Hyperfractionated radiation in combination with local hyperthermia in the treatment of advanced squamous cell carcinoma of the head and neck: a phase I-II study. Thermochemoradiotherapy Improves Oxygenation in Locally Advanced Breast Cancer Hyperthermia with radiation in the treatment of locally advanced head and neck cancer: a report of randomized trial. Effectiveness of RF capacitive hyperthermia combined with radiotherapy for stages III and IV oro-hypopharyngeal cancers: a non-randomized comparison between thermoradiotherapy and radiotherapy. Thermal dose fractionation affects tumour physiological response Head and neck cancers: results of thermoradiotherapy versus radiotherapy. Does pretreatment human papillomavirus (HPV) titers predict radiation response and survival outcomes in cancer cervix?--a pilot study. HPV16 DNA status is a strong prognosticator of loco-regional control after postoperative radiochemotherapy of locally advanced oropharyngeal carcinoma: results from a multicentre explorative study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: a prospective randomized clinical trial. Intracavity hyperthermia in nasopharyngeal cancer: A phase III clinical study Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a Report by the Radiation Therapy Oncology Group. Randomized Phase III Study Comparing Irradiation and Hyperthermia with Irradiation Alone in Superficial Measurable Tumors: Final Report by the Radiation Therapy Oncology Group
Twenty-seven patients with cervical metastases from squamous cell head and neck tumours were treated with hyperfractionated XRT ( total dose 69.60 - 76.80 Gy , 1.2 Gy b.i.d . five times a week ) combined with a total of two to six sessions of superficial external HT .  Acute local toxicity was mild ; as major acute side effects , only one ulceration was recorded . No severe late side effects were observed . Late toxicity was similar to that observed in our previous studies with the combination of heat and radiation . Nodal complete response was observed in 77 % of patients , partial response was observed in 15 % of patients and no change was observed in 8 % of patients . Five-year actuarial nodal control was 64.5 + /- 19 % and 5-year actuarial survival was 24 + /- 10 % . The treatment of nodal metastases from head and neck tumours with the combination of HT and hyperfractionated XRT is feasible with an acceptable acute and late toxicity profile Purpose : The purpose of this research was to evaluate toxicity , response , and changes in oxygenation ( pO2 ) in patients with locally advanced breast cancer ( LABC ) treated with concurrent taxol , hyperthermia ( HT ) , and radiation therapy ( RT ) followed by mastectomy . Experimental Design : Eighteen patients with LABC were enrolled from October 1995 through February 1999 . Treatment consisted of taxol ( 175 mg/m2 ) given every 3 weeks for three cycles . Radiation therapy included the breast and regional nodes with a dose of 50 Gy , followed by a boost to 60–65 Gy for those not undergoing surgery . Mastectomy was performed for patients deemed resectable after this neoadjuvant program . HT was administered twice per week . Oxygenation was measured before the first HT treatment and 24 h after the first HT treatment . Results : Fifteen of 18 patients responded , 6 with a clinical complete response , 9 with a partial clinical response , and 3 nonresponders . Thirteen underwent mastectomy with 3 pathological complete responses . Tumor hypoxia was present in 8 of 13 patients ( pO2 = 4.7 ± 1.2 mmHg ) . Five patients had well-oxygenated tumors ( pO2 = 27.6 ± 7.8 mmHg ) . Patients with well-oxygenated tumors before treatment as well as those with significant reoxygenation had a favorable clinical response . Tumor reoxygenation appeared to be temperature dependent and associated with the lower thermal doses . Conclusions : This novel therapeutic program result ed in a high response rate in patients with LABC . Hyperthermia may offer a strategy for improving tumor reoxygenation with consequent treatment response . However , the effect of hyperthermia on tumor reoxygenation appears to depend on thermal dose and requires additional investigation BACKGROUND Head and neck cancer is the leading cause of male mortality due to cancer in India . Surgery , radiation alone or in combination has been the backbone of treatment strategies . Chemo-radiation has emerged as the st and ard of care in most types of head and neck cancer . This strategy has the advantage of maintaining both structure and functions , albeit with increased acute and delayed side effects . Radiation with hyperthermia can achieve the same objective without additional toxicities . MATERIAL S AND METHODS A total of 56 patients were r and omized to radiation therapy ( RT ) alone or RT-hyperthermia ( RT-HT ) arm . Twenty-six patients were included in RT alone arm and 28 patients in the RT-HT arm . Both groups were evenly matched for age , sex , and stage . Patients in both the arms received radiation to a dose of 66 - 70 Gy in 6.5 - 7 weeks . Patients in the study group received weekly HT . HT was started after impedance matching to last for 30 minutes . RESULTS Complete response was seen in 42.4 % of RT alone group compare to 78.6 % in the HT group . The difference was statistically significant ( < 0.05 ) . Kaplan-Meir analysis of survival also showed a significant improvement in favor of RT-HT . No dose limiting thermal burns and excessive mucosal or thermal toxicity were recorded . CONCLUSION Radiofrequency ( RF ) based heating and radical radiation of head and neck cancers is better than in RT alone group . HT should be considered as a valid option wherever the facility for HT is available . This report should infuse greater confidence in radiation Oncologists to practice HT as an adjuvant treatment modality Seventy-two patients with Stages III and IV ( TNM , UICC , 1987 ) squamous-cell carcinoma of the oropharynx and hypopharynx ( oro-hypopharyngeal cancer ) were treated with external irradiation , or irradiation plus 13.56 MHz radiofrequency ( RF ) capacitive hyperthermia from 1989 to 1995 . This study compared initial response , histological effect and 5-year survival rate of  thermoradiotherapy ( TRT ) group with those of radiotherapy alone ( RT ) group . In the TRT group , 15 patients were treated definitively , and 18 patients preoperatively . In the RT group , 15 patients were treated definitively , and 24 patients preoperatively . With definitive irradiation , the complete response rate of the primary lesions was 73 % in the TRT group and 27 % in the RT group ( p = 0.009 ) and the complete response rate of the metastatic lymph nodes was 80 % in the TRT group and 27 % in the RT group ( p = 0.005 ) . With preoperative irradiation , the pathological CR ( No residual cancerous cells ) rate of the primary lesions was 56 % in the TRT group and 8 % in the RT group ( p = 0.01 ) , and the pathological CR rate of the lymph nodes was 72 % in the TRT group and 21 % in the RT group ( p = 0.001 ) . The 5-year survival rates with definitive irradiation were 47.6 % in the TRT group and 18.7 % in the RT group ( p = 0.025 ) . Thus TRT was more effective than RT for advanced oro-hypopharyngeal cancer Purpose : It is unknown whether a thermal dose should be administered using a few large fractions with higher temperatures or a larger number of fractions with lower temperatures . To evaluate this we assessed the effect of administering the same total thermal dose , approximately 30 CEM43T90 , in one versus three to four fractions per week , over 5 weeks . Material s and methods : Canine sarcomas were r and omised to receive one of the hyperthermia fractionation schemes along with fractionated radiotherapy .  Tumour response was based on changes in tumour volume , oxygenation , water diffusion quantified using MRI , and a panel of histological and immunohistochemical end points . Results : There was a greater reduction in tumour volume and water diffusion at the end of therapy in tumours receiving one hyperthermia fraction per week . There was a weak but significant association between improved tumour oxygenation 24 h after the first hyperthermia treatment and extent of volume reduction at the end of therapy . Finally , the direction of change of HIF-1α and CA-IX immunoreactivity after the first hyperthermia fraction was similar and there was an inverse relationship between temperature and the direction of change of CA-IX . There were no significant changes in interstitial fluid pressure , VEGF , vWF , apoptosis or necrosis as a function of treatment group or temperature . Conclusions : We did not identify an advantage to a three to four per week hyperthermia prescription , and response data pointed to a one per week prescription being superior Sixty-five patients were included in a r and omized clinical study to evaluate the efficacy of local hyperthermia as a concomitant agent to radiotherapy in the treatment of carcinoma of the head and neck region . Local hyperthermia at 42 - 43 degrees C was generated by a 27 x 12 MHz radiofrequency diathermy unit and was used before radiotherapy in 33 patients ; the remaining 32 patients were subjected to radiotherapy alone . The response in patients with early lesions ( Stage I and II ) was similar for both the groups , while in patients with advanced disease ( Stage III and IV ) a significantly better tumour control was obtained by the use of the combined treatment 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 OBJECTIVE To investigate the impact of HPV status in patients with locally advanced head and neck squamous cell carcinoma ( HNSCC ) , who received surgery and cisplatin-based postoperative radiochemotherapy .  MATERIAL S AND METHODS For 221 patients with locally advanced squamous cell carcinoma of the hypopharynx , oropharynx or oral cavity treated at the 8 partner sites of the German Cancer Consortium , the impact of HPV DNA , p16 overexpression and p53 expression on outcome were retrospectively analysed . The primary endpoint was loco-regional tumour control ; secondary endpoints were distant metastases and overall survival . RESULTS In the total patient population , univariate analyses revealed a significant impact of HPV16 DNA positivity , p16 overexpression , p53 positivity and tumour site on loco-regional tumour control . Multivariate analysis stratified for tumour site showed that positive HPV 16 DNA status correlated with loco-regional tumour control in patients with oropharyngeal carcinoma ( p=0.02 ) but not in the oral cavity carcinoma group . Multivariate evaluation of the secondary endpoints in the total population revealed a significant association of HPV16 DNA positivity with overall survival ( p<0.01 ) but not with distant metastases . CONCLUSIONS HPV16 DNA status appears to be a strong prognosticator of loco-regional tumour control after postoperative cisplatin-based radiochemotherapy of locally advanced oropharyngeal carcinoma and is now being explored in a prospect i ve validation trial Between September 1985 and December 1986 , 44 N3 ( TNM-UICC ) metastatic squamous cell cervical lymph-nodes were r and omized to receive conventionally fractionated radical irradiation ( RT ) to a total dose of 64 - 70 Gy , or conventionally fractionated radical irradiation plus twice a week local microwave hyperthermia ( Ht ) . The two major end points of this study were ( a ) local control rates evaluated at 3 months after the end of combined therapy and ( b ) incidence of acute local toxicity .  Thirty-six nodes ( 82 % ) were evaluable as of December 1986 , at which time there was a premature closure of this study due to ethical reasons . An interim analysis had revealed a statistically significant difference in complete response rates in favor of the combined arm ( p = 0.0152 ) . The complete response rates were 82.3 % ( 14/17 ) for the combined treatment arm versus 36.8 % ( 7/19 ) for the control irradiation arm , leading to an iso-dose thermal enhancement ratio ( TER ) value of 2.23 . Both arms are comparable in average total RT dose delivered ( RT : 67.05 Gy ; RT + Ht : 67.85 Gy ) and in average maximum node diameter ( RT arm : 4.81 cm ; RT + Ht : 4.88 cm ) . Acute local toxicities were similar in irradiated and heated plus irradiated neck regions ; only one skin burn was observed . As possible treatment related death , one patient in the RT + Ht arm died 2 months after completion of therapy with a carotid rupture associated with extensive tumor necrosis . These results confirm previous non-r and omized reports suggesting that hyperthermia in combination with full dose conventionally fractionated irradiation significantly enhances the chance of early local control of fixed N3 neck nodes without exhibiting an increase of acute local toxicity Purpose : To compare the local tumour control , survival , and acute mucous toxicity of nasopharyngeal cancer ( NPC ) patients treated with conventional radiotherapy ( RT ) combined with intracavity hyperthermia versus conventional RT alone . Methods and material s : Previously untreated NPC patients were assigned r and omly into the conventional RT group and the hyperthermia group . In addition to curative RT , hyperthermia group patients received intracavity hyperthermia before or after RT ; T90 was 42.5 ° –43 ° C for 50 min twice a week for 7 weeks . Results : From August 2001 to July 2006 , 180 eligible patients with NPC were enrolled in this study .  The complete response ( CR ) rate in the two arms ( RT plus hyperthermia versus conventional RT ) was 95.6 % and 81.1 % , respectively ( p = 0.003 , χ2 test ) . CR rates for T2 and T3 patients in the hyperthermia group were 97.1 % and 96.9 % , respectively , while in the conventional RT group they were 79.5 % and 76.7 % , respectively . The difference between the two groups was statistically significant ( p = 0.03 and p = 0.024 , respectively ) . The 5-year local control rate was 91.1 % and 78.9 % for the two arms , respectively ( p = 0.022 ) . Oral mucous toxicity in both arms was comparable . The 5-year PFS and 5-year OS rate for the hyperthermia arm vs. the conventional arm were 72.7 % versus 63.1 % ( p = 0.039 ) and 78.2 % versus 70.3 % ( p = 0.14 ) , respectively . Conclusions : Conventional RT treatment followed by intracavity hyperthermia was well tolerated by the NPC patients . The addition of hyperthermia improved the local tumour control , and our results indicated a positive impact on PFS of NPC patients BACKGROUND Previous results from our phase 3 r and omised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) at 3 years . Here we report the 5-year survival data , and investigate the relation between cetuximab-induced rash and survival . METHODS Patients with LASCCHN of the oropharynx , hypopharynx , or larynx with measurable disease were r and omly allocated in a 1:1 ratio to receive either  comprehensive head and neck radiotherapy alone  for 6 - 7 weeks or radiotherapy plus weekly doses of cetuximab : 400 mg/m(2 ) initial dose , followed by seven weekly doses at 250 mg/m(2 ) . R and omisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score , T stage , N stage , and radiation fractionation . The trial was un-blinded . The primary endpoint was locoregional control , with a secondary endpoint of survival . Following discussion s with the US Food and Drug Administration , the data set was locked , except for queries to the sites about overall survival , before our previous report in 2006 , so that an independent review could be done . Analyses were done on an intention-to-treat basis . Following completion of treatment , patients underwent physical examination and radiographic imaging every 4 months for 2 years , and then every 6 months thereafter . The trial is registered at www . Clinical Trials.gov , number NCT00004227 . FINDINGS Patients were r and omly assigned to receive radiotherapy with ( n=211 ) or without ( n=213 ) cetuximab , and all patients were followed for survival . Up date d median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months ( 95 % CI 32.8 - 69.5 ) versus 29.3 months ( 20.6 - 41.4 ) in the radiotherapy-alone group ( hazard ratio [ HR ] 0.73 , 95 % CI 0.56 - 0.95 ; p=0.018 ) . 5-year overall survival was 45.6 % in the cetuximab-plus-radiotherapy group and 36.4 % in the radiotherapy-alone group . Additionally , for the patients treated with cetuximab , overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash ( HR 0.49 , 0.34 - 0.72 ; p=0.002 ) . INTERPRETATION For patients with LASCCHN , cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone , confirming cetuximab plus radiotherapy as an important treatment option in this group of patients . Cetuximab-treated patients with prominent cetuximab-induced rash ( grade 2 or above ) have better survival than patients with no or grade 1 rash . FUNDING ImClone Systems , Merck KGaA , and Bristol-Myers Squibb The objective of this study was to determine prognostic factors for response and survival on three consecutive institutional trials utilizing  concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck ( SCCHN ) Since February 1981 , 300 patients with superficial measurable tumors were r and omized on an RTOG protocol ( 81 - 04 ) involving fractionated radiation therapy ( 4.00 Gy twice weekly for a total of 32.00 Gy ) , either alone or followed immediately by hyperthermia ( 42.5 degrees C , 60 min ) . This is a report of 218 eligible patients with single lesions : 107 treated with radiotherapy alone ( RT ) , 111 with radiotherapy plus hyperthermia ( RT + HT ) .  Only 56 % of the 24 tumors less than 3 cm and 36 % of the 53 lesions larger than 3 cm received what was felt to be " adequate " therapy ( greater than or equal to 29 Gy and 8 heating sessions ) . Overall complete response ( CR ) was observed in 28 % of the patients treated with RT , and 32 % of the patients receiving RT and heat . Response has been found in previous analyses of this and other RTOG studies to be significantly related to both maximum tumor diameter ( less than 3 or greater than or equal to 3 cm ) and site/histology ( breast/adenocarcinoma , head and neck/squamous , or other site/histologies ) . In the head and neck tumors less than 3 cm in diameter there was no difference in CR with irradiation alone or combined with hyperthermia ( 46 % vs 43 % ) . However , in the breast , and trunk and extremities a better CR rate was noted with irradiation and heat ( 55 % and 67 % ) than with irradiation alone ( 33 % and 0 ) . In lesions less than 3 cm treated with irradiation and heat the probability of remaining in response was 80 % compared with 15 % with irradiation alone . In lesions larger than 3 cm no difference in CR was observed in either treatment group . It has been hypothesized that the response rate is higher in patients with smaller lesions ( less than 3 cm ) and in breast/chest wall , trunk/extremity lesions because these tumors and anatomical sites are easier to heat adequately . Problems encountered in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to accurately represent the temperature distribution in a tumor . Furthermore , differences in equipment and treatment practice s among institutions add to the variability in heat administration data collected . In addition , tumor response may be difficult to judge because of short survival of some patients and occasionally rapid tumor regression that may cause necrosis which may be misinterpreted as persistent tumor . ( ABSTRACT TRUNCATED AT 400 WORDS A total of 307 patients with superficial measurable tumors were registered on a Radiation Therapy Oncology Group ( RTOG ) protocol involving fractionated radiation therapy , either alone or followed immediately by hyperthermia ( 42.5 ° C , 45–60 min ) . Overall complete response ( CR ) was observed in 30 % of the lesions treated with radiotherapy ( RT ) and 32 % of those receiving RT and heat .  Response was found to be significantly related to both maximum tumor diameter ( <3 or > 3 cm ) and site/histology ( breast/adenocarcinoma , head and neck/squamous , or other site/histologies ) . In tumors < 3 cm in diameter in the breast , trunk , and extremities , a better CR rate was noted with irradiation and heat ( 62 and 67 % ) than with irradiation alone ( 40 and 0 % ) . However , in the head and neck there was only minimal difference in CR with irradiation alone or combined with hyperthermia ( 50 vs 38 % ) . In lesions < 3 cm treated with irradiation and heat , there was improved local control . In lesions > 3 cm , there was no difference in local control between the two treatment arms . The higher response rate in patients with smaller lesions ( <3 cm ) may be explained by the fact that these tumors are easier to heat . Problems in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to map the temperature distribution in a tumor . Acute and late toxicities in both treatment arms were comparable , except for an overall 30 % incidence of thermal blisters in the heated tumors
Abstract Purpose : A systematic review and meta- analysis was conducted to evaluate the outcome of controlled clinical trials in head and neck cancers ( HNCs ) using hyperthermia and radiotherapy versus radiotherapy alone .