Radiotherapy of SCHNN can be associated with significant toxicity including dermatitis and oral mucositis, particularly if it is combined with simultaneous chemotherapy. In the randomized trial of Calais et al. from 1999 that compared definitive radio-chemotherapy to radiotherapy alone for advanced-stage cancer of the oropharynx, 67% and 59% of the patients, respectively, experienced grade ≥ 3 dermatitis, and 71% and 39% of the patients, respectively, grade ≥ 3 mucositis [14]. Dermatitis and mucositis rates may also be high when modern radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) are used. For example, in the prospective observational study of Kucha et al. that compared three-dimensional conformal radiotherapy (3D-CRT) and IMRT, grade ≥ 2 dermatitis and mucositis rates were 90% and 100%, respectively, in the IMRT-group [15]. Grade ≥ 3 dermatitis and mucositis rates were 5% and 21%, respectively. In the randomized prospective study of Grover et al., patients receiving IMRT with a sequential boost had grade ≥ 2 dermatitis and mucositis rates of 59% and 88%, respectively, and corresponding grade ≥ 3 rates of 45% and 14%, respectively [16]. In another randomized study, patients receiving IMRT plus weekly cisplatin grade ≥ 2 dermatitis and mucositis rates were 72% and 100%, respectively, and corresponding grade ≥ 3 rates were 12% and 60%, respectively [17].
Severe acute toxicity may lead to interruption of radiotherapy, which was reported to impair the outcomes of radiotherapy or radio-chemotherapy. In the multivariate analysis of a retrospective study from 2008, patients without interruptions of radiotherapy for longer than one week had significantly better loco-regional control (risk ratio 3.32, 95% confidence interval: 1.26 – 8.79, p = 0.015) and survival (risk ratio: 2.59, 95% confidence interval: 1.15 – 5.78, p = 0.021) [2]. Another study investigated interruptions of radiotherapy in elderly (≥ 66 years) Medicare beneficiaries with head-and-neck cancers identified from a surveillance, epidemiology, and end results-Medicare linked database [3]. Patients with larynx cancer and interruption of their treatment had a significantly increased risk of death by 68% (95% confidence interval: 41%-200%) compared to patients without an interruption. Similar associations were found for other tumor sites but differences did not achieve statistical significance, most likely due to small sample sizes. Moreover, in the review article of Ferreira et al., a strong relationship was found between prolongation of the overall treatment time and loco-regional control and/or survival in patients irradiated for head-and-neck cancers [18]. It was concluded that such a prolongation may result in an average decrease of loco-regional control ranging from 1.2% per day to 12–14% per week.
These data illustrate that interruptions of treatment due to acute toxicity should be avoided in patients irradiated for SCCHN. It is important to decrease grade 2 adverse events or at least postpone their occurrence so they don’t get worse (grade ≥ 3). In the previous studies used for the sample size calculations of the present trial, 86–92% of patients receiving radiotherapy or radio-chemotherapy for SCCHN experienced grade ≥ 2 radiation dermatitis and 86–100% grade ≥ 2 oral mucositis, respectively [1, 11,12,13]. These unacceptably high toxicity rates were found despite standard skin and mouth care. One possible explanation is the limited compliance of the patients, since daily skin and mouth care, which needs to be performed several times per day, requires a high level of discipline. This hypothesis was supported by the results of a previous randomized phase III trial that compared a new absorbent, self-adhesive dressing (experimental arm) to standard skin care (control arm) with respect to prevention of radiation dermatitis [4, 5]. In this trial, the dermatitis rates were significantly lower than expected in both arms, i.e. also in the control arm. This unexpected result was believed to be due to the fact that the patients received daily reminders by at least two medical staff members (instead of routinely once a week by one staff member) to perform their skin care. This likely led to a better compliance, more intensive and regular skin care, and consecutively a reduction in radiation-induced dermatitis. Therefore, besides novel agents for skin and mouth care, new approaches are required that can improve the patients’ compliance.
However, due to limited personal resources, it is difficult to remind the patients every day, particularly in times of high patient load. Therefore, alternative options are required. One option could be a mobile application that reminds the patients every day to perform their skin and mouth care. The present randomized trial investigated the effect of such a reminder app on radiation dermatitis and oral mucositis by comparing standard care supported by an app to standard care alone. According to the sample size calculations, a total of 168 patients (including 5% not qualifying for the analyses) were required. Interim analyses were planned after completion of radiotherapy in one third (n = 56) and two thirds (n = 112) of the patients. At the time of the first interim analysis, it was decided to prematurely terminate the trial, mainly due to delayed and slow accrual of patients. In addition to its early termination, the RAREST-02 trial had further limitations. Only 53 of the 56 patients who had completed curative radiotherapy, did qualify for the analyses within the per-protocol-set. Although the distribution of chemotherapy types was not significantly different between the experimental arm and the control arm, an impact of the type of chemotherapy on the study results, particularly regarding oral mucositis, could not be completely excluded. Moreover, the fact that patients without a smartphone were not eligible for participating in the trial, has led to a selection bias. Patients without a smartphone may be older, less interested in technology, and of lower social status when compared to patients possessing a smartphone. This problem could have been solved by including patients with mobile phones without smartphone features and sending them SMS reminders. However, due to data protection regulations, SMS reminders were not allowed in this trial. After discussions with the corresponding authorities, only the use of a reminder app was possible, and the patient’s e-mail address had to be deleted by Nextlabel OHG immediately after the download of the app. No further transfer of patient-related data was required. To send regular SMS reminders, the patient’s telephone number must have been stored. The fact that it was not regularly checked whether patients disabled the app, was another major methodological drawback of this study. Because of these limitations, the results reported here should be interpreted with caution. According to these results, the use of the reminder app in addition to standard skin and mouth care was associated with non-significantly less grade ≥ 2 dermatitis, grade ≥ 2 mucositis and grade ≥ 3 mucositis. No reduction was found for grade ≥ 3 dermatitis until 60 Gy and EOT. This may be explained by the small numbers of events (8 and 11, respectively) regarding this endpoint, which were lower than for the other endpoints. In the subgroup analyses, several trends were found for reduction of dermatitis and mucositis until 60 Gy; rates of reduction ranged between 18 and 39%. However, the number of patients in these subgroup analyses appeared too small to draw valid conclusions. One may speculate whether some of the observed differences would have achieved statistical significance, if the trial was completed regularly.
In summary, the reminder app led to non-significant reduction of grade ≥ 2 dermatitis and grade ≥ 2 and ≥ 3 mucositis. The limitations of this trial, mainly its early termination, need to be considered when interpreting the results. Additional randomized trials are required to properly define the value of a reminder app to reduce the acute toxicity during radiotherapy of SCCHN.