Romano Demicheli

The exponential-Gompertzian tumor growth model: data from six tumor cell lines in vitro and in vivo. Estimate of the transition point from exponential to Gompertzian growth and potential clinical implications.

The published growth data were examined for six tumor cell lines (FSA, Line 1, MCA-11, EMT6/RO, MGH-U1, MLS) grown in vivo and in vitro as monolayer cultures and as multicell spheroids cultured under different experimental conditions. Serial estimates of tumor sizes were fitted by Gompertzian equations obtained with a non-linear computerized program. When the growth equations of the same tumor growing in different experimental conditions were compared, the Gompertzian parameters α0 (initial specific growth rate) and β (retardation factor) showed a strong linear correlation in all the examined lines, with no exception. This occurrence supports the exponential-Gompertzian growth model, where an early exponential phase (which is virtually not influenced by exogenous factors) is followed by a Gompertzian phase, the characteristics of which are greatly dependent on environmental conditions. The transition between the two phases was estimated to occur when tumor size reached 102–104 cells, depending on the cell line. This kinetic change in tumor growth may be clinically relevant as regards cytotoxic treatments. It could explain some consequences of delays in adjuvant (postoperative) chemotherapy observed in clinical trials on primary breast cancer.

4'Epidoxorubicin Plus Verapamil in Anthracycline - Refractory Cancer Patients

Four patients refractory to doxorubicin (DX) and 9 patients refractory to 4epidoxorubicin (4EpiDX) were treated with verapamil (VRP) (120 mg every 6 h for 3 days) plus 4EpiDX (80 mg/m2 i.v. bolus, together with the 6th VRP administration). Three patients had partial remissions lasting 3, 3.5 and 7 months, respectively. Toxicity grading did not exceed usual levels. The study demonstrates that VRP, when added at conventional doses to 4EpiDX, can induce objective responses in some patients refractory to anthracyclines.

Pharmacologic data and technical feasibility of intraperitoneal doxorubicin administration.

Seventy intraperitoneal administrations of doxorubicin were performed in 12 patients with malignant disease in the abdominopelvic space. Peritoneal and hematologic drug levels were measured by fluorimetric assay. A first-order decline in the peritoneal level was determined (T1/2 96 ± 18 min), with a mean drug absorption of 84 % in 4 h (range 40-96 %) and a mean ratio of a peak dialysate/peak serum level of 111 (range 12-390). Gastrointestinal toxicity was common and peritoneal phlogosis occurred twice. The doxorubicin level and the time of peritoneal exposure seem to be critical factors for major local toxicity. At a moderate concentration doxorubicin can be intraperitoneally administered, but its usefullness is probably confined to patients with minimal abdominal disease.

Pharmacological data and technical feasibility of intraperitoneal 5-fluorouracil administration.

Via a surgically implanted Tenckhoff catheter, 5-fluorouracil was intraperitoneally administered to patients with malignant disease confined to abdominal space. Treatment was well tolerated without local complications. Peritoneal and plasmatic drug levels were measured, showing that: 1) peritoneal drug levels declined as a first order function; 2) plasmatic levels were very close to those reported for continuous i.v. administration, but peritoneal concentrations were much higher (log 1 to 3); 3) concentration × time product had a peritoneum: plasma ratio ranging from 120 to 1350. The hypothesized role of intraperitoneal 5-fluorouracil administration and the questions still to be answered are summarized.

Relative role of host and tumor in the growth pattern of murine and human neoplasms following subcutaneous transplantation in mice.

The growth patterns of two murine and eight human tumors, bilaterally implanted into subcutaneous tissue of groups of recipient mice, were studied. A Gompertz equation was fitted to experimental data for each individual implant and the Gompertz parameters were utilized as quantitative growth characteristics. The relative roles of the tumor-implanted flank (right versus left), of the individual host and of the tumor were analyzed by the paired t-test, simple linear regression model, one-way and two-way analysis of variance. Sixty pairs of Gompertz curves were obtained in seventy animals. Heterogeneity was the main characteristic of the growth pattern in all tumors under study, with a wide variability among the Gompertz parameters. Statistical analysis of experimental data showed that only the tumor systematically influenced the growth characteristics, whereas neither the tumor-implanted flank nor the individual host played a significant role. These results have both theoretical and practical implications.

Influence of Tumor Growth Kinetics on Response to Doxorubicin Treatment of C3H Mammary Carcinoma

The influence of tumor growth kinetics on response to doxorubicin treatment of C3H mammary carcinoma was investigated. Gompertzian growth curves were obtained for the tumor mass of each mouse by a computerized best fit program. The response was assessed by evaluating: a) the total clonogenic cell reduction as a fraction of the initial tumor volume or the tumor volume that should result at the end of treatment in a free growth condition, and b) the partial clonogenic cell reduction at each drug administration, assuming a first order cell kill hypothesis. Slowly growing tumors at each dose level showed a significantly poorer response than rapidly growing tumors. Each response index exhibited a linear correlation with the specific instantaneous growth rate at the time of treatment. Data also suggested a dose-response dependence.

Pilot study of intravenous administration of the acid-treated Salmonella minnesota R595 (Re) in cancer patients.

The clinical toxicity of acetic acid-treated « Salmonella minnesota » R595 (Re) organisms was evaluated in 24 cancer patients. Bacteria were injected i.v. four times at increasing doses for a total of 6.5 μg. This therapeutic regimen was free of major side effects (one patient had fever higher than 38 °C and 10 patients complained of pruritus). Furthermore, this bacterial preparation which possesses a more exposed lipid A on its surface, exhibited immunomodulating capacities in that it normalized the inverted T helper/T suppressor ratio and enhanced natural killer activity in tumor patients. The mechanisms of the lower toxicity and immunomodulating activities of these bacteria compared to other lipid A preparations are discussed.

Bleomycin, Vincristine, Mitomycin and Cisplatin Alternated with Cyclophosphamide, 4'-Epidoxorubicin and Procarbazine in Advanced Non-small-cell Lung Cancer

Thirty-eight patients with histologically confirmed non-small-cell lung cancer were treated with bleomycin, vincristin, mitomycin and cisplatin (BOMP) alternated with cyclophosphamide, 4-epidoxorubicin and procarbazine (CEP). Twenty patients were randomized to start the treatment with BOMP and 18 with CEP. Patients underwent a median of 4 cycles (range, 1-8). The overall response rate was 36% with 2 clinical complete responses. The median duration of response was 6.5 months, the median survival time was 7.5 months, and 37% of patients survived for more than one year. The comparison between the two arms of this study and between this study and a previous investigation on the effectiveness of BOMP suggests that CEP regimen added to BOMP does not significantly improve patient outcome.

Phase II trial of mitomycin plus cisplatin in the treatment of advanced colorectal adenocarcinoma.

Cisplatinum may be synergistic if used in combination with other agents. This study was undertaken to investigate whether a mitomycin plus cisplatin in combination could show any promising data in colorectal cancer. The regimen did not show sufficient activity to encourage further trials.

Factors causing dose variability in drug administration.

SummaryThe variability of the drug dose actually given to cancer patients was analyzed. Three variability factors were quantitatively examined (body surface calculation, personalized dose calculation, and drug residuum in commercially available vials) and their variability was experimentally measured. A systematic reduction (mean, 7%; range, 2%–15%) and a random variability (4%–5%) of the dose given were demonstrated. These results draw attention to the role of some of the procedures of routine clinical activity in determining the amount of drug actually delivered. The analysis suggests that personalization of doses must be very accurate in both measurement and calculation and that the staff giving the drug needs to be carefully informed about the importance of drug residuum. The variability of the delivered dose can lead to the misclassification of patients in investigations on the dose-response relationship. This factor may be added to pitfalls previously reported to affect this type of retrospective analysis.