Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer: A multicenter retrospective observational comparative study.

BACKGROUND: Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electro-hyperthermia (mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer. AIM: To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer. METHODS: This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer (stage III and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128 (59%) of them were treated with CHT (no-mEHT) and 89 (41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT. RESULTS: Median patients' age was 67 years (range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group (20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses (45% vs 24%, P = 0.0018) and a lower number of progressions (4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions. CONCLUSION: mEHT seems safe and has beneficial effects on survival and tumor response of stage III-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

Modulated Electro-Hyperthermia as Palliative Treatment for Pancreatic Cancer: A Retrospective Observational Study on 106 Patients.

Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a <10% survival rate at 5 years. Modulated electro-hyperthermia (mEHT) has been increasingly used for pancreatic cancer palliative care and therapy. Objective: To monitor the efficacy and safety of mEHT for the treatment of advanced pancreatic cancer. Methods: We collected data retrospectively on 106 patients affected by stage III-IV pancreatic adenocarcinoma. They were divided into 2 groups: patients who did not receive mEHT (no-mEHT) and patients who were treated with mEHT. We performed mEHT applying a power of 60 to 150 W for 40 to 90 minutes. The mEHT treatment was associated with chemotherapy and/or radiotherapy for 33 (84.6%) patients, whereas 6 (15.4%) patients received mEHT alone. The patients of the no-mEHT group received chemotherapy and/or radiotherapy in 55.2% of cases. Results: Median age of the sample was 65.3 years (range = 31-80 years). After 3 months of therapy, the mEHT group had partial response in 22/34 patients (64.7%), stable disease in 10/34 patients (29.4%), and progressive disease in 2/34 patients (8.3%). The no-mEHT group had partial response in 3/36 patients (8.3%), stable disease in 10/36 patients (27.8%), and progressive disease in 23/36 patients (34.3%). The median overall survival of the mEHT group was 18.0 months (range = 1.5-68.0 months) and 10.9 months (range = 0.4-55.4 months) for the non-mEHT group. Conclusions: mEHT may improve tumor response and survival of pancreatic cancer patients.

Modulated Electrohyperthermia in Integrative Cancer Treatment for Relapsed Malignant Glioblastoma and Astrocytoma: Retrospective Multicenter Controlled Study.

BACKGROUND: There are interesting studies on glioma therapy with modulated electrohyperthermia (mEHT), which combines heat therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response. PURPOSE: To study the efficacy and safety of mEHT for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC). METHODS: We collected data retrospectively on 149 patients affected by malignant glioma and astrocytoma. Inclusion criteria were informed consent signed; >18 years old; histological diagnosis of malignant glioma or astrocytoma; relapsed after surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy; and indication for treatment with mEHT in palliative setting. mEHT was performed with capacitive coupling technique keeping the skin surface at 26°C and the tumor temperature at 40°C to 42.5°C for > 90% of treatment duration (20-60 minutes). The applied power was 40 to 150 W using a step-up heating protocol. Results from patients treated with mEHT were compared with those treated with BSC. RESULTS: A total of 149 consecutive patients were enrolled in the study, 111 (74%) had glioblastoma multiforme (GBM), and 38 (26%) had astrocytoma (AST). mEHT was performed for 28 (25%) of GBM and 24 (63%) of AST patients. Tumor response at the 3-month follow-up was observed in 29% and 48% of GBM and AST patients after mEHT, and in 4% and 10% of GBM and AST patients after BSC, respectively. The survival rate at first and second year in the mEHT group was 77.3% and 40.9% for AST, and 61% and 29% for GBM, respectively. The 5-year overall survival of AST was 83% after mEHT versus 25% after BSC and 3.5% after mEHT versus 1.2% after BSC for GBM. The median overall survival of mEHT was 14 months (range 2-108 months) for GBM and 16.5 months (range 3-156 months) for the AST group. We observed 4 long-term survivors in the AST and 2 in the GBM group. Two of the long survivors in AST and 1 in GBM group were treated by mEHT. CONCLUSIONS: mEHT in integrative therapy may have a promising role in the treatment and palliation of relapsed GBM and AST.

Clinical experience of treatment of metastatic melanoma and solid tumours adopting a derivative of diphtheria toxin: cross-reacting material 197.

BACKGROUND: Diphtheria toxin (DT) has shown anticancer activity in both experimental models and humans but its adverse effects stopped further developments. Cross-reacting Material 197 (CRM197) is the product of a single missense mutation (Gly52 to Glu) within fragment A of DT. It has been shown to induce weak toxicity in some cell strains, but it shares immunological properties with native DT. CRM197 commonly acts as an immunological adjuvant, or as an inhibitor of heparin-binding epidermal growth factor. Recently, CRM197 was shown to have promising antitumor activity. To better-define this property, we planned a phase I-II study. PATIENTS AND METHODS: Twenty-nine patients bearing advanced melanoma (18 cases), and other solid tumors (two ovarian cancer, two sarcoma, two gastrointestinal cancers, one urinary bladder carcinoma, one glioblastoma, one neuroblastoma, one ocular melanoma and one primitive neuroectodermal embriogenic tumor (PNET) were evaluated and 19 of them, sub-divided in cohorts, received the following levels of CRM197: Level 1, 0.3 mg; level 2, 1.0 mg; level 3, 2.5 mg; level 4, 3.5 mg; level 5, 5.0 mg; level 6, 7.5 mg. The drug was given once every two days for 4 times and then, after a 2-week rest period, once every 2 days for 4 times. CRM197 was administered subcutaneously in the abdominal wall. RESULTS: grade 1-2 common toxicities included fever, chills, fatigue, dizziness, nausea, vomiting and headache, neutrophilia and skin painful reactions appeared regularly at levels 3 and 4 (2.5 mg and 3.5 mg). Vomiting and abdominal pain, skin reaction tachycardia and hypotension appeared in two patients at level 5. At 7.5 mg, we observed a severe grade 3 reaction with hypotension, dyspnea and grade 4 myalgia. This was considered the dose-limiting toxicity. Eleven patients (seven with melanoma and four with other tumors) were treated to evaluate anticancer effects at the maximum tolerated dose (5 mg). Only one patient reported a minor response, lasting eight weeks. Ten patients reported progressive disease. CONCLUSION: CRM197, injected subcutaneously at 5 mg, elicited a generic inflammatory response causing toxicity, and did not exert a significant degree of antitumor activity in patients with advanced melanoma and solid tumour.

Advanced cancer of the ovary: intraperitoneal chemotherapy as a new therapeutical option.

Intraperitoneal (IP) chemotherapy has been used in patients presenting different stages of ovarian cancer. We performed a critical review of the available literature on IP as first-line treatment in advanced ovarian cancer to consider if this new option should be incorporated into the commonly applied guidelines for treatment of ovarian cancer. We concluded that without further data, it would not be ethically correct to administer chemotherapy intraperitoneally. Outside of planned clinical trials, patients should not be exposed to this treatment modality and its associated toxicity. The present international guidelines are still valid and recommended chemotherapy in advanced ovarian cancer remains treatment with paclitaxel and carboplatin. Further studies on this topic are, however, warranted.

Imatinib mesylate induces responses in patients with liver metastases from gastrointestinal stromal tumor failing intra-arterial hepatic chemotherapy.

BACKGROUND: Imatinib mesylate represents a real major paradigm shift in cancer therapy, targeting the specific molecular abnormalities, crucial in the etiology of tumor. Intra-arterial hepatic chemotherapy (IAHC) followed by embolization, has been considered an interesting palliative option for patients with liver metastases from gastrointestinal stromal tumor (GIST), due to the typically hypervascular pattern of the tumor. AIMS: We report our experience with IAHC followed by Imatinib mesylate, in order to show the superiority of the specific molecular approach in liver metastases from GIST. MATERIALS AND METHODS: Three patients (pts) with pretreated massive liver metastases from GIST, received IAHC with Epirubicin 50 mg/mq, every 3 weeks for 6 cycles. At the evidence of progression, they received Imatinib mesylate. RESULTS: We observed progressive diseases in all cases. In 1998, one patient underwent Thalidomide at 150 mg orally, every day for 4 months, with evidence of stable disease and clinical improvement. In 2001, two patients received Imatinib mesylate at 400 mg orally, every day, with evidence of partial response lasting 18+ months and 16 months. One of them had grade 3 neutropenia, with suspension of therapy for 3 weeks. CONCLUSION: No patient treated with IAHC, reported objective responses, but two of them obtained partial response after the assumption of Imatinib mesylate and one showed temporary stabilization with thalidomide. Imatinib mesylate represents a new opportunity in GIST therapy, targeting the specific molecular alteration. It seems to be superior to conventional intra arterial hepatic chemotherapy.

Hepatic arterial chemotherapy in combination with systemic chemotherapy compared with hepatic arterial chemotherapy alone for liver metastases from colorectal cancer: results of a multi-centric randomized study.

Hepatic arterial infusion (HAI) chemotherapy is accepted to be an option in patients with non-resectable metastases from colorectal cancer confined to the liver. In a multi-istitutional trial, 76 patients were randomly assigned to receive HAI versus HAI plus systemic bolus 5-fluorouracil and leucovorin. The primary endpoint was survival, followed by response, recurrence and toxicity. Survival was longer for HAI plus systemic chemotherapy (HAI+SYC) than HAI (median, 20 vs. 14 months; p = 0.0033), as were responses (47.5% and 41.7%; p = 0.09) and time to hepatic progression (12 vs. 8 months; p = 0.039). Side effects included haematological toxicity that was mostly mild and reversible in 432 cases. Neutropenia grade 3 occurred in four patients in the HAI+SYC arm and one in the HAI arm. Diarrhoea occurred in 20% and 7% of patients and stomatitis occurred in 18% and 2%, respectively. On the contrary biliary toxicity was significant; twelve patients had evidence of bilirubin elevations of more than 3 mg/dl (six in each arm), and two had asymptomatic arterial biliary-tree fistulae: one in the HAI+SYC arm and one in the HAI arm. Grade 3 elevation in alkaline phosphatase and aminotransferase levels occurred in 26% and 24%, respectively. In conclusion, the combination of HAI+SYC is active and safe showing a clinical advantage with respect to simple HAI, increasing overall survival, response rate and time to progression.

A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia.

The purpose of this study was to evaluate the activity and toxicity of electro-hyperthermia (ET) on relapsed malignant glioma patients. Twelve patients with histologically diagnosed malignant glioma entered the study. Eight patients had glioblastoma multiforme, two had anaplastic astrocytoma grade III and two had anaplastic oligodendroglioma. All patients were pre-treated with temozolamide-based chemotherapy and radiotherapy. Hyperthermia with short radiofrequency waves of 13.56 MHz was applied using a capacitive coupling technique keeping the skin surface at 20 degrees C. The applied power ranged between 40-150 Watts and the calculated average equivalent temperature in the tumours was above 40 degrees C for more than 90% of the treatment duration. One complete remission and 2 partial remission were achieved, with a response rate of 25%. The median duration of response was 10 months (range 4-32). The median survival of the entire patient population was 9 months, with 25% survival rate at 1 year. ET appears to have some effectiveness in adults with relapsed malignant glioma.

Oxaliplatin hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: a phase I-II clinical study.

Oxaliplatin is a new drug active in the treatment of advanced colorectal cancer. Hepatic arterial infusion chemotherapy is under evaluation because of the high target dose and low general toxicity. Twelve patients with liver metastases from colorectal cancer were enrolled, all pretreated with evidence of progressive disease: three after a partial remission induced by oxaliplatin, folinic acid and 5-FU, three patients after a partial remission induced by irinotecan, folinic acid and 5-FU and six patients after failing a 5-FU and folinic acid regimen. They received hepatic arterial infusion chemotherapy with oxaliplatin as 30-min infusion on an outpatient basis every 3 weeks. Dose-limiting toxicity was observed at 175 mg/m2/cycle and consisted of obliteration of the hepatic artery in one patient, abdominal pain requiring morphine in one patient and severe hypotension requiring plasma expander in a third. Following phase 1, all patients received 150 mg/m2 for six cycles. We reported four cases of partial remission (33%) lasting 24, 15, 12 and 10+ weeks, respectively, 2 stabilisation of disease (17%) lasting more than 12 weeks and six progressions (50%). Six patients (50%) presented CEA reduction of > 30% and five patients (41%) showed an increase of > 8% of body weight. The median survival was 13 months (range 6-19). Oxaliplatin did not present significant toxicity for liver parenchyma and biliary tree. We advise that further studies be undertaken with oxaliplatin 150 mg/m2.

Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: a phase II clinical study.

AIMS AND BACKGROUND: The advantage of delivering chemotherapy by hepatic arterial infusion is the acquisition of a high concentration of the drug in the target. Irinotecan (CPT-11) is active for the treatment of advanced colorectal cancer. In phase I studies, doses of 20 mg/m2/d for 5 days given every 4 weeks as continuous infusion or 200 mg/m2 as a short 30-min infusion given every 3 weeks is recommended for phase II studies. METHODS AND STUDY DESIGN: Twelve patients with a median liver substitution of 30% (20-50%) were enrolled, 6 progressed after a FOLFOX-induced partial response and 6 progressed after 5-fluorouracil and folinic acid. All patients had a surgically (n = 6) or angiographically placed port (n = 6). They received hepatic arterial infusion chemotherapy with CPT-11 (200 mg/m2) on an out-patient basis, every 3 weeks as a short 30-min infusion for six cycles. RESULTS: Four partial responses were observed (33%) lasting 24, 15, 12 and 8+ weeks, 3 stable disease (25%) lasting more than 12 weeks, and 5 progressions (41%). Six patients (50%) presented a >30% reduction in CEA. Toxicity was G2 diarrhea in 5 patients (41%) and G2 myelosuppression in 6 (50%); one patient had abdominal right upper quadrant pain requiring analgesics. CONCLUSIONS: CPT-11 is active as hepatic arterial infusion chemotherapy in liver metastases from colorectal cancer and can rescue systemically pretreated patients. Our schedule seems safe, feasible and well accepted on an out-patient basis.