receive at least two cycles of an infused stomatotoxic chemotherapy regimen were enrolled at 16 US sites. Inclusion criteria were purposefully left broad with respect to regimen and primary tumor diagnosis. Patients were not arbitrarily excluded if short half-live drugs were included in their treatment plan. Patients planned to receive oxaliplatin-containing regimen were excluded due to the drug’s known association with cold sensitivity [ 17 ]. Patients planned to receive concomitant radiotherapy were excluded as were. Those dependent on opioid analgesia at the time of screening were excluded.
Device description
The device (Chemo MouthpieceTM, CMP) is entirely self-contained made of durable, medical-grade silicone, and pre-filled with filtered water, and a proprietary saline solution (Figs. 1 and 2 ) by the manufacturer. It can be reused throughout the duration of treatment for up to 1 year. The device received FDA marketing approval in early 2024. As noted, two device sizes were available for this study. The shaft of the device is the same size; only the mouthpiece portion differs in size. In vitro testing had previously confirmed that the surface temperature of the device-imparted mucosal cooling which was equivalent to or superior to ice and which was maintained for a period of 30 min. Fig. 1 Chemo mouthpiece device. The device consists of an outer clear chamber prefilled with a proprietary saline solution with the inner, blue chamber prefilled with filtered water. Once filled by the manufacturer, the device does not require refilling Fig. 2 Consort diagram. Of patients randomized to the device arm ( A ), randomization failures were largely attributable to device fit or comfort. Of the 36 patients in the device arm who discontinued, the majority of early terminations occurred before a small device option was introduced
Patients were provided with written and verbal instructions on device use. The device’s chamber was inserted into the mouth to allow the lips to overlap the outer edge. Once inserted, the insulated sleeve and base were squeezed to circulate cold water throughout the device and to repeat squeezing during its use. Patients were advised to tilt their head back while the device was used. Breathing tubes in the device-facilitated breathing.
Procedures and assessments
Patients completed a diary at the time of screening and then daily for the first 14 days of chemotherapy cycles 1 and 2. If a patient chose to use the device on additional days beyond day 14 during their first two chemotherapy cycles, completion of the daily diary was required. On the first day of cycle 3, patients in arm A provided feedback on ease of use of the device by way of an End of Study Device Assessment questionnaire.
Efficacy data was obtained using a daily diary in an ePRO or paper format. Patients rated symptoms using a categorical 0–5 scale (0 “feels normal” and “5 feels marked discomfort and inability to swallow solids or liquids necessitating supplemental nutrition”; Oral Mucositis Symptom Assessment [OMSA] Supplemental Table 1 ) and questions related to medications taken for oral pain. For patients in arm A, the diary also included questions related to device use. All patients were instructed to complete the daily diary for the first 14 days of chemotherapy cycles 1 and 2 at a minimum. The OMSA severity criteria were based on those described by CTCAE v5.0 [ 18 ]. However, for the purposes of our analyses, we elected to use the data in a binary way in which pain of any severity was considered a treatment failure.
Safety was assessed by collecting and recording all unanticipated adverse device effects (UADEs).
End-of-study device assessment
On the first day of cycle 3, patients in arm A provided feedback on device ease of use using the End of Study Device Assessment (Supplemental Table 2 ). The device assessment included six questions that patients answered using a scale from 0 (do not agree) to 10 (completely agree).
Analysis
Efficacy was assessed based on the incidence of any OM symptomatic event (scores > 0), observed during the first two cycles of chemotherapy as reported by patients’ self-report using the Oral Mucositis Symptom Assessment scale.
In addition, per cycle, mucositis symptom incidence and severity, duration of symptoms, and analgesic use were evaluated.
Descriptive statistical methods were used to summarize the data including the number of patients ( n ), mean, median, standard deviation (SD), standard error of the mean (SEM), minimum and maximum for continuous data, and frequencies and percentages for categorical data. An estimated number of 200 patients with a 2:1 allocation (device:control) yielded a power in excess of 90% to detect a 20% decrease in incidence and 80% to detect a 25% reduction.
A Generalized Linear Mixed Model (GLMM) for repeated binary measures was employed to compare the treatment groups based on the efficacy endpoint comprising the pain dichotomized response (0 or 1). The GLMM model was fit by maximum likelihood (Laplace approximation) and a negative binomial link function. The GLMM model fit included the binary pain outcome as a response variable, treatment group membership and visit as (nonlinear) factors, and patient as a random factor. Further analyses included a two-sided Fisher’s exact test carried out on specific days (visits) with multiplicity of comparisons accounted for in the statistical significance reporting.
Analyses were performed for all randomized patients regardless of the number of visits for which data was available (the Intent-to-Treat population (ITT)) and for those patients for whom, as prescribed in the protocol, data was available for every study visit (the Per-Protocol population; PP).
Results
Patients
One-hundred and sixty-four patients were randomized (ITT population): 110 in arm A and 54 in arm B. Patients were balanced between cohorts for sex (arm A 73.6% female, arm B 83.3% female), age (arm A median 63.5 years, arm B 57.5 years), and ethnicity (Fig. 2 , Table 1 ). The majority of patients in both cohorts received chemotherapy for breast cancer (arm A 52.7%, arm B 61.1%), with colorectal cancers being the second most common diagnosis (arm A 10%, arm B 7.4%). Specific primary tumor sites or diagnoses were not noted for 11 patients in arm A (10%) (Table 1 ). While the trial’s inclusion criteria relative to chemotherapy regimens and drugs were purposively broad (Supplementary Table 4 ), the distribution between arms was not significantly different. The most common regimens in both arms included cyclophosphamide plus either doxorubicin or docetaxel (arm A 35%; arm B 37%). Table 1 Demographics of randomized patients Device (all sites) n = 110 Control (all sites) n = 54 Male 29 [26.4] 9 [16.7] Female 81 [73.6] 45 [83.3] White 78 [70.9] 33 [61.1] Black 14 [12.7] 13 [24.1] Asian 6 [5.5] 2 [3.7] Latino 3 [2.7] 2 [3.7] Unknown/not reported 9 [8.2] 3 [5.6] More than 1 0 [0] 1 [1.9] Median age 63.5 57.5 Mean age 60.8 57.3 Breast 58 [52.7] 33 [61.1] Colon 11 [10] 4 [7.4] Epithelial cancer 1 [0.9] 0 [0] Esophageal 0 [0] 1 [1.9] Gastrointestinal, hepatobiliary 3 [2.7] 0 [0] Hodgkin’s lymphoma 6 [5.5] 2 [3.7] Lymphoma 4 [3.6] 2 [3.7] Malignant neoplasm of endometrium 1 [0.9] 0 [0] Posterior pharynx 1 [0.9] 0 [0] Multiple myeloma 1 [0.9] 0 [0] Ovarian 2 [1.8] 3 [5.6] Testicular 1 [0.9] 0 [0] Sarcoma 0 [0] 1 [0.9] Carcinoma 7 [6.4] 5 [9.3] Lung 2 [1.8] 2 [3.7] Leukemia 1 [0.9] 1 [1.9] Other 11 [10] 0 [0]
Table 1
Demographics of randomized patients
| Device (all sites) n = 110 | Control (all sites) n = 54 | |
| Male | 29 [26.4] | 9 [16.7] |
| Female | 81 [73.6] | 45 [83.3] |
| White | 78 [70.9] | 33 [61.1] |
| Black | 14 [12.7] | 13 [24.1] |
| Asian | 6 [5.5] | 2 [3.7] |
| Latino | 3 [2.7] | 2 [3.7] |
| Unknown/not reported | 9 [8.2] | 3 [5.6] |
| More than 1 | 0 [0] | 1 [1.9] |
| Median age | 63.5 | 57.5 |
| Mean age | 60.8 | 57.3 |
| Breast | 58 [52.7] | 33 [61.1] |
| Colon | 11 [10] | 4 [7.4] |
| Epithelial cancer | 1 [0.9] | 0 [0] |
| Esophageal | 0 [0] | 1 [1.9] |
| Gastrointestinal, hepatobiliary | 3 [2.7] | 0 [0] |
| Hodgkin’s lymphoma | 6 [5.5] | 2 [3.7] |
| Lymphoma | 4 [3.6] | 2 [3.7] |
| Malignant neoplasm of endometrium | 1 [0.9] | 0 [0] |
| Posterior pharynx | 1 [0.9] | 0 [0] |
| Multiple myeloma | 1 [0.9] | 0 [0] |
| Ovarian | 2 [1.8] | 3 [5.6] |
| Testicular | 1 [0.9] | 0 [0] |
| Sarcoma | 0 [0] | 1 [0.9] |
| Carcinoma | 7 [6.4] | 5 [9.3] |
| Lung | 2 [1.8] | 2 [3.7] |
| Leukemia | 1 [0.9] | 1 [1.9] |
| Other | 11 [10] | 0 [0] |
Efficacy
Pain outcomes as scored by patients favored the cryotherapy device compared to the control (Table 2 ). Among the Intent-to-treat population (all randomized patients), the percentage of visits in which patients reported any mucosal pain (> 0) in cycles 1 and 2 was significantly less among device-using individuals (CMP 17.8% vs Control 24.6%; p < 0.001). The trend was the same for patients in the per-protocol population (individuals for whom data was available for every data point) (CMP 12.8% v Control 23.9%; p < 0.001). Table 2 Comparison of the effect of the CMP between patients treated for cancers of the breast vs. patients treated for other primary cancers for cycle 1 (C1) and cycle 2 (C2). For this purpose, we categorized patient response by rate (number of patients with any score > 0: number of patients) in five increments: 0, 1–20%, 21–40%, 41–60%, and more than 61% Rate Device C1 breast ( n = 27) Control C1 breast ( n = 23) Device C2 breast ( n = 24) Control C2 breast ( n = 21) Device C1 non-breast ( n = 24) Control C1 non-breast ( n = 13) Device C2 non-breast ( n = 22) Control C2 non-breast ( n = 10) 0 66.7% (18/27) 43.5% (10/23) 70.1% (17/24) 57.1% (12/21) 70.1% (17/24) 92.3% (12/13) 72.7% (16/22) 50% (5/10) 1–20% 7.4% (2/7) 8.7% (2/23) 12.5% (3/24) 0 8.3% (2/24) 0 13.6% (3/22) 0 21–40% 11.1% (3/27) 8.7% (2/23) 4.2% (1/24) 19% (4/21) 4.2% (1/24) 0 4.5% (1/22) 30% (3/10) 41–60% 3.7% (1/27) 13% (3/23) 8.3% (2/24) 0 0 0 4.5% (1/22) 10% (1/10) 61% + 11.1% (3/27) 26.1% (6/23) 4.2% (1/24) 23.8% (5/21) 16.7% (4/24) 7.7% (1/13) 4.5% (1/22) 10% (1/10)
Table 2
Comparison of the effect of the CMP between patients treated for cancers of the breast vs. patients treated for other primary cancers for cycle 1 (C1) and cycle 2 (C2). For this purpose, we categorized patient response by rate (number of patients with any score > 0: number of patients) in five increments: 0, 1–20%, 21–40%, 41–60%, and more than 61%
| Rate | Device C1 breast ( n = 27) | Control C1 breast ( n = 23) | Device C2 breast ( n = 24) | Control C2 breast ( n = 21) | Device C1 non-breast ( n = 24) | Control C1 non-breast ( n = 13) | Device C2 non-breast ( n = 22) | Control C2 non-breast ( n = 10) |
| 0 | 66.7% (18/27) | 43.5% (10/23) | 70.1% (17/24) | 57.1% (12/21) | 70.1% (17/24) | 92.3% (12/13) | 72.7% (16/22) | 50% (5/10) |
| 1–20% | 7.4% (2/7) | 8.7% (2/23) | 12.5% (3/24) | 0 | 8.3% (2/24) | 0 | 13.6% (3/22) | 0 |
| 21–40% | 11.1% (3/27) | 8.7% (2/23) | 4.2% (1/24) | 19% (4/21) | 4.2% (1/24) | 0 | 4.5% (1/22) | 30% (3/10) |
| 41–60% | 3.7% (1/27) | 13% (3/23) | 8.3% (2/24) | 0 | 0 | 0 | 4.5% (1/22) | 10% (1/10) |
| 61% + | 11.1% (3/27) | 26.1% (6/23) | 4.2% (1/24) | 23.8% (5/21) | 16.7% (4/24) | 7.7% (1/13) | 4.5% (1/22) | 10% (1/10) |
We extended the assessment to include a longitudinal analysis of dichotomized scores (Fig. 3 A) in which pain mitigation response was examined. The trajectory of symptoms was consistent for that expected for chemotherapy-associated mucosal injury with peak symptoms seen between days 4 and 10 of each cycle with separation of the study arms. To better understand the device’s effect at the time of greatest symptom risk, we further compared response for days 4–10 of cycle 1 and days 4–10 of cycle 2. In both cycles, patients using the device were consistently pain free (no score > 0) compared to those patients in the SOC arm ( p = 0.068). Cumulatively for cycle 1 visits 4, 8, and 10 and cycle 2 visits 4, 6, 10, and 14, the difference as assessed using the GLMM demonstrated a difference in predicted pain response over the treatment period favoring the CMP (CMP 80.1% vs SOC 67.6%; p value as noted above 0.0481). Fig. 3 A Longitudinal analysis of pain scores by visit for all randomized patients (ITT population) and those who completed questionnaires for every study day (PP population). Patients recorded their level of comfort/pain using a six point categorical scale (0 = feels normal to 5 = marked discomfort and inability to swallow solids or liquids necessitating supplemental nutrition). Pain was rated in binary fashion, none (0) vs. any (> 0). Patients completed an Oral Mucositis Symptom Assessment (Supplemental Table 1 ) from day 1 to day 14 of their first two cycles of chemotherapy. B Analgesic use patients recorded the need for mouth symptom palliation by analgesic medications for days 1-14 of their first two cycles of chemotherapy. Analgesic use was evaluated in binary fashion. This figure compares the percent of patients in each arm (CMP device users vs. controls) who did not require analgesics (responders) to control mouth pain during cycle days
We reasoned that analgesic use associated with oral pain would present with results which were the reciprocal of patient pain experience. This was the case (Fig. 3 B). Whereas 26% of patients in the ITT control cohort reported the need for analgesics during their two cycles of treatment, the frequency of use was only 11.3% among CMP users ( p = 0.01). Similarly, of study visits for the ITT population, control patients indicated analgesic use 7.7% of the time compared to 1.8% of CMP patients ( p < 0.001). A similar trend was seen in the PP population where the rate of analgesic use in the CMP cohort (9.2%) was better than that noted in the control population (29.3%; p = 0.007). The frequency in analgesic use was no different than seen in the ITT population (1.8% CMP vs. 7.5% Control; p , 0.001). Longitudinal analysis supported the differences in analgesic use over time with greatest use in both arms being synergistic with reported pain.
While a stratified comparison of efficacy based on cancer treatment regimen was not feasible given the limitations of patient numbers, we did compare response based on a cancer diagnoses of patients with breast cancer vs those with non-breast disease (Table 2 ). For this purpose, we categorized patient response by rate (number of patients with any score > 0: number of patients) in five increments: 0, 1–20%, 21–40%, 41–60%, and more than 61%. Whereas breast cancer device users consistently responded favorably to the device in both cycle 1 and cycle 2 of the treatment regimens, non-breast cancer patients appeared to derive greatest benefit in cycle 2.
Safety and tolerability
There were no safety issues associated with the use of the device. Among the first 30 patients randomized to the trial, the early termination rate (ETR) of arm A patients (10 of 19; 52.6%) was dramatically higher than the control (arm B) cohort (1 of 11; 9.1%). In response to this observation, a smaller version of the device was offered which favorably affected the ETR for the remaining device-using patients (26 of 92; 28.3%) compared to 11.6% (5 of 43) in the control group. We further compared the reasons for early termination between the two cohorts (Supplementary Table 3 ). Of early terminators in arm A, 50% (18 of 36) discontinued for reasons attributable to the device, whereas chemotherapy side effects were the reason given by 50% of patients in the control group who discontinued the trial (3 of 6).
An assessment of device use compliance indicated that 65% of arm A patients used the device completely as instructed (minimum of two 30-min periods for 5 days following infusion) during cycle 1 of their chemotherapy. Compliance was essentially the same in cycle 2 (63%). Of patients randomized to arm A, 15.7% in cycle 1 and 21.7% in cycle 2 failed to use the device at all following infusion. These rates compare exactly with those reported with per oral drug compliance [ 19 ].
Upon completion of the active phase of the study, patients in the device arm completed an end of study survey of device tolerability using a 6-item questionnaire in which patients ranked answers from 0 (do not agree) to 10 (completely agree). Generally, responses were positive and ranged from 6.8 (the chemo mouthpiece was comfortable) to 9.3 (the patient instruction sheet was clear). Tellingly, to the question “I would recommend the CMP to other patients undergoing chemotherapy,” the average score was 8.3 (Table 3 ). Table 3 End of Study Device Assessment. The device assessment included 6 questions that patients answered using a scale from 0 (do not agree) to 10 (completely agree) Question Average 1. The Chemo Mouthpiece (CMP) was comfortable 6.8 2. The patient instruction sheet on how to use the CMP was clear 9.3 3. My CMP fit perfectly 7.5 4. I was able to breathe normally with my CMP in place 8.9 5. The length of time that I had to keep the CMP in place was adequate 7.9 6. I would recommend the CMP for other patients undergoing chemotherapy 8.3
Table 3
End of Study Device Assessment. The device assessment included 6 questions that patients answered using a scale from 0 (do not agree) to 10 (completely agree)
| Question | Average |
| 1. The Chemo Mouthpiece (CMP) was comfortable | 6.8 |
| 2. The patient instruction sheet on how to use the CMP was clear | 9.3 |
| 3. My CMP fit perfectly | 7.5 |
| 4. I was able to breathe normally with my CMP in place | 8.9 |
| 5. The length of time that I had to keep the CMP in place was adequate | 7.9 |
| 6. I would recommend the CMP for other patients undergoing chemotherapy | 8.3 |
Discussion
Cryotherapy has a long history in OM management among patients being treated with cytotoxic chemotherapy. Based on a biological rationale in which mucosal hypothermia-induced vasoconstriction limits local levels of injurious agent, numerous clinical trials have confirmed its efficacy [ 20 , 21 ]. Interestingly, data suggest that cryotherapy is equivalent to photobiomodulation in mitigating oral mucositis among patients receiving conditioning regimens prior to stem cell transplant [ 22 ]. Consequently, the use of cryotherapy is included in guidelines for the management of OM [ 19 ].
Cryotherapy is particularly effective in mitigating mucosal injury associated with 5-FU-based regimens but has also shown to be of benefit in favorably impacting the incidence and severity of OM across a range of regimens in which treatment was provided during part or all of chemotherapy infusion [ 21 ]. Traditionally, cryotherapy has been administered using ice chips, ice cubes, or cold rinses just before and for part or all of the infusion period. While technically easy and seemingly “free,” logistically replenishing ice and controlling melted fluids adds staff time and cost, and is somewhat unpleasant for patients [ 16 ].
Consequently, a self-administered, reusable device was developed to provide a sustained cold surface temperature. In this trial, the efficacy of the device on mitigating oral mucosal pain associated with cytotoxic chemotherapy was assessed. In contrast to the time course typically used for ice, use of the device included, not only the time of infusion, but an extended period thereafter based on the variations in the pharmacokinetics of different cytotoxic agents, and to assess the potential analgesic benefit of cold on damaged mucosa. The device proved to be significantly efficacious in mitigating symptoms associated with mucosal injury as measured by patient-reported symptoms and analgesic use during the first two cycles of patients’ chemotherapy. The frequency of visits at which device-using patients reported any pain was significantly less than patients complying with standard of care. Likewise, in the ITT population, fewer than half of device-using patients reported using analgesics during cycles 1 and 2 compared to control patients.
An analysis of the trajectories of mucosal pain in the test and control groups was informative. As expected, mucosal pain increased to a peak between days 4 to 10 following infusion in the control population. Interestingly, it appeared that symptoms were marginally more pronounced in cycle 2 compared to cycle 1, a trend which has been reported elsewhere [ 5 ]. Device-administered cryotherapy was effective during both cycles.
The size of the trial and the broad inclusion criteria limited our ability to stratify patients by regimen. However, given the distribution of patients by cancer type, we assigned patients to one of two diagnostic categories, those being treated for breast cancer and those being treated for non-breast cancers. We noted a consistent positive signal for both cycles 1 and 2 for the breast cancer cohort (Table 3 ) during which both the incidence and severity of pain were significantly lower in the test group. In contrast, whereas the efficacy of the device during cycle 2 for non-breast cancer patients had a consistent impact on incidence and severity of pain, it was not impactful during cycle 1. While the limited number of evaluable patients must be noted, this observation requires additional study.
Whereas the majority of ice-based cryotherapy protocols limit cold application to the time of infusion, the current study design dictated an extended period of application, far exceeding the expected mucosal levels of chemotherapy noted dictated by drug pharmacokinetics. We reasoned that, in addition to its benefit in reducing mucosal perfusion, the cold itself might be of benefit in controlled local pain. The finding that both pain and analgesic use extended well beyond the timing of acute symptoms may this hypothesis, although an alternative explanation might be that device effectiveness during the period when mucosal drug levels were thought to be most injurious resulted in a “protective” effect that extended throughout the remaining days of the cycle.
Introducing an intraoral device to patients undergoing chemotherapy could be challenging. As indicated by the first group of patients enrolled in this study, providing patients with a choice of device size markedly improved compliance as determined by early terminations. End-of-study reporting indicated that overwhelmingly patients considered its use as positive.
There are two notable limitations to this study. First, while the trial was randomized and controlled, it was impossible to perform in blinded fashion. Nonetheless, the observation that the trajectory of symptoms seen in the trial is consistent with those which have been extensively reported seems to minimize a “placebo” effect. Second, the numbers of patients having non-breast cancers and the small numbers of patients per specific drug regimens precludes any substantive conclusions around diagnosis- or regimen-specific cryotherapy efficacy for which additional data is required.
Conclusion
Application of cold to the mucosa by a self-administered, contained device confirmed the efficacy of cryotherapy as an intervention for oral pain associated with chemotherapy-induced injury and provided sustained symptom prevention for patients infused with drugs of both short and long half-lives. Its continued use beyond the period during which mucosal levels of drug would be expected suggests that cold itself has analgesic benefit. The device was an effective, well-tolerated, convenient surrogate for ice and provided an alternative platform for the delivery of a consistent course of cryotherapy for patients at OM risk.
Supplementary Information
Below is the link to the electronic supplementary material. Supplementary File 1 (DOCX 23.4 KB)
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Acknowledgements
We thank Dr. Savitha Balaraman and Dr. Adil Akhtar for their contribution to patient recruitment for the trial.
Author contributions
R.Z. V.D., C.N., T.G., G.C., E.K., M.G., and E.T. Investigation, reviewing, and editing. S.S. Conceptualization, data processing and review, wrote main manuscript text, editing. F.J. Funding acquisition, resources, editing. All authors have read and agreed to the published version of the manuscript.
Funding
This trial was funded by ChemoMouthpiece, LLC.
Data availability
Data is provided within the manuscript or supplementary information files.
Declarations
Institutional review board statement
The study was conducted in accordance with the Declaration of Helsinki and reviewed and approved by regional (WIRB-Copernicus Group IRB) or institutional IRBs.
Additional Information
Preliminary results of portions of this trial were presented as an abstract at the 2024 Annual Meeting of MASCC held in Lille, France; Supportive Care in Cancer (2024) 32 (Suppl 1):S434.
Competing interests
RZ is a consultant for Mirati Therapeutics, Flatiron and Bristol-Myers Squibb (BMS) and has received research and travel support from ChemoMouthpiece, LLC; VD participates in a Speaker Bureau for BMS/Regeneron and has equity in BMS; NA, GC, CN, EK, ET, MG, TG have no conflicts to declare; FJ is an employee of ChemoMouthpiece; SS is an employee of Biomodels, LLC and Primary Endpoint Solutions, LLC. Both companies assist industry (including ChemoMouthpiece), government and academics to study and enable drugs, biologicals, and devices to treat patients for a variety of indications including cancer and side effects and toxicities of its treatment.
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