Preoperative Hyperthermia Research Articles

Multimodale Therapien bei Sarkomen: Standards und Neues in der medikamentösen und radioonkologischen Behandlung

Patients with localized high-risk soft tissue sarcoma are at high risk for both local recurrence and distant metastases despite optimal surgical treatment. Importance of preoperative or postoperative chemotherapy and hyperthermia. Evaluation and overview of published study results. Preoperative or postoperative radiotherapy is considered as standard for patients with localized high-risk soft tissue sarcoma. The results of two randomized studies on neoadjuvant chemotherapy showed asurvival benefit. As both studies did not have acontrol arm without chemotherapy but in one case the superiority of anthracycline/ifosfamide-based chemotherapy in combination with hyperthermia over chemotherapy alone and in the other case the superiority of anthracycline/ifosfamide-based chemotherapy over histology-specific chemotherapy were shown, the formal proof of the superiority of this treatment is still missing. Stratifying the patients treated in the so far largest randomized adjuvant chemotherapy trial according to current risk criteria ( http://www.sarculator.com ) revealed asignificant survival benefit for patients at high risk of recurrence. For high-risk soft tissue sarcomas, multimodal treatment strategies involving perioperative chemotherapy, radiotherapy and, if possible, hyperthermia should be considered in addition to tumor resection. Preoperative chemotherapy should be given preference over postoperative chemotherapy based on available data.

Preoperative hyperthermia combined with chemoradiotherapy in locally advanced rectal cancer: Analysis in 67 patients.

e14630 Background: Recent studies suggest that preoperative chemoradiotherapy in locally advanced rectal cancer can induce downstaging, but after resection the incidence of local recurrences remain...

Regional hyperthermia added to intensified preoperative chemo-radiation in locally advanced adenocarcinoma of middle and lower rectum

Purpose: To evaluate the safety of delivering pre-operative regional hyperthermia (HT) plus an intensified chemo-radiotherapy (CRT) regimen in patients suffering from locally advanced rectal cancer.Methods: Between June 2000 and April 2006, 76 patients with locally advanced (cT3-4 N0/+) rectal adenocarcinoma were treated with HT plus CRT. HT was given once a week, to a total of five treatments, 1 to4 h after radiotherapy (50 Gy with 2-Gy fractions for 5 weeks, plus a 10-Gy boost on the tumour bed, with the same fractionation schedule). Chemotherapy consisted in 5FU 200 mg/m2 continuous infusion throughout the 6 weeks of irradiation and OXA 45 mg/m2 in a weekly bolus. Surgery followed 4 to 6 weeks after the completion of HT plus CRT.Results: HT plus CRT was generally well tolerated. At pathologic examination, there was a pathologic complete response (pCR) (ypT0 ypN0) in 18 out of 76 patients (23.6%), a partial response (PR) in 34/76 ones (44.7%) and a stable disease (SD) in 20/76 (26.3%) ones; 4/76 patients (5.2%) had a progression disease (PD) (distant metastases) at the time of surgery. Good predictors of a longer disease-free survival (DFS) were in order ypN status (log-rank test: p = 0.0008), ypT status (p = 0.002) and pCR (p = 0.03).Conclusion: Preoperative CRT combined with regional HT yielded acceptable toxicity. The rate of pCR was encouraging, although further studies are needed to prove the long-term efficacy of adding HT to CRT.

Monitoring of response to pre-operative chemoradiation in combination with hyperthermia in oesophageal cancer by FDG-PET

Purpose: To evaluate the use of positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) to assess early response to pre-operative chemoradiation therapy in combination with external locoregional hyperthermia in patients with oesophageal cancer by correlating the reduction of metabolic activity with histopathologic response. Material and methods: Twenty-six patients with histopathologically proven intra-thoracic oesophageal cancer (with ≤2 cm gastric involvement), scheduled to undergo a 5-week course of pre-operative chemoradiation therapy and hyperthermia, were included. FDG-PET was performed before (n = 26) and 2 weeks after initiation of therapy (n = 17). FDG uptake was quantitatively assessed by standardized uptake values. Results: After neoadjuvant therapy, 24 of the 26 patients underwent surgery. In 16 patients changes in FDG uptake were correlated to histopathologic response. In these patients, histopathologic evaluation revealed less than 10% viable tumour cells in eight patients (responders) and more than 10% viable tumour cells in eight patients (non-responders). In responders, FDG uptake decreased by a median −44% (−75 to 2); in non-responders, it decreased by a median of −15% (−46 to 40). At a threshold of 31% decrease of FDG uptake compared with baseline, sensitivity to detect response was 75%, with a corresponding specificity of 75%. The positive and negative predictive values were both 75%. Conclusion: FDG-PET is a promising tool for early response monitoring in patients undergoing chemoradiation therapy in combination with hyperthermia.

Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review and meta-analysis.

BackgroundCarcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. The large and growing number of patients affected, the high mortality rates, the worldwide geographic variation in practice, and the large body of good quality research warrants a systematic review with meta-analysis.MethodsA systematic review and meta-analysis investigating the impact of neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer to inform evidence-based practice was produced.MEDLINE, CANCERLIT, Cochrane Library, EMBASE, and abstracts from the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were searched for trial reports.Included were randomized trials or meta-analyses of neoadjuvant or adjuvant treatments compared with surgery alone or other treatments in patients with resectable thoracic esophageal cancer. Outcomes of interest were survival, adverse effects, and quality of life. Either one- or three-year mortality data were pooled and reported as relative risk ratios.ResultsThirty-four randomized controlled trials and six meta-analyses were obtained and grouped into 13 basic treatment approaches.Single randomized controlled trials detected no differences in mortality between treatments for the following comparisons:- Preoperative radiotherapy versus postoperative radiotherapy.- Preoperative and postoperative radiotherapy versus postoperative radiotherapy. Preoperative and postoperative radiotherapy was associated with a significantly higher mortality rate.- Postoperative chemotherapy versus postoperative radiotherapy.- Postoperative radiotherapy versus postoperative radiotherapy plus protein-bound polysaccharide versus chemoradiation versus chemoradiation plus protein-bound polysaccharide.Pooling one-year mortality detected no statistically significant differences in mortality between treatments for the following comparisons:- Preoperative radiotherapy compared with surgery alone (five randomized trials).- Postoperative radiotherapy compared with surgery alone (five randomized trials).- Preoperative chemotherapy versus surgery alone (six randomized trials).- Preoperative and postoperative chemotherapy versus surgery alone (two randomized trials).- Preoperative chemoradiation therapy versus surgery alone (six randomized trials).Single randomized controlled trials detected differences in mortality between treatments for the following comparison:- Preoperative hyperthermia and chemoradiotherapy versus preoperative chemoradiotherapy in favour of hyperthermia.Pooling three-year mortality detected no statistically significant difference in mortality between treatments for the following comparison:- Postoperative chemotherapy compared with surgery alone (two randomized trials).Pooling three-year mortality detected statistically significant differences between treatments for the following comparisons:- Preoperative chemoradiation therapy versus surgery alone (six randomized trials) in favour of preoperative chemoradiation with surgery.- Preoperative chemotherapy compared with preoperative radiotherapy (one randomized trial) in favour of preoperative radiotherapy.ConclusionFor adult patients with resectable thoracic esophageal cancer for whom surgery is considered appropriate, surgery alone (i.e., without neoadjuvant or adjuvant therapy) is recommended as the standard practice.

Pre-operative radio-chemotherapy plus regional hyperthermia in the treatment of advanced rectal cancer: experience with radiation dose escalation

Pre-operative radio-chemotherapy plus regional hyperthermia in the treatment of advanced rectal cancer: experience with radiation dose escalation

Restaging of Locally Advanced Carcinoma of the Rectum with MR Imaging after Preoperative Radio-Chemotherapy plus Regional Hyperthermia

Background: The restaging accuracy of MR imaging in advanced primary rectal carcinoma after preoperative radiochemotherapy and regional hyperthermia was evaluated and compared with the histopathologically verified degree of tumor remission after a course of radio-chemo-thermo-therapy. Patients and Methods: 35 patients with primary rectal carcinoma (uT3/uT4) underwent MRI using a surface coil 4–6 weeks after radiochemotherapy (n = 35), regional hyperthermia (n = 23), and before curative surgery. We defined as gold standard for the remission status the comparison of pretherapeutic endosonography with the histopathology of the resected specimen. Results: T category was correctly restaged after preoperative treatment in only 19 (54%) of 35 patients. Nine of 20 responders were overstaged and seven of 15 non-responders were understaged. Concurrently, the N category was correctly restaged in 19 (54%) of 35 patients (twelve responders and seven non-responders). Overstaging occurred in four responders and two non-responders, understaging occurred in four responders and six non-responders. Conclusions: MRI proved independent of the response status as not suitable to restage locally advanced rectal carcinoma after preoperative radiochemotherapy despite optimized imaging technique and spatial resolution. Basically, imaging the morphology of a tumor cannot clearly differentiate between vital and devitalized tissue after a treatment. Functional imaging such as PET (positron emission tomography) appears more feasible for restaging after radio-chemo-therapy-therapy.

Preoperative hyperthermochemoradio-therapy for esophageal carcinoma

In order to acquire an improved prognosis, preoperative hyperthermia combined with chemotherapy and radiotherapy (HCR) has been performed in our department for patients with esophageal carcinoma. The experimental and clinical investigations that have been continuously performed in our department were introduced with regard to the therapeutic effect brought by HCR for carcinoma, chiefly for esophageal carcinoma. A series of our investigations have demonstrated the excellent anticancer effect of HCR for esophageal carcinoma. Preoperative HCR has contributed to improvements in the prognosis of patients with esophageal carcinoma and is expected to make marked progress in the future with further development of anticancer agents and improvements in the hyperthermia devices.

進行直腸癌に対する術前温熱照射併用療法の有用性

進行直腸癌に対する術前温熱照射併用療法の有用性

Induction chemotherapy and radiotherapy to avoid mastectomy in stage IIA-IIIA breast cancer.

The aim of the presented protocol was to investigate tumour remission and breast conservation rates with and without flap supported surgery after preoperative chemotherapy, radiotherapy and hyperthermia. 101 patients with stage IIA-IIIA breast cancers were initially treated with chemotherapy, radiotherapy and hyperthermia. 96 patients underwent salvage surgery. Complete pathologic response was not related to tumour diameter at diagnosis, the applied chemotherapy regime, number of chemotherapy cycles, overall radiation treatment time and time interval between radiotherapy and surgery. A breast conserving approach was possible in 55 patients (54%). After a median follow-up of 18 months no patient developed an isolated local recurrence.

Preoperative hyperthermochemoradiotherapy for soft tissue sarcoma

We investigated the efficacy of preoperative hyperthermia combined with radiation therapy and systemic chemotherapy (hyperthermochemoradiotherapy; HCRT) as a multimodality limb-sparing approach for soft tissue sarcomas. From January 1991 to December 1994, HCRT was performed in 13 patients with soft tissue sarcomas at our institute. Hyperthermia, with an intratumoral temperature of ≥42.0°C, was given for 1h for a total of eight to ten times. Radiation therapy (30–40Gy) was given at 200cGy per fraction. Two cycles of chemotherapy were given before surgery. It took 4–5weeks to accomplish the HCRT, and surgery was performed 3weeks later. Partial response (PR) was achieved in 3 patients and no change (NC) was shown in 10. The mean reduction of tumor volume was 20.2%. Pathological examination of the resected specimen revealed 10%–100% tumor necrosis (mean 76.4 %). There was no correlation between histologic response and reduction of tumor volume. Limb-sparing surgery was feasible in 12 patients (92.3%) and the final limb salvage rate was 84.6%. No local recurrence was observed during a mean follow-up time of 25months. Four patients developed distant metastases and 2 patients died of the disease. The results of this study indicate that HCRT is an effective treatment for limb-threatening soft tissue sarcomas.

下咽頭癌に対する術前温熱併用放射線療法

下咽頭癌に対する術前温熱併用放射線療法

147 O - Effect of preoperative hyperthermia with radio-chemo-therapy on resectability of locally advanced rectal cancer. A phase II clinical

In locally advanced rectal cancer pre-operative radio-chemotherapy can increase resectability and may provide local control in unresectable cases, but response rates are still unsatisfactory. In a phase II study we investigated whether regional hyperthemia in combination with preoperative radio-chemo-therapy (HRCT) is feasible and will result in downstaging as well as improve resectability. 18 patients (pts) with primary non resectable rectal cancer entered the trial. Initial tumor stage was assessed by endorectal ultrasound (EU) and computed tomography (CT). Pre-operative treatment consisted of 5-FU (300–500 mg/m 2 , dose escalation) and leucovorin (50mg) on days 1–5 and 22–28. Regional hyperthermia (RHT) was carried out using the SIGMA 60 applicaton BSD 2000 once a week prior to radiotherapy. Radiotherapy was applied in prone position using a belly board, three-field technique, standard blocks, 5×1,8 Gy up to 45 Gy. Re-staging was carried out using EU and CT. Four weeks after HRCT, surgery was performed. Treatment-related adverse events were observed in 3 pts with grade III gastrointestinal toxicity requiring a short hospitalisation because of dehydration and/or abdominal discomfort. One patient developed grad IV toxicity with haemorrhagic enterocolitis and treatment was stopped. After treatment 14/18 pts (78%) proved resectable (R0 n = 11/R2 n = 3; Abdomino-perineal resection n = 5 and sphincter saving surgery n = 9). Nonresectable disease after explorative laparotomy was found in 4/18pts in 5 of 18 pts (27%) postoperative complications were observed with anastomatic leakage (n = 2) and perineal abscess (n = 3). A complete histological remission (pCR) was confirmed in 2/18 pts (11%). In median follow up of 13 months (rang 3–21 months) all but one R0-resected pts (n = 11) had no evidence of tumor recurrence. The patients with non-resectable carcinomas (n = 4) had a progression free survival with the range of 5–28 months. Preoperative HRCT in fessible and effective in primary non resectable rectal cancer resulting in a resectability rate of 78% with pCR in 11% of the patients. Treatment related toxicity and postoperative complication-rate are acceptable. Our results suggest that RHT in addition to radio-chemotherapy can improve treatment results in rectal cancer. Therefore a randomized phase III- study has been initiated to validate the effects of HRCT in locally advanced non resectable rectal cancer.

Therapy monitoring in human and canine soft tissue sarcomas using magnetic resonance imaging and spectroscopy

Purpose : The goals of this study were to determine whether magnetic resonance parameters (a) can identify early during therapy those patients most likely to respond to hyperthermia and radiotherapy, (b) can provide prior to or early during therapy information about the temperature distributions which can be obtained in patients receiving hyperthermia, and (c) can provide an understanding of the effects of hyperthermia on tumor metabolic status. Methods and Materials : Twenty-one human patients and 10 canine patients with soft tissue sarcomas treated with preoperative hyperthermia and radiation had a series of magnetic resonance imaging and phosphorus spectroscopy studies done. To address the goals for both the human and canine populations, changes in mean T 2 relaxation times, pH, and various phosphometabolite ratios from the pretreatment (Study 1) to the post first hyperthermia study (Study 2) were correlated with treatment outcome; pretreatment magnetic resonance parameters and changes in magnetic resonance parameters (Study 2-Study 1) were compared with various cumulative thermal descriptors; and thermal descriptors of the first hyperthermia were compared with changes in magnetic resonance phosphometabolite ratios. Results : A decrease in adenosine triphosphate/phosphomonoester from study 1 to study 2 is associated with a greater chance of ≥ 95% necrosis in surgical resected tumors from human patients, but no significant relationships were observed between changes in tumor pH or phosphometabolite ratios and time to local failure in dogs. Pretreatment magnetic resonance parameters correlated with various thermal dose descriptors in canines but not in humans. Change in adenosine triphosphate/inorganic phosphate and phosphomonoester signal to noise ratio correlated with cumulative thermal descriptors in dogs and humans, respectively. In dogs only, increases in thermal dose resulted in decreases in high energy phosphometabolites. Conclusion : Changes in magnetic resonance parameters early during therapy may be predictive of treatment outcome. Pretreatment and changes in magnetic resonance parameters appear to predict how well a tumor will be heated during hyperthermia. Magnetic resonance spectroscopy also appears to be a useful tool to study the effects of various thermal doses on tumor metabolic status.

Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft tissue sarcomas

The lack of an unambiguous thermal dosimetry continues to impede progress in clinical hyperthermia. In an attempt to define better this dosimetry, a model based on the cumulative minutes during which arbitrary percentages of measured tumor temperature points exceeded an index temperature was tested in patients with soft tissue sarcomas treated with preoperative hyperthermia and conventional radiation therapy. Patients received 5000–5040cGy at 180–200 cGy per fraction. Hyperthermia was delivered 30–60 minutes after radiation therapy and given for 60 minutes. Patients were randomized between one and two hyperthermia treatments per week for a total of five or 10 treatments, respectively. Lesions were excised 4–6 weeks after completion of hyperthermia/radiation therapy. Successful treatment outcome was considered to be the finding of greater than 80% necrosis of the sarcoma upon histopathologic examination of the resected specimen. Forty-five patients were eligible with thermometry data available in 44 patients. An average of 19 interstitial sites were monitored each treatment per tumor. Sixty percent of tumors had a successful histopathologic outcome. Univariate analysis demonstrated that several descriptors of the temperature distribution were strongly related to treatment outcome; more strongly than nonthermometric factors, such as the number of treatments per week, tumor volume and patient age and more strongly than the commonly used temperature descriptors T min and T max. Descriptors that incorporated both temperature and time were also superior to the more commonly used descriptors T min and T max. Multivariate stepwise logistic regression analysis revealed that a descriptor of both the hyperthermia treatment time and the frequency distribution of intratumoral temperatures was the strongest predictor of histopathologic outcome and that the best predictive model combined this time/temperature descriptor and one versus two treatment per week grouping. The more conventional temperature descriptor, minimum measured tumor temperature, did not significantly enhance the predictive power of treatment group. Based on these results, we recommend that descriptors based on both the frequency distribution of intratumoral temperatures and hyperthermia treatment time be tested for relationships with treatment outcome in other clinical data bases. Furthermore, we recommend that temperature descriptors that are less sensitive to catheter placement and tumor boundary identification than T min and T max (such as T 90, T 50, and T 10) be tested prospectively along with other important thermal variables in Phase II trials in further, efforts to define a thermal dosimetry for spatially nonuniform temperature distributions.

Preoperative hyperthermia and radiation for soft tissue sarcomas: Advantage of two vs one hyperthermia treatments per week

As part of an ongoing Phase II trial at Duke University Medical Center (DUMC), patients with Stage IIB-IVA soft tissue sarcomas (STS) potentially amenable to wide local excision were treated with preoperative hyperthermia (HT) plus radiation therapy (RT), with HT randomized to one versus two treatments per week, stratified with respect to tumor volume. 17 patients were treated and analyzed. HT was given 30–60 minutes after RT, with heating maintained for 1 hour after 42.0°C was reached. In patients treated with 2 HT per week, treatments were separated by 48 hrs. Concurrent RT was given with 180–200 cGy fractions, five treatments per week, to a nominal tumor dose of 5000–5040 cGy. Surgical extirpation was performed 4 weeks after completion of HT/RT. Treatment effect was evaluated by histopathologic examination of the resected lesions, according to a previously reported system. The mean number of HT given in the 1 and 2/wk groups was 4.4 and 7.3, respectively ( p < 0.01). T max for the 1 and 2 HT/wk groups was 42.4 ± 2.1°C and 43.5 ± 1.8°C, and T min was 38.1 ± 0.8°C and 38.6 ± 0.5°C, respectively. The increase in T min from first to last treatment was 0.5 ± 1.2°C and 1.0 ± 0.8°C, respectively. The T min from the best treatment was 39.1 ± 1.2°C and 40.0 ± 1.0°C, and the T max from the best treatment was 44.5 ± 3.4°C and 45.4 ± 2.5°C for the 1 and 2 HT/wk groups, respectively. There were no statistically significant differences between the 2 treatment groups for any of the above temperature parameters. Severe histopathologic changes were found in 71% (12 of 17) of the lesions. T min and T max and highest T min and T max were between 0.4–1.1°C higher in patients with severe changes ( p = NS). All 9 patients in the 2 HT/wk group had extensive changes, versus only 3 of the 8 patients in the 1 HT/wk group. This difference was highly statistically significant ( p = 0.009, two-tailed Fisher's exact test). These findings suggest an advantage to twice weekly, as opposed to weekly, HT in the setting of this study. Whether there is a corresponding therapeutic gain, or whether these results can be extrapolated to other settings requires further investigational efforts. It is recommended that treatment parameters, particularly temperature parameters, continue to be examined in Phase II trials.

Pre-operative hyperthermia and radiation for soft tissue sarcomas: Continued advantage of two vs. one hyperthermia treatments per week

Pre-operative hyperthermia and radiation for soft tissue sarcomas: Continued advantage of two vs. one hyperthermia treatments per week

Preoperative hyperthermia combined with radiotherapy and chemotherapy for patients with incompletely resected carcinoma of the esophagus.

Two hundred eighty-nine patients with squamous cell carcinoma of the esophagus underwent subtotal esophagectomy from December 1965 to June 1986. Resection of esophageal carcinoma was absolutely noncurative in 64 patients (20%) due to invasion to the surrounding structures. These 64 patients were subdivided as follows into three groups based on the type of preoperative treatment: Group I included 16 patients without preoperative treatment; Group II included 38 patients with preoperative radiotherapy combined with chemotherapy (average doses: radiation 37.3 Gy, 1-(2-tetrahydrofuryl)-5-fluorouracil [tegafur] 8.4 g); Group III included 10 patients who underwent preoperative hyperthermia (42 degrees C to 45 degrees C) combined with chemotherapy and radiotherapy (average doses: radiation 33 Gy, bleomycin 33.9 mg, or cis-diamine dichloroplatinum 75 mg, hyperthermia 6.2 times). There were no significant differences in terms of postoperative therapy among the three groups. The median survival times for patients in Groups I, II, and III were 6, 7.5 and 11 months, respectively. The 2-year survival rates for patients in Groups I, II, and III were 0, 15.6%, and 34.3%, respectively. The prognosis in Group III was superior to that for Group I (P less than 0.05) and Group II. These results suggest that preoperative hyperthermia combined with radiotherapy and chemotherapy could prolong survival even in patients who have had noncurative resection.

Preoperative hyperthermo-chemo-radiotherapy effective for carcinoma of the esophagus.

We prescribed hyperthermo-chemo-radiotherapy preoperatively for 13 patients with esophageal carcinoma. Viable cancer cells disappeared in four out of 13 patients, and all of these four patients survive without recurrence 3 to 34 postoperative months, at this writing. In another seven out of the 13, cancer cells were extensively damaged, despite the presence of a small number of viable cancer cells, and three out of these seven died with a recurrence. For two, the treatment was ineffective, and they died of liver metastasis and a local recurrence, respectively. These findings suggest that preoperative hyperthermia combined with chemotherapy and radiation is highly effective for treatment of carcinoma of the esophagus.