Is there a rationale for an anesthesiologist's role against cancer recurrence?

Growth of tumors can accelerate during the peri-operative period. Accordingly, early relapse of cancer occurs in some patients during the first two postoperative years. Temporal and biologic analyses of cancer pathophysiology suggest a link between peri-operative pathophysiological changes and acceleration of tumor growth. Understanding the role of inflammation and its consequences (i.e., immune response, growth factors, dissemination of tumor cells) could lead to define a role of anesthesiologists in reducing cancer recurrence following surgery. We argue for peri-operative pharmacological interventions to reduce cancer relapse, with a focus on non-steroidal anti-inflammatory drugs.

Gene regulatory networks: a new conceptual framework to analyse breast cancer behaviour.

The study of complex systems has clearly evidenced that a few overall behavioural properties cannot be inferred from the properties of their single parts and are rather determined by their architecture. Such an approach has been recently proposed in biology to understand genome functioning and in oncology to endeavour a more consistent explanation of the variegated cancer behaviours. In the present perspective, we summarise the basic concepts of the proposed global approach and then we reconsider, in this new context, tumour dormancy and primary tumour removal effects, which recently emerged as critical points for breast cancer understanding.

The effects of surgery on tumor growth: a century of investigations.

A few clinical investigations suggest that while primary breast cancer surgical removal favorably modifies the natural history for some patients, it may also hasten the metastatic development for others. The concepts underlying this disease paradigm, i.e. tumor homeostasis, tumor dormancy and surgery-driven enhancement of metastasis development, have a long history that is reviewed. The review reveals the context in which these concepts were conceived and structured to explain experimental data and shows that they are not so new and far fetched. The idea that surgical cancer resection has both beneficial and adverse effects upon cancer spread and growth that result from the modulation of tumor dormancy by the resection should be considered a potentially fruitful working hypothesis.

Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer.

To explain bimodal relapse patterns observed in breast cancer data, we have proposed that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell phase and the avascular micrometastasis phase. The half-lives of these states are 1 and 2 years respectively. We also suggested that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. These iatrogenic events are very common in that over half of all metastatic relapses progress in that manner. Assuming this is true, there should be ample and clear evidence in clinical data. We review here the breast cancer paradigm from early detection, through treatment and follow-up, and consider how dormancy and surgery-driven escape from dormancy would be observed. We examine mammography data, effectiveness of adjuvant chemotherapy, heterogeneity and aggressiveness, timing of surgery within the menstrual cycle and racial differences in outcome. Dormancy can be identified in these diverse data but most conspicuous is the sudden escape from dormancy following primary surgery. These quantitative findings provide linkage between experimental studies of tumor dormancy and clinical efforts to improve patient outcome.

Local recurrences following mastectomy: support for the concept of tumor dormancy.

BACKGROUND: Local or regional recurrence of breast cancer occurs in 5%-30% of patients treated by Halsted radical or modified radical mastectomy. Lag time between treatment and recurrence varies widely, and it is not known whether the recurring tumor grows at a constant growth rate or at a more rapid rate after a period of tumor dormancy. PURPOSE: This study was undertaken to discriminate between the above-mentioned hypotheses, i.e., determine whether a tumor that recurs after mastectomy grows at a constant rate or whether it grows rapidly following a period of tumor dormancy. METHODS: A series of 122 patients with local recurrence as a first event after mastectomy for resectable breast cancer was evaluated. We measured the diameter of the recurring tumor (Dr) in each patient and calculated the diameter that the recurring tumor could have reached at the immediately preceding physical examination (Dpe), when no local relapse had yet been detected, by assuming an exponential growth during the treatment-free interval. For patients who had a calculated diameter Dpe that was large enough to have been detected at the previous examination, we assumed that a tumor 5 mm in diameter had been mistakenly missed, and the expected corresponding tumor diameter at the time of detection (Drc) was calculated. Finally, the minimum growth rate (mGR) consistent with the sequence "no detection-->recurrence of diameter Dr" was obtained by assuming an exponential growth from the tumor volume corresponding to a diameter 1 mm less than the diameter detection threshold. RESULTS: A wide overlap between Dr and Dpe values was observed. Seventy-two (59%) of 122 Dpe values were larger than the minimum Dr; 18 (15%) were even larger than the median Dr value. The difference between expected and observed detection rates was highly significant (P < .0001). Furthermore, when treatment-free intervals were longer than 4 years, the difference between median Dr and median Dpe values failed to reach statistical significance. The Drc values were significantly lower than the related Dr values, while the mGR values were significantly higher than the corresponding growth rates (paired sample t test: P < .001). CONCLUSION: This study provides evidence that the hypothesis of uninterrupted constant growth of locally recurring breast tumors should be rejected, as it implies a statistically significant departure from observed data. Our results suggest that a period of tumor dormancy followed by more rapid growth could provide an alternative and more reasonable description of tumor recurrence.

An exponential-Gompertzian description of LoVo cell tumor growth from in vivo and in vitro data.

The data of nine monolayer cultures, 48 multicellular spheroids, and 19 s.c. xenografts of LoVo cells were fitted, on an individual basis, by exponential and Gompertzian equations, respectively. The mean growth parameters alpha 0 (initial growth rate) and beta (retardation factor) of the three experimental systems presented a strong linear correlation alpha 0 = 6.88 beta + 0.56, r = 0.9843. This implies that, at the particular tumor size of 155 microns in diameter (mean +/- SD = 50-310 microns), the tumor growths described by Gompertzian curves (from spheroids as well as from s.c. xenografts) have the same growth rate as monolayer cultures. This occurrence strongly supports an exponential-Gompertzian growth model, where an exponential monolayer-like phase changes to a Gompertzian growth, controlled by environmental conditions, when the tumor size has reached a critical value.

Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: results of a randomized cooperative trial.

Diethylstilbestrol (DES) can induce a recruitment into the proliferative pool of previously resting breast cancer cells in vivo. In order to verify if estrogenic recruitment could result in a larger tumor cell killing by chemotherapy, 117 patients with metastatic breast cancer were randomized to receive CEF (cyclophosphamide, 600 mg/m2; epidoxorubicin, 60 mg/m2; and 5-fluorouracil, 600 mg/m2 on day 1); DES-CEF (cyclophosphamide, 600 mg/m2 on day 1; DES, 1 mg orally on days 5, 6, and 7; and epidoxorubicin, 60 mg/m2, and 5-fluorouracil, 600 mg/m2, on day 8) every 21 days. No significant difference in objective response rates, survival, or progression-free survival was seen between the two regimens. Patients in the DES-CEF arm experienced a higher complete response (CR) rate (24.1% v 16.1%), which reached statistical significance in the case of soft-tissue metastasis (48% v 27.3%; P less than .05) and estrogen receptor-negative tumors (35.7% v 11.1%; P less than .025). Survival and progression-free survival of patients refractory to treatment were not worsened by estrogenic recruitment. In the subset of patients failing after adjuvant polychemotherapy, DES-CEF unexpectedly induced a significantly longer survival (greater than 802 days v 375 days; P = .029) and progression-free survival (239 days v 192 days; P = .041) than CEF. The DES-CEF regimen was more myelotoxic, and 43.3% of the DES-CEF cycles had to be delayed because of leukopenia in comparison with 11.8% of the CEF cycles (P less than .0001). In conclusion, chemotherapy with estrogenic recruitment was able to induce more CRs in certain subsets of patients and a significant prolongation in survival and progression-free survival of patients failing after adjuvant polychemotherapy. These results have been achieved despite a significantly lower dose intensity of chemotherapy.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

Sequential Adriamycin and CMF in Metastatic Breast Cancer.

PURPOSE: To evaluate the clinical activity of a sequential treatment with Adriamycin followed by CMF (cyclophosphamide, methotrexate, fluorouracil) and the relative therapeutic contribution of the two drug regimens given at full conventional doses in metastatic breast cancer. PATIENTS AND METHODS: From August 1990 to February 1993, 44 patients with advanced breast cancer previously untreated with chemotherapy entered the study. Treatment consisted of the intravenous administration of Adriamycin (75 mg/m² on day 1 every three weeks) for four cycles followed by intravenous CMF (cyclophosphamide, 600 mg/m²; methotrexate, 40 mg/m²; fluorouracil 600 mg/m²) on days 1 and 8 every four weeks for four total courses. RESULTS: In 41 evaluable patients, four cycles of full-dose Adriamycin were able to achieve an overall response rate of 75%, including 17% complete remissions. Four cycles of CMF administered after Adriamycin were able to increase tumor response in 64% of evaluable cases. At the end of the sequential treatment program, 78% of 41 patients achieved an objective remission and in 30% of them a clinical complete response was documented. Main side effects, i.e., leukopenia and gastrointestinal disturbances, were moderate and short-lasting. One patient died because of acute myocardial infarction. CONCLUSION: In untreated metastatic breast cancer patients, the sequential administration of Adriamycin and CMF is highly effective at the expense of a moderate toxicity profile that allows high-dose intensity of both drug regimens. CMF treatment after upfront Adriamycin is able to exert a further therapeutic advantage.

In vivo manipulation of human breast cancer growth by estrogens and growth hormone: kinetic and clinical results.

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent alpha-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polychemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.

Prospective study with HEXA-CAF combination in ovarian carcinoma.

The value of combination chemotherapy with HEXA-CAF was analyzed in 31 patients with histologically documented epithelial ovarian cancer in advanced stages (minimal or gross disease). No patient had been previously treated with chemotherapy. Peritoneoscopy with diaphragmatic inspection, peritoneal cytology, lymphography, and chest X-ray were routinely used in staging and restaging the patients. Complete (CR) plus partial (PR) responses were obtained in 13/31 fully restaged patients (41.9%). CR was recorded in seven patients (22.5%) and PR in six patients (19.3%). Remission duration was significantly longer in patients who achieved CR (20 months) than in those who attained PR (9.5 months) (P Less Than 0.01). In all treated patients the median duration of survival was 16.5 months. Survival was significantly longer in patients with CR than in patients who did not achieve CR (P Less Than 0.05). Nevertheless, considering the rate of CR in patients with gross disease (20.6%), HEXA-CAF combination seems a useful but not yet a hopeful treatment for patients with advanced ovarian carcinoma.

Factors causing dose variability in drug administration.

The 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.

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 alpha 0 (initial specific growth rate) and beta (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 10(2)-10(4) 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.

A new CMF regimen.

In CMF regimen, gastric disturbances secondary to oral administration of cyclophosphamide (CTX) frequently induce many patients to take the drug erratically, to lower the daily dose, or to divide it in many administrations. These alterations act as a source of uncertainty in the evaluation of treatment results and may decrease the chemotherapy effectiveness. An i.v. CTX administration is proposed, and the rationale of such a proposal in examined. Data on the mild toxicity of the new schedule are reported.

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.

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.

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.

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, vincristine, 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.

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 micrograms. This therapeutic regimen was free of major side effects (one patient had fever higher than 38 degrees 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.

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 x 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.