First results of triple‐modality treatment combining radiotherapy, chemotherapy, and hyperthermia for the treatment of patients with Stage IIB, III, and IVA cervical carcinoma The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma. Side-effects of local hyperthermia: results of a prospectively randomized clinical study. Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial. Does pretreatment human papillomavirus (HPV) titers predict radiation response and survival outcomes in cancer cervix?--a pilot study. HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy: A phase I study Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial. Long-term survival data of triple modality treatment of stage IIB–III–IVA cervical cancer with the combination of radiotherapy, chemotherapy and hyperthermia – an update Regional hyperthermia combined with radiotherapy for uterine cervical cancers: a multi-institutional prospective randomized trial of the international atomic energy agency. The Cervix Cancer Research Network: A Global Outreach Effort on Behalf of the Gynecologic Cancer InterGroup. HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy--a phase III study. Hyperthermia adds to chemotherapy. Radiotherapy and hyperthermia for treatment of primary locally advanced cervix cancer: results in 378 patients.
Patients with advanced cervical carcinoma are treated routinely with radiotherapy and cisplatin‐containing chemotherapy . It has been shown that hyperthermia can improve the results of both radiotherapy and cisplatin . In the current study , the feasibility and efficacy of the combination of all three modalities was studied in previously untreated patients with cervical carcinoma Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more To clarify the role of thermoradiotherapy for FIGO Stage IIIB cervical carcinomas , both the clinical response and survival of patients treated with radio- or thermoradiotherapy  were investigated . Forty patients with Stage IIIB uterine cervix carcinoma were treated with external beam irradiation to the pelvis , combined with iridium 192 high-dose-rate intracavitary brachytherapy . All patients were divided r and omly into the following two groups : the radiotherapy ( RT ) group of 20 patients , who underwent radiotherapy alone ; and the thermoradiotherapy ( TRT ) group of 20 patients , who underwent three sessions of hyperthermia in addition to radiotherapy . The primary endpoint of this study was local complete response and survival . A complete response was achieved in 50 % ( 10 of 20 ) in the RT group versus 80 % ( 16 of 20 ) in the TRT group ( p = 0.048 ) . The 3-year overall survival and disease-free survival of the patients who were treated with TRT ( 58.2 and 63.6 % ) were better than those of the patients treated with RT ( 48.1 and 45 % ) , but these differences were not significant . The 3-year local relapse-free survival of the patients who were treated with TRT ( 79.7 % ) was significantly better than that of the patients treated with RT ( 48.5 % ) ( p = 0.048 ) . TRT , as delivered in this trial , was well tolerated and did not significantly add to either the relevant clinical acute or long-term toxicity over radiation alone . TRT result ed in a better treatment response and 3-year local relapse-free survival rate than RT for patients with FIGO Stage IIIB cervical carcinoma In 1986 , 25 patients with stage II and III carcinoma of the cervix were treated by a combination of radiation and local hyperthermia using an endotract intravaginal applicator . Another 25 patients were treated with radiation alone . Both groups were followed up for a minimum period of 18 months . The acute and long-term toxicity of local hyperthermia was closely monitored . Our study shows that whereas local hyperthermia adds significantly to the local control achieved with radiation alone , it is not in any way associated with any significant short- or long-term toxicity , and does not enhance the radiation reactions PURPOSE The local failure rate in patients with locoregionally advanced cervical cancer is 41 - 72 % after radiotherapy ( RT ) alone , whereas local control is a prerequisite for cure . The Dutch Deep Hyperthermia Trial showed that combining RT with hyperthermia ( HT ) improved 3-year local control rates of 41 - 61 % , as we reported earlier . In this study , we evaluate long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up . METHODS AND MATERIAL S From 1990 to 1996 , a total of 114 women with locoregionally advanced cervical carcinoma were r and omly assigned to RT or RT+HT . The RT was applied to a median total dose of 68 Gy . The HT was given once weekly . The primary end point was local control . Secondary end points were overall survival and late toxicity . RESULTS At the 12-year follow-up , local control remained better in the RT+HT group ( 37 % vs. 56 % ; p=0.01 ) . Survival was persistently better after 12 years : 20 % ( RT ) and 37 % ( RT+HT ; p=0.03 ) . World Health Organization ( WHO ) performance status was a significant prognostic factor for local control . The WHO performance status , International Federation of Gynaecology and Obstetrics ( FIGO ) stage , and tumor diameter were significant for survival . The benefit of HT remained significant after correction for these factors . European Organization for Research and Treatment of Cancer Grade 3 or higher radiation-induced late toxicities were similar in both groups . CONCLUSIONS For locoregionally advanced cervical cancer , the addition of HT to RT result ed in long-term major improvement in local control and survival without increasing late toxicity . This combined treatment should be considered for patients who are unfit to receive chemotherapy . For other patients , the optimal treatment strategy is the subject of ongoing research OBJECTIVE To evaluate if pretreatment HPV titers in cancer cervix could predict radiation response and survival outcomes . METHODS Twenty-one patients of cancer cervix were treated by radiotherapy ( RT ) alone .  HPV titers were estimated using DNA Hybrid Capture II test . Loco-regional response at 1 month of RT -- complete or partial response ( CR and PR respectively ) and survival outcomes --local disease-free ( LDFS ) , disease-free ( DFS ) and overall ( OS ) survivals were evaluated against pre- and posttreatment HPV titers . RESULTS Pretreatment HPV titers ranged from 0.81 to 3966.10 RLU/cut off ( mean + /- SD : 1264.39 + /- 1148.22 , median : 1129.98 ) . Of the demographic features evaluated , mean HPV titers were significantly different only for patients achieving CR or PR at completion of RT ( mean + /- SD for CR vs. PR : 1616.31 + /- 1146.86 vs. 384.57 + /- 538.80 , P = 0.022 ) . HPV titers at end of RT ranged from 0.12 to 487.42 RLU/cut off ( mean + /- SD : 37.31 + /- 108.60 , median : 2.33 ) . Patients with higher pretreatment HPV titers ( > 1000 RLU/cutoff ) had a higher CR ( P = 0.022 ) and better survival compared to those with < or = 1000 RLU/cutoff ( LDFS , P = 0.004 ; DFS , P = 0.005 ; OS , P = 0.012 ) . At completion of RT , those having > or = 99.5 % fall in HPV had superior survival outcomes than those with < 99.5 % reduction ( LDFS , P = 0.002 ; DFS , P = 0.002 ; OS , P = 0.004 ) . CONCLUSIONS Higher pretreatment HPV titers ( > 1000 RLU/cutoff ) could be considered as a predictor of radiotherapy response and survival in cancer cervix . A reduction in these titers to 99.5 % of their baseline values at end of radiotherapy is also associated with better survival outcomes Background and purpose : The aim of this study was to investigate whether hyperthermia ( HT ) combined with interstitial brachytherapy ( ISBT ) has any influence on acute and late side effects in patients with advanced cervical cancer .  Local control ( LC ) and disease-free survival ( DFS ) were also analysed . Material s and methods : Following the completion of radiochemotherapy , patients with cervical cancer ( FIGO stages I – III ) were assigned to two treatment groups , either ISBT combined with interstitial hyperthermia ( ISHT ) or ISBT alone as a control group . Selection criterion for the ISBT combined with HT group was advanced cervical cancer with poor response to external beam radiotherapy . A total of 76 patients were included in the statistical analysis . Once a week , HT ( at a temperature above 42.5 ° C ) was administered for 45 min before and during high dose rate ( HDR ) brachytherapy ( BT ) in 43 patients . Four HT treatments were administered . Results : The median follow-up time was 43 months ( range 4–73 months ) . Significant differences were not observed for the distribution of early and late complications between the HT and no HT groups . Despite this , LC was similar in both groups . The 5-year DFS for the BT and BT + HT groups was 73.6 % and 65.8 % , respectively . The 5-year LC for the BT and BT + HT groups was 89 % and 83 % , respectively . For the majority of patients the maximum temperature level of 44–45 ° C was achieved during the ISHT . Conclusions : ISHT is well tolerated and does not affect treatment-related early or late complications BACKGROUND Chemoradiation ( RT-CT ) is st and ard treatment for locally advanced cervical cancer ( LACC ) . This study tried to establish if radiotherapy combined with hyperthermia ( RT-HT ) should be preferred in bulky and /or FIGO-stage ⩾III . METHODS In this open-label , multicenter r and omized trial , patients with LACC were r and omly assigned by a computer-generated , biased coin minimization technique to RT-CT or RT-HT . Central r and omization was done with stratification by FIGO-stage , tumour diameter and nodal status . Primary endpoint was event free survival ( EFS ) . Secondary endpoints were pelvic recurrence free survival ( PRFS ) , overall survival ( OS ) and treatment related toxicity . Analysis was done by intention to treat . RESULTS The trial was closed prematurely ( 87 of 376 planned patients enrolled : 43 RT-CT ; 44 RT-HT ) . Median follow-up time was 7.1 years . The cumulative incidence of an event was 33 % in the RT-CT group and 35 % in the RT-HT group . The corresponding hazard rate ( HR ) for EFS was 1.15 ( CI : 0.56 - 2.36 , p=0.7 ) . Also the hazards for PRFS ( 0.94 ; CI 0.36 - 2.44 ) and OS ( 1.04 ; CI 0.48 - 2.23 ) at 5 years were comparable between both treatment arms as was grade ⩾3 radiation related late toxicity  ( 6 RT-CT and 5 RT-HT patients ) . CONCLUSION After 25 % of intended accrual , data suggest comparable outcome for RT-CT and RT-HT Background : Advanced cervical cancer is routinely treated with radiotherapy and cisplatin-containing chemotherapy . Hyperthermia has been shown to improve the results of both radiotherapy and cisplatin . The feasibility of the combination of all three modalities was demonstrated and reported in a study of 68 previously untreated cervical cancer patients in 2005 . Long-term follow-up is presented here . Methods : Sixty-eight patients with advanced cervical cancer were prospect ively registered in the USA , Norway and the Netherl and s , and treated with a combination of radiotherapy ( external beam radiotherapy and brachytherapy for a biologically effective dose of at least 86.7 Gy ) , chemotherapy ( at least four courses of weekly cisplatin ( 40 mg/m2 ) ) and locoregional hyperthermia ( four weekly sessions ) . Long-term follow-up was gathered and recurrence-free survival ( RFS ) and overall survival ( OS ) curves and survival estimates were obtained . Results : Median follow-up was 81 months . Tumours in 28 patients have recurred , 21 of whom have died . Five-year RFS from the day of registration in the study is 57.5 % ( 95%CI : 46.6–71.0 ) and five-year OS is 66.1 % ( 95%CI : 55.1–79.3 ) . Differences between countries can be explained by patient characteristics . Conclusion : The long-term survival results of the combination of full-dose radiotherapy , chemotherapy and hyperthermia fall well within previous reports for this patient group in r and omised trials . The small trial size and lack of r and omisation do not permit further interpretation PURPOSE Hyperthermia can be used to enhance the effects of radiation , and a combined treatment may , in some circumstances , be an advantage . Uterine cervical cancer is very common in developing countries . The control of locally advanced pelvic tumors is difficult with conventional treatment modalities . Based upon the biologic rationale and in view of the recent advances in heating and thermometry techniques , radiotherapy in combination with hyperthermia was investigated in a multi-institutional prospect i ve r and omized trial sponsored by the International Atomic Energy Agency . The primary purpose was to clarify whether the combination of hyperthermia and radiotherapy improves the rate of local control , compared with radiotherapy alone . METHODS AND MATERIAL S A total of 110 patients with biopsy-proven , locally advanced carcinoma of the uterine cervix were r and omized to treatment by radiotherapy with or without hyperthermia .  The patients were stratified by institution , stage , and histologic type . Each patient received external beam radiation therapy and brachytherapy . For the patients r and omized to receive hyperthermia , a minimum of five sessions ( 60 min each , once per week ) were administered , employing a radiofrequency ( RF ) capacitive heating device . Intratumoral temperature was measured at the first hyperthermic treatment , and at least once more during the course of treatment . The equipment and the policies and procedures at each participating institution except one ( Pusan ) were personally inspected at least once by the corresponding author , to ensure that quality assurance procedures were in place and were followed for treatment according to the protocol guidelines . The median follow-up period was 466 days for all the patients and 512 days for the surviving patients . RESULTS The two arms were well balanced with regard to the patient factors , tumor factors , and treatment factors . The overall survival rate at 3 years was 73.2 % , and the local control rate was 68.5 % . There were no significant differences between the patients treated with or without hyperthermia , either with regard to the survival ( p = 0.1893 ) or the rate of local control ( p = 0.58 ) . The survival was significantly worse among the patients with Stage IIb disease who received hyperthermia ( p = 0.0162 ) although there was no difference in their rate of local control ( p = 0.7988 ) . Further analysis is necessary to determine if the difference in survival is due to a greater incidence of distant metastases or some other cause . Acute Grade 2 - 3 toxicity was seen in 10/55 patients ( 18 % ) treated by hyperthermia and in 2/55 of the patients ( 4 % ) treated without hyperthermia ( p = 0.01 ) . There was no significant difference in the late toxicity observed in the two arms . CONCLUSION This prospect i ve r and omized study failed to show any benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced carcinoma of the uterine cervix . The acute toxicity was significantly greater among the patients receiving hyperthermia , and the survival was significantly worse among the Stage IIb patients receiving hyperthermia even though there was no difference in the local control rate Cervix cancer is a worldwide scourge . It is the second leading cause of cancer deaths in women worldwide with a rate of 728 deaths per day . 87 % of cervix cancer deaths occur in low- and middle-income countries , with mortality rates varying 18-fold.1 Even in high-income nations , there has been little improvement in survival rates.2 The last major improvement in cervix cancer was published 15 years ago with the superiority of cisplatin-based chemoradiotherapy to radiotherapy alone.3,4 The Cervix Cancer Research Network ( CCRN ) developed within the Gynecologic Cancer Intergroup ( GCIG ) out of a realisation that cervical cancer trials were becoming scarce . While cervical cancer rates are declining in GCIG countries , low- and middle-income countries are coping with large disease burdens . This led to extending trial development beyond GCIG borders to involve a network of accredited , capable centres in other areas of the world . It was envisaged that this could harness local enthusiasm to raise st and ards of care . The CCRN would provide the infrastructure and support for high quality trials . The CCRN recognized that many low- and middle-income countries would not be eligible to participate in trials since the degree of infrastructure required to participate would be lacking . The literature was evaluated for best practice s for clinical trials within gynecologic cancers.5 The CCRN developed st and ard operating procedures to ensure adequate infrastructure . A pre-qualifying question naire was developed to evaluate potential sites addressing clinical activity , site re sources , trials operation , radiation records , quality assurance , and clinical management information . Participation in a beam measurement program is required every two years to determine the stability of linear accelerators . The Imaging and Radiation Oncology Imaging Core ( IROC ) in Houston , Texas has partnered with CCRN to provide regular quality assurance . Site visits are performed by an audit team , including a physician and clinical trial manager , to evaluate the appropriateness to participate in CCRN trials . The GCIG has grown to include 28 member groups , and worldwide interest in the CCRN is shown in Figure 1 . To date , 17 different CCRN site visits have been performed . There are ten approved CCRN sites including Tata Memorial Hospital ; Bangalore , India ; Ramathibodi , Thail and ; Triv and rum , India ; Siriaj , Thail and ; Pramongkutklao , Thail and ; Ho Chi Minh , Vietnam ; Blokhin Russian Cancer Research Center , the Hertzen Moscow Cancer Research Institute , and the Russian Scientific Center of Roentgenoradiology . Several additional sites have been approved with contingencies , including Cluj , Romania and Minsk , Belarus . Figure 1 Worldwide GCIG and CCRN participation . CCRN currently has four multinational publicly funded clinical trials that are open for enrollment in low- , middle- , and high-income countries . The TACO Trial , which was developed by investigators from the Korean Gynecologic Oncology Group ( KGOG ) and the Thai Cooperative Group , is comparing weekly cisplatin cancer to every-three-week chemotherapy for locally advanced cervical cancer .  Cisplatin delivered every three weeks may be more effective by achieving a higher peak concentration.6 The OUTBACK Trial , sponsored by the Australia New Zeal and Gynaecology Oncology Group ( ANZGOG ) with participation from NRG Oncology and other cooperative groups , is evaluating the efficacy of extended adjuvant chemotherapy compared to the st and ard weekly cisplatin chemoradiotherapy . The extended adjuvant chemotherapy consists of four cycles of carboplatin and paclitaxel . The INTERLACE Trial is headed by the National Cancer Research Institute ( NCRI ) from the United Kingdom . This trial is evaluating neoadjuvant chemotherapy prior to definitive chemoradiotherapy . Compliance with chemotherapy may be higher in a neoadjuvant approach than in an extended adjuvant approach . In the meta- analysis for neoadjuvant chemotherapy in locally advanced cervix cancer , a benefit was observed when the dose intensity of cisplatin was greater than 25 mg/m2 per week.8 The SHAPE Trial , led by the NCIC Clinical Trials Group in Canada , is a r and omized trial evaluating radical hysterectomy  versus  simple hysterectomy  in low risk , early-stage cervix cancer ( lesions < 2 cm ) . The primary endpoint is pelvic relapse-free survival with secondary endpoints of quality of life , sexual health , and cost-effectiveness.9 The greatest burden of cervix cancer resides in low- and middle-income countries , most notably in Central and South America , sub-Saharan Africa , Eastern Europe , India , and parts of Asia . Simultaneously , the incidence of cervix cancer is declining in the high-income countries . Clinical research is an ongoing challenge , and requires collaboration amongst physicians , hospitals , and patients . In many countries , there are governmental barriers to trial participation and data sharing . The legislation and bureaucracy involved in clinical trials means there is significant cost associated with participation . Physicians and hospitals frequently donate their time to these important efforts , but even in developed nations governmental funding is not sufficient to cover all costs . As technology improves , the information sharing and data collection are easier , but rigorous quality assurance is necessary to maintain the validity of the research question and the credibility of the results . Radiotherapy quality assurance in these trials is done via an internet-based approach . Many areas of the world have experienced relatively rapid economic growth and investment in health systems , which will provide more opportunity for conducting trials . The mission of the CCRN is to promote high quality research performed in locations where there is significant need . In three years we have met with success in this endeavor : there are four fully funded cervix cancer trials ; st and ard operating procedures ; a large cadre of expert volunteer site visitors ; 8 sites have been opened in 6 countries ; and 50 patients have been accrued . The cost of clinical research is small compared with the cost of clinical care . Through these efforts , CCRN hopes to improve the care of women with cervical cancer worldwide . As CCRN exp and s , an additional goal is to provide formalized training to physicians , study staff , and patient navigators to ensure high quality care delivery and follow-up . This can be a motivational aspect for international collaboration and development of country-specific , comprehensive healthcare programs . The goal , to save more lives from cervical cancer , is one that must be achieved BACKGROUND AND PURPOSE The aim of this r and omised trial was to investigate whether hyperthermia ( HT ) combined with interstitial brachytherapy ( ISBT ) has any influence on local control ( LC ) , disease-free survival ( DFS ) , or acute and late side effects in patients with advanced cervical cancer . MATERIAL S AND METHODS After radiochemotherapy , consecutive patients with cervical cancer ( FIGO stage II-III ) were r and omly assigned to two treatment groups , either ISBT alone or ISBT combined with interstitial hyperthermia ( ISHT ) .  A total of 205 patients were included in the statistical analysis . Once a week , HT , at a temperature above 42.5 ° C , was administered for 45min before and during the HDR BT . RESULTS The median follow-up time was 45months ( range 3 - 72months ) . An effect of hyperthermia was not detected for disease-free survival ( DFS ) ( log-rank test : p=0.178 ) or for local control ( LC ) ( p=0.991 ) . According to Cox 's analysis , HT did not significantly influence failure or interactions with potential prognostic factors for LC or DFS . Statistical differences were not observed for the distribution of early and late complications between the HT and non HT groups . CONCLUSIONS ISHT is well-tolerated and does not affect treatment-related early or late complications . Improvements in DFS and LC were not observed following the addition of ISHT to ISBT The hallmarks of hyperthermia and its pleotropic effects are in favour of its combined use with chemotherapy . Pre clinical research reveals that for heat killing and synergistic effects the thermal dose is most critical . Thermal enhancement of drug cytotoxicity is accompanied by cellular death and necrosis without increasing its oncogenic potential . The induction of genetically defined stress responses can deliver danger signals to activate the host 's immune system . The positive results of r and omised trials have definitely established hyperthermia in combination with chemotherapy as a novel clinical modality for the treatment of cancer . Hyperthermia targets the action of chemotherapy within the heated tumour region without affecting systemic toxicity . In specific clinical setting s regional hyperthermia ( RHT ) or hyperthermic perfusion has proved its value and deserve a greater focus and investigation in other malignancies . In Europe , more specialised centres should be created and maintained as network of excellence for hyperthermia in the field of oncology PURPOSE To report response rate , pelvic tumor control , survival , and late toxicity after treatment with combined radiotherapy and hyperthermia ( RHT ) for patients with locally advanced cervical carcinoma ( LACC ) and compare the results with other published series . METHODS AND MATERIAL S From 1996 to 2005 , a total of 378 patients with LACC ( International Federation of Gynecology and Obstetrics Stage IB2-IVA ) were treated with RHT . External beam radiotherapy ( RT ) was applied to 46 - 50.4 Gy and combined with brachytherapy . The hyperthermia ( HT ) was prescribed once weekly . Primary end points were complete response ( CR ) and local control . Secondary end points were overall survival , disease-specific survival , and late toxicity . Patient , tumor , and treatment characteristics predictive for the end points were identified in univariate and multivariate analyses . RESULTS Overall , a CR was achieved in 77 % of patients . At 5 years , local control , disease-specific survival , and incidence of late toxicity Common Terminology Criteria for Adverse Events Grade 3 or higher were 53 % , 47 % , and 12 % , respectively . In multivariate analysis , number of HT treatments emerged as a predictor of outcome in addition to commonly identified prognostic factors . CONCLUSIONS The CR , local control , and survival rates are similar to previously observed results of RHT in the r and omized Dutch Deep Hyperthermia Trial . Reported treatment results for currently applied combined treatment modalities ( i.e. , RT with chemotherapy and /or HT ) do not permit definite conclusions about which combination is superior . The present results confirm previously shown beneficial effects from adding HT to RT and justify the application of RHT as first-line treatment in patients with LACC as an alternative to chemoradiation
Abstract Purpose : A systematic review with conventional and network meta-analyses ( NMA ) was conducted to examine the outcomes of loco-regional hyperthermia ( HT ) with radiotherapy ( RT ) and /or chemotherapy ( CT ) in locally advanced cervix cancer , IIB – IVA ( LACC ) .