Date Published: June 19, 2019
Publisher: Public Library of Science
Author(s): Carrie Anne Minnaar, Jeffrey Allan Kotzen, Olusegun Akinwale Ayeni, Thanushree Naidoo, Mariza Tunmer, Vinay Sharma, Mboyo-Di-Tamba Vangu, Ans Baeyens, Stephen Chun.
The global burden of cervical cancer remains high with the highest morbidity and mortality rates reported in developing countries. Hyperthermia as a chemo- and radiosensitiser has shown to improve treatment outcomes. This is an analysis of the local control results at six months post-treatment of patients enrolled in an ongoing study investigating the effects of the addition of modulated electro-hyperthermia (mEHT) to chemoradiotherapy for the treatment of HIV-positive and -negative cervical cancer patients in a low-resource setting.
This ongoing Phase III randomised controlled trial, conducted at a state hospital in Johannesburg, South Africa, was registered with the appropriate ethics committee. After signing an informed consent, participants with FIGO stages IIB to IIIB squamous cell carcinoma of the cervix were randomised to receive chemoradiotherapy with/without mEHT using a secure online random-sampling tool (stratum: HIV status) accounting for age and stage. Reporting physicians were blind to treatment allocation. HIV-positive participants on antiretroviral treatment, or with a CD4 count >200cell/μL were included. mEHT was administered 2/weekly immediately before external beam radiation. The primary end point is local disease control (LDC) and secondary endpoints are toxicity; quality of life analysis; and two year survival. We report on six month LDC, including nodes visualised in the radiation field on 18F-FDG PET/CT (censored for six month survival), and six month local disease free survival (LDFS) (based on intention to treat). Trial status: Recruitment closed (ClinicalTrials.gov: NCT03332069).
271 participants were recruited between January 2014 and November 2017, of which 210 were randomised for trial and 202 were available for analysis at six months post-treatment (mEHT: n = 101; Control: n = 101). Six month LDFS was higher in the mEHT Group (n = 39[38.6%]), than in the Control Group (n = 20[19.8%]); p = 0.003). LDC was also higher in the mEHT Group (n = 40[45.5%]) than the Control Group (n = 20[24.1%]); (p = 0.003).
Our results show that mEHT is effective as a chemo-radiosensitiser for cervical cancer, even in high risk a patients and resource-constrained settings.
The global burden of cervical cancer remains high, with 570 000 new cases and 311 000 deaths estimated to have occurred in 2018. It is the fourth most common cancer, and the cancer with the fourth highest mortality rate, amongst women. The mortality rate from cervical cancer is around 3 cases per 100,000 in developed countries and around 18 per 100,000 in developing countries.
This a single centre, phase III, randomised controlled (stratum: HIV status; accounting for stage and age) parallel group trial being conducted at the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), a public hospital in Gauteng, South Africa, by the Radiation Sciences department of the University of the Witwatersrand. Approval from the Human Research Ethics Committee was obtained (M1704133) on 5th June 2012. According to the requirements of the local ethics board, the trial was registered on the South African National Clinical Trials Register before recruitment was started (ID: 3012). Registration of the trial ClinicalTrials.gov (NCT03332069) was finalised after recruitment began. The authors confirm that all ongoing and related trials for the intervention are registered on ClinicalTrials.gov.
Of 271 screened participants screened between January 2014 and November 2017, 210 were randomised for trial (Fig 1). The most common reasons for omission of the second cycle of cisplatin were renal dysfunction (mEHT: n = 19; Control: n = 11) and delayed in the administration of the first cycle (mEHT: n = 10; Control: n = 7), followed by non-compliance, anaemia, vomiting and dehydration, sepsis, poor ECOG, immunosuppression and other, including supply and technical problems. Reasons for all screening failures can be found in S1 Fig. By the stratification to tumour stage, participant age, and HIV status, the numbers of participants in each group were balanced. Four randomised participants did not arrive for treatment and no further data is available on these participants. They were classified as “lost to follow up”. Patient, tumour and treatment characteristics were balanced in both treatment groups with no significant difference in the means or frequencies (Table 1). There were 104 and 102 participants treated in the mEHT and Control Groups respectively. Four participants could not be evaluated for LDC at six months post-treatment (in high care with bowel perforation: n = 1; deceased at home and cause of death unknown: n = 1; too unwell to travel: n = 2). 18FDG-PET/CT scans were conducted at a median of 186 days after completion of all RT treatments (range 154–610 days).
Our results show that the addition of mEHT to chemoradiotherapy protocols for the management of LACC patients, results in a significantly higher six month LDC and six month LDFS, in a resource-constrained setting and in immunocompromised patients. Hyperthermia is a known radiosensitiser and the heating effect of mEHT during the treatments is therefore likely to be the largest contributor to the improved outcomes seen in patients treated with mEHT in our study. Another possible contributing factor is the immunomodulating effect of mEHT described in the literature which may also contribute to the improved outcomes seen even in patients who are immunocompromised.
This phase III RCT provides the first evidence for the use of mEHT to improve treatment outcomes when added to CRT for the treatment of LACC. The results offer evidence of efficacy of a heating technique that is feasible and can be implemented in a low resource setting in a population sample in whom treatment and management of LACC is particularly challenging. The results indicate that mEHT can be integrated into the multimodal treatment regimens for LACC patients treated with radiotherapy with/without cisplatin, improving outcomes and potentially assisting in alleviating the burden of LACC on healthcare systems. There is also a potential benefit to the addition of mEHT to CRT for the treatment of LACC in less resource-constrained settings. A longer follow up period is required to assess the survival benefits and further papers are planned to report these results. The design of further phase III studies on mEHT as a chemo- or radiosensitiser for the treatment of other malignancies is warranted. The potential abscopal effect observed suggests that further investigations into the use of mEHT combined with immunotherapies are warranted.