Conference Paper Oncothermia in HIV-Positive and -Negative Locally Advanced Cervical Cancer Patients in South Africa

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1 Conference Papers in Medicine, Article ID , 3 pages Conference Paper Oncothermia in HIV-Positive and -Negative Locally Advanced Cervical Cancer Patients in South Africa Carrie A. Strauss, 1 Jeffrey A. Kotzen, 1 Ans Baeyens, 1,2 and Irma Maré 1 1 Radiation Sciences, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa 2 Radiation Biophysics, ithemba LABS, P.O. Box 722, Somerset West 7129, South Africa Correspondence should be addressed to Carrie A. Strauss; carrie@c-therm.co.za Received 16 January 2013; Accepted 9 May 2013 Academic Editors: G. F. Baronzio, M. Jackson, and A. Szasz This Conference Paper is based on a presentation given by Carrie A. Strauss at Conference of the International Clinical Hyperthermia Society 2012 held from 12 October 2012 to 14 October 2012 in Budapest, Hungary. Copyright 2013 Carrie A. Strauss et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. Investigate the clinical, economic, and cellular effects of the addition of oncothermia to standard treatment for HIV-positive and -negative locally advanced cervical cancer patients in public healthcare in South Africa. Objectives. Evaluatetheeffectthat the addition of oncothermia has on local disease control, progression-free survival, overall survival at 2 years, treatment toxicity, quality of life, economic impact, and HIV status of participants. Radiobiology investigations will evaluate thermoradiosensitivity and the molecular markers for thermoradiosensitivity. Methodology.Phase IIIrandomised clinical trial involving 236 HIV-negative and -positive stage IIb-III locally advanced cervical cancer patients. Treatment includes cisplatin, external beam radiation, and brachytherapy. The study group will receive oncothermia treatments. Participants will be monitored for two years after completion of treatment. Hypothesis. The addition of oncothermia to standard treatment protocols will result in improved clinical response without increasing treatment toxicity in HIV-positive patients or raising healthcare costs. 1. Introduction More than 80% of hospital patients in Africa receive treatment in public healthcare facilities where resources and funding are limited [1]. The economic impact of cancer extends from the financial costs of treatment, rehabilitation, end-of-life care and loss of life to the economic costs of days off work, loss of productivity, and the social-economic pressures on the family and community of cancer patients [2]. Sub-Saharan Africa has the highest HIV prevalence in the world [3]. It is a growing concern that the HIV status of a person and the antiretroviral medications increase the patients sensitivity to toxicity from radiation therapy and chemotherapy [4 6]. There is therefore a strong need for the investigation and application of technologies which can increase cancer treatment efficacy without increasing the treatment costs in Africa. Research from The Netherlands indicates that hyperthermia technology may increase the treatment efficacy whilst lowering the healthcare costs of cervical cancer patients [7]. The investigation of the use of affordable hyperthermia technology is therefore warranted. 2. Background Cervical cancer is classified as an AIDS defining illness by the World Health Organisation. Over 80% of the 555,000 new cervical cancer diagnoses globally per year will occur in developing countries where HIV is prevalent [8]. Cervical cancer is the second most prevalent female cancer in South Africa with around 5,000 new cases diagnosed per year. This was 16.24% of all new cancer diagnoses in 2001, the year in which the last official national cancer statistics were published [9]. Although recent statistics on cervical cancer in South Africa are lacking, doctors at the Charlotte Maxeke Johannesburg Academic hospital estimate that 20% of radiation oncology patients have cancer of the cervix, 60% of which are

2 2 Conference Papers in Medicine in stage IIIb at the time of diagnosis. An estimated 30% of the cervical cancer patients in public healthcare facilities are HIV positive [10]. 3. Aim To investigate the clinical, economic, and cellular effects of the addition of oncothermia to standard treatment protocols for HIV-positive and -negative locally advanced cervical cancer patients in public healthcare in South Africa. 4. Methodology Study Design. Phase III randomised clinical trial. Sample. 236 HIV-negative and HIV-positive stage IIIb-III locally advanced cervical cancer patients will be recruited. This isbasedontheestimatedrequiredsamplesizeforatwosample comparison of survivors function at two years. The statistical significance is defined as a two-sided alpha <0.05 for a log-rank test, with a constant hazard ratio of , a statistical power of 90%, a 15% withdrawal rate, and an estimated 140 events. We anticipate that at least 50% of recruited participants will be in stage III of thediseaseandaround30%ofparticipantswillbehiv positive. Randomisation. The participants will be divided into a control group(n = 118) and a study group (N = 118), andthesamplingmethodusedwillbestratifiedrandom sampling (stratum: HIV status). Location. Charlotte Maxeke Johannesburg Academic Hospital, Gauteng, South Africa. Treatment. Participants from both groups will receive 3 doses of cisplatin (80 mg/m 2 )administeredthreeweeksapart, external beam radiation (50 Gy administered over 25 factions of 2 Gy), and 3 HDR intracavitary brachytherapy treatments of8gyeach.thestudygroupwillreceivetwo60-minutemodulated electrohyperthermia (oncothermia) treatments per week during the external beam radiation therapy (total 10 treatments). Duration. The study is scheduled to start in early 2013, and the recruitment period is expected to take two years. Participants will be monitored for two years after completion of treatment protocols. The total study duration is expected to be four years. Preliminary results for the local disease control and radiobiology research are expected to be available within the first three years. Radiobiology Research. Radiobiology research will be conducted on tissue and tumour samples in order to study the effect that heating tumours has on the systemic and local response and toxicity resulting from treatment with ionising radiation. Ethics. Ethics clearance from the Human Research Ethics Committee (Medical) has been obtained (ethics clearance number: M120477) and the trial has been registered on the Department of Health s National Trial Database. 5. Objectives Primary Objectives. Evaluate the effect that the addition of oncothermia has on local disease control at 6 months (assessed by PET scans), progression free survival at 12, 18 and 24 months, and overall survival at 2 years (and the cause of death) in HIV-positive and -negative cervical cancer patients. Secondary Objectives. (1) To evaluate the adverse effects that canbedirectlyattributedtooncothermiatreatments.(2) To evaluate the effects of oncothermia on tolerability and toxicityoftheprescribedtreatments.(3)toevaluatethe economic impact of the addition of oncothermia to standard treatment protocols in public healthcare (based on quality adjusted life years). (4) To evaluate the effect of the addition of oncothermia on the quality of life of patients (EuroQOL EQ- 5D-5L questionnaire and the EORTC QLQ-CX24 cervical carcinomaspecificquestionnaire).(5)toevaluatetheeffect,if any, of oncothermia treatments on the HIV disease status of HIV-positive participants by assessing the CD4 count, HIV viral load, and the concurrent AIDS-defining conditions. (6) To describe cervical cancer recurrence patterns in both groups by locoregional and distant recurrences and by initial stage and suspicion for nodal metastasis pretreatment. Radiobiology. (1)Toevaluatethermoradiosensitivitybymeasuring DNA damage (double strand breaks) in lymphocytes in response to ionising radiation combined with oncothermia. Haematological samples will be taken from patients in all four groups before and after the administration of radiation therapy. Double strand breaks will be measured using micronucleus (MN) assays, and the results will be analysed in order to determine whether the addition of oncothermia had an effect on the systemic toxicity of ionising radiation therapy in HIV-positive and HIV-negative cancer patients. (2) To investigate the molecular markers for thermoradiosensitivity. This will be done by comparing gene expression profiles of cells extracted from biopsies of thermoradiosensitive and thermoradioresistant tumours. Gene profiling of tumour samples will be used to identify potential molecular markers in the tumour cells which are associated with increased response or with resistance to radiochemotherapy combined with oncothermia. 6. Expected Outcomes It is expected that the addition of oncothermia to standard treatment protocols will result in improved local disease control and improved two year survival rates without increasing the treatment toxicity. We hypothesise that the addition of oncothermia will result in a reduction in healthcare costs associated with the treatment of cervical cancer. 7. Study Rationale Hyperthermia has been investigated for the treatment of cervical carcinoma combined with chemotherapy [11, 12] and radiotherapy [13 15]. The combination of hyperthermia and radiotherapy showed promising results in a phase III randomisedstudybyvanderzeeetal.(2000)[15], however, a prospective randomised trial by Vasanthan et al. (2005) did not demonstrate the same advantages[16]. The inconsistencies in the results are likely due to the lack of fixed reference points for temperature and dose calculations [17] and the differences between the heating methods. This emphasises the importance of the present study in order to clarify the current controversies and to investigate the trimodality combination of thermochemoradiotherapy for cervical carcinoma [18 20].

3 Conference Papers in Medicine 3 Thiswillbethefirsttrialtodatetoinvestigatetheeffectsof hyperthermia on HIV-positive cancer patients and will be the first hyperthermia trial to be conducted in Africa. This will be the first phase III trial investigating oncotherm s hyperthermia in cervical cancer patients and the first phase III trial investigating the trimodality treatment of cervical cancer patients. The investigation into the economic impact of the addition of oncotherm s hyperthermia in public healthcare protocols in Africa and the radiobiology and genetic profiling objectives are unique to this study. Acknowledgments The hyperthermia device being used is the EHY 2000 Plus which is being supplied by Oncotherm GmbH at no charge for the duration of the research. The service and maintenance of the device during this period will be done by the local distributor of the hyperthermia technology: C-Therm Africa (Pty) Ltd. The primary author is employed by the local distributor. The radiobiology research is being made possible by ithemba LABS and the National Research Foundation of South Africa. References [1] C. Keeton, Bridging the gap in South Africa, Bulletin of the World Health Organization,vol.88,no.11,pp ,2010. [2] American Cancer Society, Global cancer facts & figures, 2007, [3] World Health Organisation, Global HIV/AIDS response: epidemic update and health sector progress towards Universal Access Progress report, 2011, tuapr2011 annex8 web.xls. [4]S.Mallik,K.Talapatra,andJ.Goswami, AIDS:aradiation oncologist s perspective, Cancer Research and Therapeutics,vol.6,no.4,pp ,2010. [5] A. Baeyens, J. P. Slabbert, P. Willem, S. Jozela, D. van der Merwe, and A. Vral, Chromosomal radiosensitivity of HIV positive individuals, International Radiation Biology,vol.86, no.7,pp ,2010. [6] N. Housri, R. Yarchoan, and A. Kaushal, Radiotherapy for patients with the human immunodeficiency virus: are special precautions necessary? Cancer, vol. 116, no. 2, pp , [7] J. van der Zee and D. G. González, The Dutch deep hyperthermia trial: results in cervical cancer, International Journal of Hyperthermia,vol.18,no.1,pp.1 12,2002. [8] UNAIDS, South Africa, 2009, [9] National Cancer Registry of South Africa, 2001 National Cancer Registry Tables Published in Cancer in South Africa, , [10] J. Kotzen, Personal communication; radiation oncology, Charlotte Maxeke Johannesburg Academic Hospital, [11] K. Sekiba, T. Hasegawa, and Y. Kobashi, Hyperthermic treatment for gynaecological malignancies, in Cancer Treatment by Hyperthermia, Radiation and Drugs, T.Matsuda,Ed.,pp , Taylor & Francis, [12] R.C.Rietbroek,M.S.Schilthuis,P.J.M.Bakkeretal., Phase II trial of weekly locoregional hyperthermia and cisplatin in patients with a previously irradiated recurrent carcinoma of the uterine cervix, Cancer,vol.79, no.5,pp , [13] F. A. Gibbs, Thermoradiotherapy for genituorinary and gynecological tumors, in Thermoradiotherapy & ThermochemotherapyVol.2:ClinicalApplications, M. H. Seegenschmiedt, P. Fessenden, and C. C. Vernon, Eds., Springer, [14] Y.Harima,K.Nagata,K.Harima,V.V.Ostapenko,Y.Tanaka, and S. Sawada, A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma, International Hyperthermia,vol.17,no.2,pp , [15] J.vanderZee,D.G.González, G. C. van Rhoon, J. D. P. van Dijk,W.L.J.vanPutten,andA.A.M.Hart, Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial, Lancet,vol. 355, no. 9210, pp ,2000. [16] A. Vasanthan, M. Mitsumori, J. H. Park et al., Regional hyperthermia combined with radiotherapy for uterine cervical cancers: a multi-institutional prospective randomized trial of the international atomic energy agency, International Journal of Radiation Oncology Biology Physics,vol.61,no.1,pp , [17] D. Fatehi, J. van der Zee, E. van der Wal, W. N. van Wieringen, and G. C. van Rhoon, Temperature data analysis for 22 patients with advanced cervical carcinoma treated in Rotterdam using radiotherapy, hyperthermia and chemotherapy: a reference point is needed, International Hyperthermia,vol.22, no. 4, pp , [18] E. L. Jones, T. V. Samulski, M. W. Dewhirst et al., A Pilot Phase II trial of concurrent radiotherapy, chemotherapy, and hyperthermia for locally advanced cervical carcinoma, Cancer, vol. 98, no. 2, pp , [19] H. Tsuda, M. Tanaka, T. Manabe et al., Phase I study of combined radiation, hyperthermia and intra-arterial carboplatin for local recurrence of cervical cancer, Annals of Oncology,vol.14, no. 2, pp , [20] A. M. Westermann, E. L. Jones, B. C. Schem et al., First results of triple-modality treatment combining radiotherapy, chemotherapy, and hyperthermia for the treatment of patients with stage IIB, III, and IVA cervical carcinoma, Cancer, vol. 104, no. 4, pp , 2005.

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