Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma.

BACKGROUND: Prognosis for patients with malignant pleural mesothelioma (MPM) remains poor and such patients require intensive treatment. Few studies have examined hyperthermia for MPM. The present study investigated the feasibility of hyperthermia combined with weekly chemo-radiotherapy for patients with MPM and estimated the efficacy of this regimen. METHODS: A total of 11 patients (median patient age was 67 and all had pleural effusion) with MPM were enrolled in this study. The treatment regimen comprised of weekly thermo-radiotherapy with intra-thoracic chemotherapy 2-5 times at initiation of treatment. Hyperthermia was performed once per week for approximately 60 min. Hemithorax external radiotherapy was administered once weekly on the same day as hyperthermia and just before thermochemotherapy. Median total radiation dose was 6 Gy (range, 2-10 Gy). Chemotherapy was administered into the thoracic cavity through a tube. Chemotherapeutic agents administered were CDDP for seven patients, carboplatinum (CBDCA) for three patients and both CDDP and CBDCA for one patient. Dose of CDDP was 50 mg/body and dose of CBDCA was 200-300 mg m-2. Response rate and median survival time (MST) and palliative effect were investigated. RESULTS: Complete response was not achieved in any of the 11 patients. Partial response was achieved in three of 11 patients (27.3%), SD in six patients (54.5%) and PD in two patients (18.2%). There was no correlational relationship between thermal parameters and response. MST was 27.1 months. Pleural fluid decreased in all patients after therapy, while all patients displayed improved performance status and could be discharged from hospital. Patients with partial response had a relatively longer survival time than SD or PD. All patients underwent the complete course of treatment and only one of 11 patients developed grade 4 thrombocytopenia. CONCLUSION: It was therefore concluded that hyperthermia combined with intra-thoracic chemotherapy using cisplatinum or carboplatinum may be tolerable. This approach appears effective and more acceptable for patients with MPM with pleural effusion than other multi-modality therapy.     

A phase I study to study arsenic trioxide with radiation and hyperthermia in advanced head and neck cancer

Purpose: Arsenic trioxide [ATO] is a pluripotent drug with potentials to have pro-oxidant, angiogenesis inhibitor, flow inhibitor and radiation sensitizer properties.

Methods: The present study is a Phase I trial to assess the safety of ATO in advanced or recurrent head and neck cancer treated with radiation and hyperthermia. Patients received ATO at 10, 20 and 30?mg per week a day prior to hyperthermia.

Results: It was assumed that vascular collapse would be complete by 24?h. Administration of ATO at 20?mg was safe with no toxicity due to ATO. No amplification of toxicities due to radiation or hyperthermia was evident. Patients without prior treatment showed better response. A total of 11 patients were included in this Phase I study.

Conclusions: Patients who received 30?mg of ATO weekly showed non-serious acute toxicities. No further escalation of dose was attempted.     

Reversal of cervical dysplasia with hyperthermia

Purpose: Patients with recurrent cervical carcinoma within a previously irradiated area respond poorly to chemotherapy. We have treated these patients with simultaneous cisplatin and hyperthermia (CDDP?+?HT) and investigated response, toxicity, palliative effect and survival.

Materials and methods: Between 1992 and 2005 47 patients received CDDP?+?HT. Response was evaluated by gynaecologic examination and CT-scan. The Common Toxicity Criteria (CTC) were used for evaluation of toxicity and palliative effect. The Kaplan-Meier method was used to estimate survival, and Cox regression analysis to evaluate the influence of prognostic factors.

Results: The objective response rate was 55%, palliation was achieved in 74% and operability in 19% of patients. Two patients are currently disease free at 9 years and 18?+?months following treatment and 2 remained disease free until death by other causes. The median survival was 8 months and was influenced by duration of disease free interval and tumour diameter. Grade 3–4 haematological toxicity was observed in 36% of patients and renal toxicity was maximum grade 2.

Conclusion: CDDP?+?HT results in a high response rate and acceptable toxicity in patients with recurrent cervical cancer.     

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.     

Hyperthermia classic commentary: ‘Arrhenius relationships from the molecule and cell to the clinic’ by William Dewey,Int. J. Hyperthermia, 10:457–483, 1994

Purpose: The management of head and neck cancer requires skilled integration of multiple modalities such as surgery, radiation, chemotherapy and hyperthermia. Chemoradiation can benefit from the addition of a proven modality such as hyperthermia in increasing survival, disease-free survival and quality of life without increasing the risk of complication.

The purpose of this retrospective study was to evaluate the feasibility and efficacy of hyperthermia with chemoradiation in advanced head and neck cancers.

Materials and methods: Between January 2004 and May 2008 40 patients with advanced head and neck cancers were allocated for hyperthermia with chemoradiotherapy. All patients underwent radiation on a telecobalt machine. A total dose of 70 Gy in 7 weeks with conventional fractionation was given with weekly chemotherapy of cisplatin 50 mg or paclitaxel 60 mg. Patients underwent hyperthermia on a radiofrequency machine at 8.2 MHz for 30 min at 41°–43°C with 10 min pre-cooling to 5°C.

Results: No patient had life-threatening complications. Only 38 out of 40 patients were eligible for assessment of immediate response as one patient died during treatment and the other did not complete treatment. Complete response was 76.23% (29 pts), and 23.68% (9 pts) had partial response. Overall survival by the Kaplan?Meir method was 75.69% at 1 year and 63.08% at 2 years.

No enhanced mucosal or thermal toxicities were documented as compared to our earlier experience with chemoradiation.

Conclusion: This retrospective analysis demonstrates the feasibility and efficacy of chemoradiation with hyperthermia in advanced head and neck cancer. The study is encouraging enough to start a randomised trial to compare chemoradiation with triple modality of treatment.     

Effect of tumor presence on cisplatin and carboplatin: disposition in the isolated,perfused tumor and skin flap

The purpose of this study was to evaluate the disposition of elemental platinum (Pt) derived from cisplatin (CDDP) or carboplatin (CBDCA) in the isolated, perfused tumor and skin flap (IPTSF). Flaps were perfused with either 3.0 g CDDP/ml perfusion medium (n=4 tumor,n=4 control) or 15 g CBDCA/ml (n=4 tumor,n=3 control) at a rate of 1 ml/min for 3 h. A 2-h (CDDP experiments) or 3-h (CBDCA experiments) washout phase using undosed medium was then performed. The disposition kinetics of free (ultrafilterable) Pt were characterized using a four-compartment physiologically relevant pharmacokinetic model. A tumor effect on the disposition of Pt was noted in that the Pt mass from CDDP in the central and mobile tissue compartments was greater in tumor flaps than in control flaps (P<0.05). Similar trends were noted in CBDCA-treated flaps, but these were not significant. The Pt mass in the fixed tumor and non-tumor tissue compartments was significantly greater when Pt was derived from CDDP than when it was derived from CBDCA (P<0.05). A linear relationship existed between the estimated micrograms of Pt in the flaps from both CDDP and CBDCA and the cross-sectional vascular resistance of the flaps at 30 (CDDP,r=0.78; CBDCA,r=0.89) and 60 min (CDDP,r=0.65; CBDCA,r=0.85) of perfusion. We conclude that the IPTSF is a useful model for evaluating the disposition of Pt drugs in tumor and non-tumor tissue and that tumor presence alters the disposition of CDDP.This work was supported in part by grants 08822 and 43745 from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official news of the National Cancer Institute     

Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma

BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is expected to increase due to delayed control of occupational exposure to asbestos in Japan. We investigated the use of triplet combination chemotherapy with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR) for the treatment of Japanese patients with MPM. METHODS: From December 2000 to August 2003, 12 patients received the following regimen: CDDP 40 mg/m(2), GEM 800 mg/m(2) and VNR 20 mg/m(2) on days 1 and 8 every 4 weeks. Among the 12 patients, six selected patients underwent an extrapleural pneumonectomy (EP) after a median of three cycles of triplet chemotherapy. RESULTS: The overall response rate for all patients and the response rate for chemotherapy-naive cases were 58 and 67%, respectively. The median survival time and survival rate at 2 years for all patients were 11 months and 50%, respectively. The 2-year survival rates for the patients with and without EP were 83.3 and 16.7%, respectively. CONCLUSIONS: Triplet chemotherapy with CDDP, GEM and VNR was thus found to be highly effective for patients with MPM and its toxicity was manageable. A multi-institutional phase II trial is now being planned to establish the effectiveness of this new regimen in chemotherapy-naive patients with MPM.     

Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer

Purpose: Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer.

Methods: Eligibility criteria included histologically proven, locally advanced or metastatic pancreatic cancer. Gemcitabine was administered intravenously at a dose of 1000?mg/m² on days 1, 8, and 15 every 4 weeks. Regional hyperthermia was performed once weekly, 1 day preceding or following gemcitabine administration. The primary end point was the 1-year survival rate. Secondary objectives were determination of tumour response and safety.

Results: We enrolled 18 patients with advanced pancreatic cancer between November 2008 and May 2010. The major grade 3–4 adverse events were neutropenia and anaemia; however, there were no episodes of infection. The objective response rate (ORR) and disease control rate (ORR + stable disease) were 11.1% and 61.1%, respectively. Median overall survival (OS) was 8 months, and the 1-year survival rate was 33.3%. Median OS of patients with locally advanced pancreatic cancer was 17.7 months.

Conclusions: Regional hyperthermia combined with gemcitabine is well tolerated and active in patients with locally advanced pancreatic cancer.     

Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer

Purpose: CPT-11 (60 mg/m² on days 1, 8 and 15) in combination with CDDP (80 mg/m² on day 1) has shown promising antitumor activity for non-small-cell lung cancer (NSCLC), but dose-limiting toxicities (DLT) are leukopenia and diarrhea, with a wide variation among patients. To estimate weekly CDDP administration in combination with CPT-11, a phase I study for patients with advanced NSCLC was conducted. Methods: Patients were treated with CPT-11 at a fixed dose of 60 mg/m² together with CDDP at 27 mg/m² (level 1, 6 patients), 33 mg/m² (level 2, 12 patients), and 40 mg/m² (level 3, 6 patients) with 1600 ml hydration on days 1, 8 and 15 over 4 weeks. During the treatment course, drug was not administered on the day it was due in the presence of leukopenia (<3000/ml) and/or diarrhea. Results: The planned administration was completed in 5 of 6 patients at level 1, 6 of 12 patients at level 2, and 2 of 6 patients at level 3. The most common toxicity observed was leukopenia (five patients with grade 3 and one patient with grade 4). Leukopenia was considered to be a DLT, and the maximum tolerated dose (MTD) was level 2. Although there were patients who suffered from diarrhea (four patients with higher than grade 2), diarrhea was judged not to be a DLT with this weekly regimen. Nausea and vomiting were mild. Pharmacokinetic analysis of free platinum from CDDP demonstrated that the area under the curve (AUC) from 33 mg/m² CDDP was 0.92 ± 0.29 g/ml h. In 13 patients evaluated for response, the response rate was 54%. Conclusion: The value of weekly administration of CDDP in combination with CPT-11 was shown by (1) diarrhea not being dose-limiting, (2) mild nausea, (3) well-maintained AUC of free platinum, and (4) promising activity. Received: 4 April 1997 / Accepted: 8 October 1997     

Antitumor activity of cis-malonato[(4R,5R)-4,5-bis(aminomethy1)-2-isopropyl-1,3-dioxolanelplatinum(II), a new platinum analogue,as an anticancer agent

 The in vitro and in vivo antitumor activity of a new antitumor platinum complex, cis-malonato[(4R, 5R)-4, 5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), were evaluated and compared with those of cisplatin (CDDP) and carboplatin (CBDCA) using murine tumors. SKI 2053R was highly active in vitro against both L1210 murine leukemia and its CDDP-resistant subline, L1210/DDP; the relative resistances were 20.0-, 14.5-, and 2.7-fold for CDDP, CBDCA, and SKI 2053R, respectively. SKI 2053R showed activity comparable with or superior to either CDDP or CBDCA in mice implanted with L1210. In mice implanted with L1210/DDP, as compared with CBDCA, SKI 2053R showed high values for the percentage of treated survivors relative to controls and for numbers of cured mice, whereas CDDP had virtually no activity. In mice implanted with P388, all three drugs were highly active, but the intensity of activity was shown to be ranked in the following order: SKI 2053R > CDDP > CBDCA. The antitumor activity of SKI 2053R against Lewis lung carcinoma was comparable with that of both CDDP and CBDCA. The antitumor activity of SKI 2053R was further investigated against two human tumor xenografts, KATO III (stomach adenocarcinoma) and WiDr (colon adenocarcinoma), implanted s.c. in nude mice and was compared with that of CDDP. In SKI 2053R-treated groups, the time required for a mean tumor weight of 1,000 mg was 33.1 days in KATO III xenografts and 35.0 days in WiDr xenografts as compared with 30.2 and 27.2 days in CDDP-treated groups, respectively. SKI 2053R achieved growth-inhibition rates comparable with those of CDDP against KATO III (65% versus 59%) and WiDr xenografts (64% versus 54%) on day 35. These results indicate that SKI 2053R is an attractive candidate for further development as a clinically useful anticancer drug. Received: 7 June 1994 / Accepted: 27 September 1994     

Cost-effectiveness analysis comparing carboplatin and weekly paclitaxel with cisplatin and docetaxel in the treatment of advanced non-small cell lung carcinoma

Carboplatin plus weekly paclitaxel (CBDCA/wPTX) and cisplatin plus docetaxel (CDDP/DTX) are the standard regimens used in the first-line treatment of advanced non-small cell lung carcinoma (NSCLC), with no significant difference in efficacy between the two. However, because there has been no study of the cost-effectiveness of CBDCA/wPTX versus CDDP/DTX to data, we compared these two regimens in the present study. Expected costs were calculated based on data from patients with Stage III b/IV NSCLC who were treated with either CBDCA/wPTX or CDDP/DTX in the Nippon Medical School Hospital. Efficacy (1-year survival rate) was determined by pooled analysis of studies extracted from the database. The cost-effectiveness ratio was calculated from expected costs and 1-year survival rates for both the CBDCA/wPTX and CDDP/DTX regimens. The expected costs per patient of the CBDCA/wPTX and CDDP/DTX regimens were ￥2, 847, 514 and ￥3, 513, 195, respectively, with 1-year survival rates of 38.6% and 42.5%, respectively. Thus, the cost-effectiveness ratio for the CBDCA/wPTX and CDDP/DTX regimens is ￥6, 750, 863 and ￥8, 329, 054, respectively. These findings clearly suggest that, CBDCA/wPTX is a more cost-effective regimen than CDDP/DTX.     

Results of concurrent chemotherapy and hyperthermia in patients with recurrent cervical cancer after previous chemoradiation

Background: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation.

Objective: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin.

Methods: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant.

Results: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27–74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3–4 haematological complications did not exceed 10%.

Conclusion: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical cancer.     

Local treatment of rabbit VX2 rectal carcinoma with combined hyperthermia and intratumoral CDDP injection

The efficacy of combined use of hyperthermia and intratumoral cisplatin (CDDP) injection was investigated in rabbit rectal carcinoma models produced by VX2 carcinoma injection. Local hyperthermia was administered with a 13·56 MHz radiofrequency generator at 42·43 °C for 30 min. CDDP (3 mg) was injected into two sites within tumours. Temperatures in the VX2 rectal carcinomas reached 42–43°C within 3 min following initiation of heating and remained stable. Tumour growth was inhibited markedly in rabbit undergoing combined treatment with intratumoral CDDP and hyperthermia, when compared with rabbit treated with hyperthermia or intratumoral CDDP alone. Histological examination further revealed that combined treatment resulted in more extensive tumour necrosis, when compared with hyperthermia or CDDP alone. Therefore, combined hyperthermia and CDDP intratumoral injection may be useful for neoadjuvant preoperative treatment of advanced rectal carcinomas as well as patients with recurrent rectal carcinoma.     

Pharmacokinetics and antitumor activity of a new platinum compound,cis-malonato[(4R,5R )-4,5-bis(aminomethyl)-2-isopropyl- 1, 3-dioxolane]platinum(II), as determined by ex vivo pharmacodynamics

The pharmacokinetics and ex vivo pharmacodynamics studies oncis-malonato[(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC₀) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72±2.74 g h ml^–1 (mean ± SD), with an initial half-life of 0.37±0.20 h, a terminal half-life of 2.19±0.93 h, a total clearance of 16.83±4.76 ml min^–1 kg^–1, and a steady-state volume of distribution of 1.57±0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P<0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.     

The effect of modulated electro-hyperthermia on temperature and blood flow in human cervical carcinoma

Introduction: Mild hyperthermia has been known to enhance the response of tumours to radiotherapy or chemotherapy by increasing tumour blood flow, thereby increasing tumour oxygenation or drug delivery. The purpose of this study was to assess the changes in temperature and blood flow in human cervical cancer in response to regional heating with modulated electro-hyperthermia (mEHT).

Methods: The pelvic area of 20 patients with cervical carcinoma was heated with mEHT. The peri-tumour temperature was measured using an internal organ temperature probe. The tumour blood flow was measured using 3D colour Doppler ultrasound by determining the peak systolic velocity/end-diastolic velocity ratio (S/D ratio) and the resistance index (RI) within blood vessels.

Results: The mean peri-tumour temperature was 36.7?±?0.2?°C before heating and increased to 38.5?±?0.8?°C at the end of heating for 60?min. The marked declines in RI and S/D values strongly demonstrated that heating significantly increased tumour blood perfusion.

Conclusions: Regional heating of the pelvic area with mEHT significantly increased the peri-tumour temperature and improved the blood flow in cervical cancer. This is the first demonstration that the blood flow in cervical cancer is increased by regional hyperthermia. Such increases in temperature and blood flow may account for the clinical observations that hyperthermia improves the response of cervical cancer to radiotherapy or chemotherapy.     

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

Objective: In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients.

Methods and materials: We searched MEDLINE and Embase, supplemented by handsearching, for clinical studies involving hyperthermia in pancreatic cancer patients. The quality of studies was evaluated using the Oxford Centre for Evidence-Based Medicine levels of evidence. Primary outcome was treatment efficacy; we calculated overall response rate and the weighted estimate of the population median overall survival (m_p) and compared these between hyperthermia and control cohorts.

Results: Overall, 14 studies were included, with 395 patients with locally advanced and/or metastatic pancreatic cancer of whom 248 received hyperthermia. Patients were treated with regional (n?=?189), intraoperative (n?=?39) or whole-body hyperthermia (n?=?20), combined with chemotherapy, radiotherapy or both. Quality of the studies was low, with level of evidence 3 (five studies) and 4. The six studies including a control group showed a longer m_p in the hyperthermia groups than in the control groups (11.7 vs. 5.6?months). Overall response rate, reported in three studies with a control group, was also better for the hyperthermia groups (43.9% vs. 35.3%).

Conclusions: Hyperthermia, when added to chemotherapy and/or radiotherapy, may positively affect treatment outcome for patients with pancreatic cancer. However, the quality of the reviewed studies was limited and future randomised controlled trials are needed to establish efficacy.     

Carboplatin and cisplatin pharmacokinetics after intrapleural combination treatment in patients with malignant pleural effusion

Background: Cisplatin (DDP) and carboplatin (CBDCA) are two of the mosteffective drugs in a locoregional approach. Since simultaneous combinedtreatment with intrapleural DDP and CBDCA has not been reported in humans, weinvestigated its use in patients with malignant effusions, focusing onpharmacokinetics.Patients and methods: The pharmacokinetics of DDP and CBDCA were studiedin 10 patients with malignant pleural effusion treated intrapleurally with acombination of DDP (60 mg/m²) and CBDCA (270mg/m²) and in additional patients who received the same dosesof drugs administered intravenously as single agents or in combination.Platinum (Pt) species originating from DDP (metabolites plus unchanged DDP)and intact CBDCA in plasma and pleural fluid ultrafiltrates were measured bymeans of high performance liquid chromatography and atomic absorptionspectrometry.Results: Both in the plasma and pleural fluid, the total levels of free Ptrepresented the additive result of the individual concentrations of CBDCA andPt-species derived from DDP. After intrapleural combination, highpleural-plasma ratios of the peak concentrations and AUCs were observed bothfor CBDCA and DDP-derived Pt species, highlighting a distinct localpharmacological advantage. However, the Pt species originating from DDP wereabsorbed more rapidly from the pleural cavity than CBDCA (K_a= 86 × 10^-3 vs. 37 ×10^-3 min^-1, P < 0.05).Intrapleural combination of CBDCA and DDP produced therapeutic plasma levelsof reactive (free) DDP species and increased the extent of their residencetime (MRT) compared with single intravenous DDP treatment [peak concentration:1.1 ± 0.1 (SD) vs. 1.6 ± 0.2 µg/ml; MRT: 5.2 ± 1.9vs. 0.5 ± 0.06 h]. Furthermore, the plasma AUC of free CBDCA afterintrapleural combined treatment (2.1 ± 0.5 mg/ml × min) wassimilar to that after intravenous administration of CBDCA alone (2.1 ±0.2 mg/ml × min). The intrapleural treatment was well tolerated by allpatients. Toxicity consisted of mild nausea and vomiting (grade 1–2according to the WHO scale) in four patients. Myelosuppression (grade1–2) was remarkable only in two heavily pretreated patients. No evidenceof recurrence of the pleural effusion was observed in six patients (completeresponse), while an asymptomatic minimal fluid reaccumulation not requiringdrainage (partial response) was observed in four patients.Conclusions: The pharmacologic results seem to exclude a pharmacokineticinteraction between CBDCA and DDP and suggest that a dose of CBDCA 2-foldhigher than that used in this study associated intrapleurally with 60mg/m² DDP could induce an acceptable and predictablemyelosuppresion.     

New regimens for the treatment of gynecologic cancers

Until the late-1980s, combination CDDP (or CBDCA)/cyclophosphamide (CPA) and CDDP (or CBDCA)/CPA/adriamycin (ADM) were the two most common choices for treating patients with ovarian cancer. In the last several years, the identification of paclitaxel (TXL) activity in previously treated ovarian cancer patients has led to its incorporation into primary chemotherapy regimens for newly diagnosed patients. Based on prospective trials by the Gynecologic Oncology Group (GOG) and European-Canadian investigators, CDDP/TXL became the new standard regimen in 1998. Now, three randomized trials by the GOG (158), AGO, and a Dutch group comparing CDDP/TXL and carboplatin (CBDCA)/TXL are also in progress. These study groups recommended that CBDCA/TXL be used as the standard regimen in 1999 because CBDCA/TXL is less toxic, allows a better quality of life during treatment, and results in an equivalent response rate and progression-free survival. In patients with high-risk corpus cancer, clinical trials comparing platinum/TXL or platinum/ADM/TXL versus platinum/ADM are in progress. In Japan, CPT-11/CDDP has been shown to be an effective and safe regimen in patients with advanced ovarian cancer, especially clear cell carcinoma and cervical cancer.     

A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861

The European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Working Party conducted a randomized trial comparing cisplatin (CDDP; 120 mg/m2, day 1) and carboplatin (CBDCA; 325 mg/m2, day 1) in combination with etoposide (VP16; 100 mg/m2, days 1, 2, and 3) in advanced non-small-cell lung cancer (NSCLC). Two hundred twenty-eight patients were eligible for survival and 202 assessable for response. We obtained 27 of 100 objective responses (ORs; 27%) in the CDDP arm and 16 of 102 (16%) in the CBDCA arm (P = .07). There was no significant difference in survival. Toxicity, consisting mainly of myelosuppression and renal function impairment, was significantly increased in the patients receiving the CDDP treatment. We conclude that CDDP plus VP16 was more active but also more toxic than CBDCA plus VP16 in advanced NSCLC.     

Ifosfamide,carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults

Purpose:?To evaluate the efficacy and safety of the combination of ICE (ifosfamide 1.5?g?m^?2, carboplatin 100?mg?m^?2 and etoposide 150?mg?m^?2, days 1–4, q 28 days, G-CSF 5?µg?kg^?1 starting from day 6) alone and in combination with regional hyperthermia (RHT) in soft tissue sarcoma (STS) refractory to previous standard doxorubicin-ifosfamide-based chemotherapy.

Patients and methods:?Twenty patients with advanced STS of different histological sub-types were treated with the ICE regimen with 13 patients receiving additional RHT. A median of four courses of ICE were administered with RHT on days 1 and 3 (60?min, T_max 42°C).

Results:?The objective response rate was 20%, with four partial responses (all treated with hyperthermia). In addition, two patients showed mixed responses and five patients stable disease. After a median follow-up time of 15 months, median time to progression was 6 months. Progression free rate estimates were 60% and 45% at 3 and 6 months, respectively. Median overall survival for all patients was 14.6 months.

Conclusion:?These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.