Hyperthermia and radiotherapy in the management of head and neck cancers: A systematic review and meta-analysis.
Topic: Hyperthermia

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.

PICO
Population: Patients with head and neck cancers
Intervention: Hyperthermia and radiotherapy
Comparison: Radiotherapy alone
Outcomes: Outcome of controlled clinical trials in head and neck cancers using hyperthermia and radiotherapy versus radiotherapy alone

Included studies:
title: 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.
abstract: 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.
title: Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer.
abstract: The purpose of this research was to evaluate toxicity, response, and changes in oxygenation (pO(2)) in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation therapy (RT) followed by mastectomy.
title: Hyperthermia with radiation in the treatment of locally advanced head and neck cancer: a report of randomized trial.
abstract: 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 standard 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.
title: Effectiveness of RF capacitive hyperthermia combined with radiotherapy for stages III and IV oro-hypopharyngeal cancers: a non-randomized comparison between thermoradiotherapy and radiotherapy.
abstract: 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.
title: Thermal dose fractionation affects tumour physiological response.
abstract: 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 CEM43T(90), in one versus three to four fractions per week, over 5 weeks.
title: Head and neck cancers: results of thermoradiotherapy versus radiotherapy.
abstract: Sixty-five patients were included in a randomized 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.
title: Does pretreatment human papillomavirus (HPV) titers predict radiation response and survival outcomes in cancer cervix?--a pilot study.
abstract: To evaluate if pretreatment HPV titers in cancer cervix could predict radiation response and survival outcomes.
title: 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).
abstract: 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.
title: Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: a prospective randomized clinical trial.
abstract: Between September 1985 and December 1986, 44 N3 (TNM-UICC) metastatic squamous cell cervical lymph-nodes were randomized 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-randomized 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.
title: Intracavity hyperthermia in nasopharyngeal cancer: a phase III clinical study.
abstract: 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.
title: 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.
abstract: Previous results from our phase 3 randomised 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.
title: Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck.
abstract: 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).
title: Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a Report by the Radiation Therapy Oncology Group.
abstract: Since February 1981, 300 patients with superficial measurable tumors were randomized 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 practices 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)
title: Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group.
abstract: 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 degrees 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 (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 tumors less than 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 less than 3 cm treated with irradiation and heat, there was improved local control. In lesions greater than 3 cm, there was no difference in local control between the two treatment arms. The higher response rate in patients with smaller lesions (less than 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.