Whole-body Hyperthermia In Combination Research Articles

Whole-body hyperthermia in combination with systemic therapy in advanced solid malignancies.

Whole-body hyperthermia (WBH) might be beneficial for patients with metastasized solid malignancies when combined with systemic therapy. This review identified and summarized the phase I/II studies (n = 13/14) conducted using this combination of therapies. Most of the phase II studies used radiant heating methods in a thermal dose of 41.8 °C (1 h). All studies used classic chemotherapy. Great inter-study heterogeneity was observed regarding treatment regimes, included patients and reported response rates (12-89%). Ovarian cancer, colorectal adenocarcinoma, lung cancer and sarcoma have been studied most. Most reported toxicity (grade 3/4) was myelosuppression. Treatment related mortality was present (4 patients) in three out 14 phase II studies (350 evaluable patients, over 966 cycles of WBH with chemotherapy). Absence of phase III trials makes the additive value of WBH highly speculative. As modern oncology offers many less invasive treatments options, it is unlikely WBH will ever find its way in routine clinical care.

Near complete remission of pulmonary metastases in triple negative breast cancer (TNBC) using low-dose immune checkpoint (IC) inhibitors with high dose (HD) interleukin-2 (IL-2) and fever range hyperthermia.

e23111 Background: TNBC is more aggressive, has shorter disease-free and overall survival times than other breast cancer subtypes. Due to the lack of personalized therapies interest is increasing for novel strategies in the metastatic setting. Scientific basis:prolonged low dose anti-CTLA-4 and anti-PD-1 IC blockade with HD IL-2 treatment would be safe and effective in patients with high tumor burden. Methods: Diagnosis of a 50-yr old female patient was primary TNBC with lymphadenopathy and disseminated lung metastases. First, an off-label low-dose PD-1 IC inhibitor nivolumab (0.5 mg/kg) with CTLA-4 IC inhibitor ipilimumab (0.3 mg/kg) was administered weekly, over three weeks. This was accompanied by loco-regional hyperthermia with radiofrequency fields (13.56 MHz) 3 times per week (max. output 400 W) over the thoracic region in combination with Vitamin-C (0.5 g/kg) and alpha lipoic acid (600 mg) over three weeks. This was followed by long duration fever range whole body hyperthermia in combination with low dose cyclophosphamide (300 mg/m²) to down modulate Treg cells. Then, a HD IL-2 (54 Mio/m2 as decrescendo regimen) therapy was administered under Taurolidine protection for five days. Results: The patient presented with widespread disease with a Karnofsky score (Ks) of 80%, felt severe pain in the left lateral chest wall during inspiration that became extremely painful during sneezing. She complained about severe shortness of breath (SOB) on exertion, lack of appetite, insomnia, and exhaustion. Six months later, chest X-ray demonstrated near complete remission of pulmonary metastases. SOB on exertion or any other cancer related symptoms vanished, Ks returned to 100%. Conclusions: We assumed that a frequently administered low dose IC blockade would prevent T cell exhaustion and premature apoptosis making main stream HD IL-2 stimulation treatment safer and more effective. Following the success of this woman, we treated seven more patients with disseminated metastases of different origins, who are responding similarly to the presented TNBC case. This combination treatment warrants further studies.

Inhibition of B16 murine melanoma metastasis and enhancement of immunity by fever-range whole body hyperthermia

Purpose: Whole body hyperthermia (WBH) has been regarded as a promising alternative therapy to cure late stage cancer with metastasis. As the final biological and therapeutic effects are dependent on the specific protocol, the potential of using a microwave-based WBH approach for metastasis inhibition is established and its typical results are discussed.Materials and methods: The effectiveness of a 30-min whole body hyperthermia (WH) on animals, raised to a rectal temperature of 40.2° ± 0.3°C for 30 min followed by 84 h observation by 2450 MHz microwave irradiation, were evaluated. In an experimental lung metastasis model by injection of B16-F10 melanoma, lungs were removed from sacrificed mice 16 days after tumour implantation, and the expression of heat shock protein, inter-cellular adhesion molecule 1 (ICAM-1), proliferating cell nuclear antigen (PCNA) and cyclin D1 was examined. CD4+, CD8+ and NK cell subpopulation in peripheral blood were measured by flow cytometry before and after the last treatment.Results: The best therapeutic effect was obtained when the mice were treated with WBH in combination with the initial chemotherapy with cis-diaminodichloroplatinum (CDDP) and dacarbazine (DTIC) (p < 0.05). The WBH alone has an advantage of reduced toxicity and lower cost. Heat shock protein (HSP) expression increased in the hyperthermia groups. Reduction of PCNA and cyclin D1 was observed in the mice treated with WH alone or in combination with chemotherapy. In the hyperthermia groups, CD4+/CD8+ decreased while the NK increased slightly.Conclusions: The whole body hyperthermia protocol described in this work inhibits B16 tumour metastasis by inhibiting cell proliferation, neovascularisation and stimulating favourable immune responses. It demonstrated that WBH treatment benefits therapy of metastasis cancers.

8041 Preliminary results of whole-body hyperthermia in combination with oxaliplatin in patients with platinum-resistant/refractory ovarian cancer

8041 Preliminary results of whole-body hyperthermia in combination with oxaliplatin in patients with platinum-resistant/refractory ovarian cancer

Whole-body hyperthermia (WBH) in combination with carboplatin in patients with recurrent ovarian cancer — A phase II study

Objective Despite considerable progress in the front-line treatment in patient with advanced ovarian cancer, the outcome of patients with recurrent or refractory disease is still poor. Based on promising results of a pilot study, we initiated a phase II study with WBH and carboplatin in pretreated patients with advanced ovarian cancer to investigate the toxicity and efficacy of WBH in combination with carboplatin. Methods 47 patients with histologically confirmed epithelial ovarian carcinoma were enrolled in the study. Patients were pretreated with at least one palliative chemotherapy regimen. Of 47 patients 24 were classified as platinum refractory or resistant and 16 as platinum sensitive. Results Main toxicity was hematological with grade 3/4 anaemia, leukopenia and thrombocytopenia occurring in 49%, 49% and 65%, respectively. Cardiac complications occurred with grade 1/2 in 22 of 47 (47%) patients and with grade 3 in 1 patient (2%). In 35 patients evaluable for response, the overall response rate was 45% [CR: 4 / 35 (11%), PR: 12 / 35 (34%), NC: 9 / 35 (26%]. In platinum refractory and resistant patients we observed CR in 6%, PR in 24% and NC in 24%. The median overall survival and progression free survival were 61.5 weeks and 29 weeks, respectively. Conclusion This study confirms that WBH in combination with carboplatin is an active salvage treatment option in patients with advanced ovarian cancer. However, significant hematological toxicity has to be considered and renders this regimen less suitable for palliative care setting. There is no evidence yet, that whole-body hyperthermia contributes to any clinical improvement beyond chemotherapy alone. This question can only be addressed in a randomized phase III trial.

Goal-Directed Therapy of Cardiac Preload in Induced Whole-Body Hyperthermia

To optimize volume therapy during induced whole-body hyperthermia (WBH) < or = 42.2 degrees C, pulmonary capillary wedge pressure (PCWP) and intrathoracic blood volume index (ITBVI) were compared as goal parameters. Prospective clinical study. ICU at university hospital. Twenty-three patients with metastatic cancers. Radiant WBH in combination with induced hyperglycemia, hyperoxemia, and chemotherapy was applied. Volume therapy was directed to the PCWP (group A, 8 to 12 mm Hg [20 treatments]), or to ITBVI (group B, 800 to 1,100 mL/m2 [19 treatments]) following a standardized protocol. Goals other than PCWP and ITBVI were cardiac index of > 3.5 L/min/m2 and mean arterial pressure of > 55 mm Hg. In addition to the primary goals PCWP and ITBVI, at defined temperatures, central venous pressure (CVP), extravascular lung water index, the number of infusions, and packed RBCs, as well as serum lactate level, norepinephrine dosage, and levels of liver enzymes, bilirubin, creatinine, and urea were measured. Patients in group A received a significantly greater mean (+/- SD) amount of crystalloids compared to those in group B (6,175 +/- 656 vs 3,947 +/- 375 mL, respectively) and required significantly lower dosages of vasoconstrictors compared with patients in group B. Except for the lower values of CVP in patients in group A during hyperthermia, all of the other hemodynamic and laboratory parameters showed no significant differences between the groups or stayed in a normal range. PCWP and ITBVI are useful parameters to assess preload in induced WBH. Differences in crystalloids and vasopressor dosages may suggest an appropriate ITBVI of > 1,100 mL/m2 for patients with good cardiopulmonary health under such extremely hypercirculatory conditions.

Whole-body hyperthermia in combination with platinum-containing drugs in patients with recurrent ovarian cancer.

Patients with advanced ovarian cancer have an enormous risk of relapse after primary therapy, and the prognosis for these patients remains bleak. Primary and acquired resistance of tumor cells to antineoplastic drugs is a major cause of the limited effectiveness of chemotherapy. The effect of whole-body hyperthermia (WBH) combined with platinum-containing chemotherapy in the treatment of recurrent ovarian cancer was examined in this study. Patients studied were those with pathologically verified epithelial ovarian cancer after operation who had had first-line chemotherapy with cisplatin or carboplatin, and relapsed. All 21 patients were treated with WBH and platinum-based chemotherapy. During the WBH, a core temperature of 41.5 degrees C-42 degrees C was attained in the rectum. We combined the WBH with 300-400 mg/dl artificial hyperglycemia. The plateau temperature was held over a period of, on average, 90 +/- 30 min, and the artificial hyperglycemia, on average, 240 +/- 30 min. WBH was repeated at the beginning of each new chemotherapy cycle. One patient (4.8%) had a complete remission, 7 patients (33.3%) had a partial remission, stable disease was noted in 10 patients (47.6%), and 3 (14.3%) patients did not respond and had progressive disease. Median time to progression was 6.5 months, and median survival time, 16.5 months. Our results validate the efficacy of WBH in the treatment of patients with recurrent platinum-resistant ovarian cancer. The overall tolerance of this treatment was good. The priority for all patients was an improvement in life quality; this was seen 3-4 days after WBH. The encouraging results should be confirmed in randomized studies. Patients with advanced ovarian cancer have an enormous risk of relapse after primary therapy, and the prognosis for these patients remains bleak. Primary and acquired resistance of tumor cells to antineoplastic drugs is a major cause of the limited effectiveness of chemotherapy. The effect of whole-body hyperthermia (WBH) combined with platinum-containing chemotherapy in the treatment of recurrent ovarian cancer was examined in this study.

Tumor oxygenation under combined whole-body-hyperthermia and polychemotherapy in a case of recurrent carcinoma of the oral cavity.

Previous studies have reported synergistic effects of combined hyperthermia and chemotherapy and/or irradiation. The discussed underlying mechanism for this effect is an synergistic cytotoxic and radiosensitizing effect of hyperthermia. In addition, tumor blood-flow and, consequently, tumor oxygenation are increased during hyperthermia. Tumor response to irradiation and chemotherapy of well-oxygenated and vascularized tumors, in general, is superior to that of hypoxic tumors. Therefore, tumor oxygenation is recognized as an important predictive factor in the therapy of malignant tumors. Technically, the head-neck area remains outside the hyperthermia chamber during whole-body hyperthermia (WBH) as currently applied in a number of cancer treatment regimens. The aim of this therapeutic approach was to evaluate whether the blood flow during WBH also increased in the head-neck region and, if so, whether tumor oxygenation increase accordingly. A 60-year-old male Caucasian patient, with the original diagnosis of pT3 pN2b M0 squamous cell carcinoma of the oral cavity, who had undergone primary surgery and irradiation (total dose 60 Gy), developed three local recurrences with consecutive surgical resection, presenting now with another recurrent local tumor (histologically confirmed) without surgical or radiotherapeutical options due to lymphangiosis carcinomatosa. WBH was applied under full anaesthesia, using a humidified radiant heat device (Enthermics Medical Systems RHS-7500) in combination with synchronous application of chemotherapy (ifosfamide and carboplatin). Four cycles of this combined treatment (one cycle per month) were given. Tumor oxygenation and temperature were continuously monitored by Licox catheters by means of one point measurement during each treatment (3.5 h). With a latency of 10 min, the increase of intratumoral temperature in the oral cavity was comparable to reference values in the esophagous. Maximum intratumoral temperature (oral cavity) was 41.8 degrees C (F). The average increase of tumor oxygenation was more than 100% in each individual cycle. Clinically, a partial tumor response was observed. During combined WBH and polychemotherapy, oxygenation is also significantly improved in a tumor in the head and neck area despite the fact that head and neck area remains outside the hyperthermia chamber during WBH. Intratumoral temperatures achieved are comparable to esophageal and rectal temperatures obtained during WBH.

Effect of altered duration of 41.5 degrees C whole body hyperthermia in combination with cis-diamminedichloroplatinum (II) on tumor and normal tissue apoptosis and tumor response in rats.

We investigated the correlation between antitumor efficacy and kinetics of tumor and normal tissue apoptosis when cis-diamminedichloroplatinum (II) (CDDP) was combined with two different durations of whole body hyperthermia [SH-WBH, at 41.5 degrees C for 1 h (1 h WBH) or 2 h (2 h WBH)]. Rats bearing a mammary adenocarcinoma (MTLn3) were treated with 1 or 2 h WBH CDDP and then assessed for tumor growth delay (TGD). A separate study examined the amount of induced apoptosis in tumor and normal tissue (thymus and ileum) over 96 h following the same treatments. 1 h WBH + CDDP increased the TGD to 10.5+/-0.5 days, which was not statistically different from the TGD of 12.3+/-0.5 days obtained with 2 h WBH + CDDP. The area under the curve (AUC) of percentage tumor apoptosis for 1 h WBH + CDDP was 50% of that of 2 h WBH + CDDP. The AUC of percentage thymus apoptosis for 1 h WBH + CDDP was 25% of that of 2 h WBH + CDDP, and the AUC of the score of ileal apoptosis for 1 h WBH + CDDP was 81% of that of 2 h WBH + CDDP. These data indicate that while 1 h WBH + CDDP induced less tumor apoptosis than 2 h WBH + CDDP, antitumor activity was enhanced to a similar degree by both 1 h and 2 h WBH + CDDP, and since 1 h WBH + CDDP caused less normal tissue apoptosis than 2 h WBH + CDDP, a 1 h duration of WBH + CDDP may be a therapy that is both, as effective as, and safer than a 2 h duration of WBH + CDDP.

Whole-body hyperthermia and ADPRT inhibition in experimental treatment of brain tumors.

Malignant primary brain tumors have hitherto been incurable. One reason for this may be the migrating tumor cells that spread into the surrounding normal brain, creating the basis for inevitable recurrences. Therefore, local therapy may have a temporary effect, but for a cure, the treatment must reach all the tumor cells. Whole-body hyperthermia (WBH) is such a general treatment, which we have studied in a rat glioma model. Cells of the RG2 rat glioma cell line were inoculated in the right caudate nucleus of Fischer-344 rats, which were then either controls or treated with WBH, induced by a radiant heat device for 4-5 sessions of 30 min at body temperature 42 degrees C (rectal), and/or nicotinamide (NAM), an effective radiosensitizer in animal tumor models and an inhibitor of ADPRT (poly adenosine diphosphate ribosyl transferase), a chromatin-bound enzyme suggested to be important in the DNA repair system. We have shown that WBH 42 degrees C alone, or in combination with NAM, has no effect upon tumor growth if a larger number of RG2 cells (5,000) are inoculated. If only 1,000 cells are inoculated, a significant inhibitory effect (p < 0.05) is observed on tumor growth as compared to the untreated control animals. Thus, WBH is feasible, and in some circumstances effective, in a rat glioma model. WBH in combination with other therapies influencing cell metabolism may be of value in future postoperative treatment of human malignant brain tumors.

Radiation plus local hyperthermia versus radiation plus the combination of local and whole-body hyperthermia in canine sarcomas

The purpose of this study was to assess the effect of increasing intratumoral temperatures by the combination of local hyperthermia (LH) and whole body hyperthermia (WBH) on the radiation response of canine sarcomas. Dogs with spontaneous soft tissue sarcomas and no evidence of metastasis were randomized to be treated with radiation combined with either LH alone or LH + WBH. Dogs were accessioned for treatment at two institutions. The radiation dose was 56.25 Gy, given in 25 2.25 Gy daily fractions. Two hyperthermia treatments were given; one during the first and one during the last week of treatment. Dogs were evaluated after treatment for local recurrence, metastasis, and complications. Sixty-four dogs were treated between 1989 and 1993. The use of LH+WBH resulted in statistically significant increases in the low and middle regions of the temperature distributions. The largest increase was in the low temperatures with median CEM 43 T90 values of 4 vs. 49 min for LH vs. LH + WBH, respectively (p<0.001). There was no difference in duration of local tumor control between hyperthermia groups (p = 0.59). The time to metastasis was shorter for dogs receiving LH + WBH (p = 0.02); the hazard ratio for metastatic disease for dogs in the LH + WBH group was 2.4 (95% confidence interval, 1.2-5.4) with respect to dogs in the LH group. Complications were greater in larger tumors and in tumors treated with LH + WBH, CONCLUSION: The combination of LH + WBH with radiation therapy, as described herein, was not associated with an increase in local tumor control in comparison to use of LH with radiation therapy. The combination of LH + WBH also appeared to alter the biology of the metastatic process and was associated with more complications than LH. We identified no rationale for further study of LH + WBH in combination with radiation for treatment of solid tumors.

Hyperthermia in cancer growth regulation.

With present techniques, hyperthermia used alone can cause complete clinical regression in 10-15% of tumours but the duration of response is very short. The greatest advantage for hyperthermia at the present time appears to be in combination with radiation in the local control of cancer growth. Currently, large randomised phase III studies are in progress to determine whether the addition of local hyperthermia to radiation or chemotherapy yields significant advantage. Phase III studies of wholebody hyperthermia in combination with chemotherapy are planned for the future and will include tumours with a high growth fraction such as small cell lung cancer and high grade non Hodgkins lymphoma.

Enhancement of murine bone marrow ablation by combining whole body hyperthermia with total body irradiation and cyclophosphamide

Bone marrow ablation using combined whole body hyperthermia (WBH), total body irradiation (TBI), and cyclophosphamidel (Cy) was investigated in C3H f/Sed mice to demonstrate cytotoxic synergism between the three modalities. TBI was given on day 0. WBH treatment was for 1 hr at 41.8°C, given in daily sessions for 1, 2 or 3 consecutive days following TBI. Total cyclophosphamide doses were 160 and 240 mg/kg given in 2 daily injections on days 1 and 2 following TBI. Polymorphonuclear leukocyte and lymphocyte numbers were determined by differential cell counts. The total peripheral blood cell counts were also determined. WBH alone, given in daily sessions for 3 days, did not reduce the total peripheral blood cell counts. However, when WBH was added to TBI (6.3 Gy) peripheral blood cellularity was reduced on day 2, but no significant heat/radiosensitization was evident after day 2. WBH (3 (daily sessions) significantly reduced the peripheral blood cellularity and resulted in bone marrow ablation when it was combined with TBI and Cy. CY (160–240 mg/kg) combined with TBI (5.4 Gy) resulted in bone marrow ablation and subsequent death in 14–22% of mice treated; 60–100% of mice died from bone marrow ablation when WBH was added to TBI (5.4 Gy) and Cy (160–240 mg/kg). Femoral and vertebral tissue sections showed total loss of progenitor cells when WBH, TBI (5.4 Gy), and Cy (240 mg/kg) were combined whereas lessor treatment was associated with histologically verified reconstitution of progenitor cells inside the marrow cavities. These studies indicate that bone marrow ablation can be achieved when using WBH in combination with lower doses of TBI and Cy.