Anna Cividalli

Radiosensitization by oxaliplatin in a mouse adenocarcinoma: influence of treatment schedule

PURPOSE The aim of our study was to investigate if oxaliplatin (1-OHP) could be used as a radiosensitizer in vivo. MATERIALS AND METHODS Experiments were performed in mice (C3D2F1) bearing a transplanted mammary carcinoma in a foot. Drugs, 1-OHP and cis-diammine-dichloro-platinum (CDDP), were administered i.p. Results were analyzed in terms of tumor growth delay (TGD). RESULTS 1-OHP and CDDP were tested in single doses of 6 and 10 mg/kg body weight. Administration of either 1-OHP or CDDP produced a significant TGD but only with the dose of 10 mg/kg. Single dose combined X-ray (10 Gy) and 1-OHP (6 and 10 mg/kg) treatments were performed with different sequences and time intervals (1 h, 4 h, and 24 h). All TGDs of these combined treatments were uniform among themselves (indicating that sequence and time interval did not influence the results), and did not depend on the drug dose. In X-ray (10 and 20 Gy) and 1-OHP (6 and 10 mg/kg) combined treatment, the TGDs increased only with X-ray dose. Different 1-OHP administration schedules were performed for fractionated experiments: two treatments every 4 days. The least toxic protocol (1-OHP total dose from 6 to 14 mg/kg) was selected for combined treatments with 10 daily X-ray treatments of 2 Gy. A clear drug dose-effect relationship was observed in those treatments with 1-OHP doses from 10 to 14 mg/kg. CONCLUSION Although low-dose 1-OHP did not induce a TGD when administered alone, in combined protocols it increased X-ray efficacy.

Radiotherapy and hyperthermia. Analysis of clinical results and identification of prognostic variables

Site‐ and tumor‐specific data obtained from two groups of patients with head and neck and melanoma lesions, respectively, showed that both immediate response and response duration were enhanced by the addition of heat. Two important variables, however, such as tumor volume and “isoeffect thermal dose” appeared to influence local tumor control. The volume effect was less pronounced in the lesions treated with radiotherapy plus heat than in those treated with radiotherapy alone, suggesting that the addition of heat was more damaging to the large than to the small lesions. Furthermore, a striking isoeffect thermal dose–response relationship was shown in head and neck lesions. Those data were collected and used to design a mathematical model relating the probability of local control to clinical and treatment variables. The analysis shows that, by using the same radiation parameters, the probability of local tumor control is a function of both “isoeffect thermal dose” and tumor volume.

Effectiveness of microwave hyperthermia combined with ionizing radiation: Clinical results on neck node metastasest☆

Abstract Patients with superficial malignant lesions have been treated with local hypertbermia in association with radiation. Heat was applied by means of a newly assembled apparatus with a variable frequency microwave generator (200–3000 MHz). The apparatus was operated at a frequency of 500 MHz; heat was delivered with non-contact applicators designed for different surface curvature. Adequate heating for depths up to about 3 cm was demonstrated by isothermal maps in chopped meat phantoms. A group of 15 patients with N2–N3 multiple cervical nodes from bead and neck cancer were treated with a multiple daily fractionation (MDF) radiotherapy, according to our previous clinical experience, and with MDF combined with local hypertbermia. A direct comparison of the two treatments on different nodes was possible for each patient: 17/20 nodes (95%) achieved a complete response with this combined schedule, 6 13 (46%) with MDF alone, and 14/46 (30%) with conventional fractionation (historical series). The same combined treatment also was delivered to a group of 4 patients with other kinds of tumors. Complete or satisfactory responses were also obtained in these patients. The results suggest that MDF can be advantageously combined with local hyperthermia.

Hyperthermia enhances the response of paclitaxel and radiation in a mouse adenocarcinoma

PURPOSE The aim of our study was to investigate if the efficacy of paclitaxel and paclitaxel-radiation treatments in vivo could be enhanced by hyperthermia. MATERIALS AND METHODS Paclitaxel was administered i.p. in doses from 30 to 60 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Local hyperthermia (41 degrees, 42 degrees, 43 degrees C) was carried out by immersing tumor-bearing legs in a water bath for 1 h. Single X-ray treatments from 10 to 90 Gy were performed. Tumor growth delay (TGD) or tumor control dose (TCD(50), radiation dose needed to induce local tumor control in 50% of irradiated animals) were the endpoints. RESULTS A significant increase of dose-dependent growth delay was observed in paclitaxel and 43 degrees C hyperthermia combined treatments, and a superadditive effect was seen with paclitaxel 45 mg/kg. Combined treatments with hyperthermia at 41 degrees and 42 degrees C were less effective. Administration of paclitaxel 24 h, 4 h, and 15 min before or 15 min and 4 h after hyperthermic treatments produced similar results (TGDs varying from 22.1 to 17 days), and administering paclitaxel 48 h before or 24 h after hyperthermic treatments decreased TGDs (about 10 days). Trimodality treatment (paclitaxel 45 mg/kg, hyperthermia, and X-ray), with a TCD(50) of 14. 1 Gy, in respect to the TCD(50) of 53.1 obtained with X-ray alone, was the most effective. CONCLUSIONS Hyperthermia enhanced the effectiveness of paclitaxel in all the tested protocols. Our results show a superadditive effect of paclitaxel 45 mg/kg combined with a hyperthermic treatment of 1 h at 43 degrees C. Trimodality treatment, evaluated in terms of percentage of cures, shows a very high enhancement ratio.

Enhanced effectiveness of adriamycin and bleomycin combined with local hyperthermia in neck node metastases from head and neck cancers.

The results of this study concern the comparison of the clinical effects of adriamycin (ADM) or bleomycin (BLM) alone and combined with local hyperthermia on 15 patients with multiple (29) neck node metastases from head and neck cancers. With repeated low fractional daily doses of drug a significant though transient tumor regression was obtained in 2/8 and in 3/6 of the lesions treated with ADM or BLM alone, respectively. When the drugs were combined with 42-43°C hyperthermia, an overall response, either complete or partial, was seen in all the lesions. Complete regression was observed in 38% (3/8) and 43% (3/7) of the lesions treated with ADM or BLM, respectively, combined with heat. At a 4-month follow-up, 33% (2/6) and 40% (2/5) of the same groups of lesions remained still undetectable. These results suggest that the combined treatment of drugs and local hyperthermia can be advantageously employed in clinical practice for treating local tumors, especially recurrences in previously irradiated areas.

Hyperthermia and paclitaxel--epirubicin chemotherapy: enhanced cytotoxic effect in a murine mammary adenocarcinoma.

Multimodality therapy is considered of great interest in the treatment of locally advanced solid tumours. In previous experiments, paclitaxel (TX) and epirubicin (EP) were combined with different schedules, obtaining a superadditive effect on the growth of a murine mammary carcinoma. In the present study, the authors have analysed the possible use of hyperthermia (HT) to increase the efficacy of TX and EP combinations. Tumours were transplanted into the right hind foot of female hybrid (C3D2F1) mice. Both TX and EP were administered i.p in two different doses. Hyperthermia was applied using a water bath at 43.2oC for 1h. Results were analysed in terms of Tumour Growth Delay (TGD). The maximum tolerated doses in combined protocols were TX 45mg/kg and EP 9mg/kg, with an interval time of 24h between the two administrations. TGDs of some of the schedules performed are reported: EP + HT=11 days, TX + HT=16 days, TX + EP (with an interval time of 24h)=14 days, and TX + EP + HT=22 days. In the experimental model, HT significantly increases the effects of both TX and EP. TX + EP + HT treatment is the most effective (significantly different from TX+ EP), but not in a significant way when compared to TX+ HT treatment. These results suggest the possible use of a TX+ HT protocol for local tumour response, whereas EP could be added in order to achieve a better systemic control.

Combined radiation and hyperthermia: Effects of the number of heat fractions and their interval on normal and tumour tissues

The effect of one or more heat treatments at 43 degrees C combined with conventional multifraction irradiation was studied in murine normal and tumoral tissues. The endpoint of this study was the TCD50 of the C3H mammary carcinoma, inoculated into the foot. For normal tissue the reaction of the skin of the foot was assessed according to a graded scoring system. Twenty X-ray fractions delivered in 20 or 26 days were combined with one, four or eight fractions of quasi-simultaneous or sequential hyperthermia (i.e. heat applied 4 h after irradiation). Tumour dose-response curves show a decrease in TCD50 and in increase in TER linked to the increasing number of heat sessions. A qualitatively similar effect of the number of sessions was observed for the different protocols (quasi-simultaneous and sequential) and for the two overall times. No significant difference was measured between one and four HT sessions plus 20 fx of RT in the normal tissue damage, while a slight difference was observed between one, four and eight HT sessions delivered with 20 fractions of RT in 26 days.

Enhancement of Radiation Response by Paclitaxel in Mice According to Different Treatment Schedules

PURPOSE The aim of our study was to determine if paclitaxel could be used as a radiosensitizer in vivo. MATERIALS AND METHODS Paclitaxel was tested as a single agent and combined with an X-ray treatment. Paclitaxel was administered i.p. in doses from 30 to 120 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Tumor growth delay (TGD) or tumor control dose (TCD50, radiation dose needed to induce local tumor control in 50% of irradiated animals) and moist desquamation dose (MDD50, radiation dose needed to induce serious moist desquamation in 50% of the non-tumor-bearing feet) were the endpoints. DNA flow cytometric analysis was performed. RESULTS DNA analysis demonstrated a G2/M block of tumor cells and a depletion of cells in S phase, with a maximum at 24 h from paclitaxel administration. Administering paclitaxel, in graded doses, 15 min before a 10-Gy X-ray treatment resulted in a linear regression line, almost parallel to that with paclitaxel alone, with a growth delay of about 6 days. In contrast, varying the X-ray dose with a constant paclitaxel injection (45 mg/kg b.w.) treatment showed some degree of synergism as the linear regression curves diverged. Interval time and sequence between paclitaxel administration and a 10 Gy X-ray treatment did not influence TGD. Protocols with paclitaxel at 30, 45, or 60 mg/kg were combined with radiation treatments at various doses (from 10 to 65 Gy). Values of TCD50 varied from 50.8 Gy for X-ray alone to 31.8 Gy for paclitaxel 60 mg/kg + X-ray. No differences were observed among MDD of different protocols. CONCLUSIONS These results suggest that, under some conditions, paclitaxel combined with radiation can show superadditive effects and this result combined with the lack of severe normal tissue damage indicate that a favorable therapeutic gain can be obtained.

Schedule dependent toxicity and efficacy of combined gemcitabine/paclitaxel treatment in mouse adenocarcinoma.

Abstract Increased interest in combining drugs with different targets has emerged over recent years. Our study aims at evaluating the effectiveness of combined gemcitabine/paclitaxel treatment taking into consideration doses, schedules, and toxicity. A spontaneous mammary carcinoma was transplanted into the right-hind foot of C3D2F1 mice. Paclitaxel (in doses from 20 to 80 mg/kg b.w.) and gemcitabine (in doses from 30 to 480 mg/kg b.w.) were administered i.p. in single or fractionated treatments. Toxicity and tumor growth delay (TGD) were the endpoints. TGDs for different gemcitabine doses in single administration (120, 240, and 360 mg/kg) overlapped (TGD ≅ 2.5 days). Toxicity was very high in daily administration. Results with gemcitabine alone showed the efficacy of treatments every 3 days. TGDs in fractionated treatments of 60 and 120 mg/kg × 4 were of ≅16 days. Also in this case, tumor growth curves overlapped pointing out the uselessness of the high drug doses. For combined treatments, we used only fractionated protocols, administering gemcitabine every 3 days. Paclitaxel was administered alone in one or two fractions and with different sequences in respect to gemcitabine administration. With 120 mg/kg of gemcitabine all the protocols showed an increased unacceptable toxicity. The best result was obtained administering paclitaxel 40 mg/kg on days 1 and 15 and gemcitabine 60 mg/kg on days 3, 6, 9, and 12 (TGD=38.2 days). The light toxicity and the high efficacy obtained with this protocol indicate the possible use of gemcitabine/paclitaxel treatment in clinical practice.

Greater antitumor efficacy of paclitaxel administered before epirubicin in a mouse mammary carcinoma

Abstract Combined treatment with paclitaxel and anthracyclines is increasingly being tested in clinical practice. Epirubicin is in general administered before paclitaxel. We have investigated, using a murine mammary adenocarcinoma, whether the efficacy and toxicity of this combination is influenced by treatment sequence, different time intervals and dose intensity. The tumor was transplanted into the right hind foot of C3D2F1 female mice. Paclitaxel was administered i.p. in doses ranging from 15 mg/kg to 75 mg/kg and epirubicin (i.p. or i.v.) in doses from 9 mg/kg to 30 mg/kg. The hepatic and peritoneal toxicity observed with epirubicin administration increased in combined treatments (stronger with i.p. than i.v. epirubicin administrations) and was dose-dependent. When paclitaxel and epirubicin were administered simultaneously or paclitaxel was given 24 h before epirubicin, the same tumor growth delays were obtained in all groups. A smaller effect was observed when paclitaxel was administered 24 h after epirubicin. Increasing the epirubicin or paclitaxel dose led to higher tumor growth delays but also an increased toxicity. In conclusion, in this experimental model, the administration of 45 mg/kg paclitaxel before 15 mg/kg epirubicin was very effective and the increased toxicity can be limited by introducing an interval of 24 h between drug administrations. These results should be considered when designing clinical trials.