Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to sunitinib in metastatic renal cancer.

BACKGROUND: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. METHODS: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. RESULTS: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. CONCLUSION: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Sorafenib in hepatocellular carcinoma - a post marketing evaluation.

BACKGROUND: Sorafenib is an orally active multikinase inhibitor licensed for the treatment of patients with unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The web-based registry, used for appraisal on new drugs, allows developing the observational prospective analysis of innovative drug therapies. To establish clinical impact of Sorafenib, institutional data were collected prospectively through the registry. RESULTS: A total of 81 patients treated with Sorafenib were reviewed (median age = 65 years) and the follow-up duration was 30 months. Every patient was checked for length of treatment, toxicity and outcomes. Based on the study sample, the median time to progression was 3 months and median overall survival was 8 months. We found 52% progressions at first evaluation and the disease control rate was 32%. CONCLUSION: Our data from real life practice showed that the clinical benefit of Sorafenib in unresectable HCC was gained in selected responder patients.

Overdose of Vinblastine in place of Vinorelbine during IGEV chemotherapy.

Any class of drugs is susceptible to errors, in case of antineoplastic agents the medication errors may cause severe and life-threatening toxicity due to very limited therapeutic index with toxic events even at therapeutic dosage, to complexity of regimens and the particular vulnerable population. We report herein a case of Vinblastine (VBL) accidental overdose, the cause of mistake, the toxic effect and the salvage therapy adopted in a young lady suffering of Hodgkin relapse during IGEV chemotherapy.

Circulating and disseminated tumor cells in the clinical management of breast cancer patients: unanswered questions.

Breast cancer is the most common cancer in women. Although survival rates have improved with the use of new therapeutic agents, many issues remain unresolved and new predictive and prognostic factors are needed in clinical practice. Several studies have suggested a prognostic and predictive role for circulating and disseminated tumor cells in metastatic disease and adjuvant treatment. Because of recent technological advances, oncologists have gained a new perspective on this disease. Circulating tumor cells could be both a new tumor marker as well as a tool to gain novel insight into the natural history of this neoplastic disease.

Taking care of older cancer patients: results of a survey addressed to the Chiefs of the Medical Oncology Divisions in Italy.

An open questionnaire on the management of older cancer patients in the Italian Divisions of Medical Oncology was sent to the Chiefs of the units in the last 4 months of the year 2004. One hundred and ninety-nine of 330 (60%) responded. The majority of the Medical Oncologists interviewed agreed that special therapeutic protocols were necessary for elderly cancer patients. Also specific guidelines were believed to be useful. In only a minority of units there were some members specifically dedicated to older patients and the Multidimensional Geriatric (MGE) was used routinely only in 12% of cases. The majority of the physicians interviewed believed that older patients accepted chemotherapy as the younger ones did, or even more (79%). Written informed consent was obtained in the majority of units (70%). Over 63% believed that oral antitumor drugs had a very important role in older patients, while 36% were sceptical or negative. More time and attention should be paid to older patients (87.4%) and more economic resources devoted to them (93.3%). In conclusion, Italian Medical Oncologists are well aware of the increasing number of old cancer patients, of the particular problems concerning drug administration and the need of specific trials and guidelines. The need of close contact with Geriatricians and the adoption of Geriatric tools (MGE) are only perceived by a minority. The majority, however, believes that more time and resources should be available in order to take care of elderly cancer patients.

Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo.

BACKGROUND: The standard treatment for advanced (stage III and IV) head and neck squamous cell carcinoma (i.e., surgery with postoperative radiotherapy in operable patients and radiotherapy alone in inoperable patients) has had poor results. A series of randomized trials of induction chemotherapy have up to now failed to demonstrate an improvement in survival. PURPOSE: This trial was designed to determine whether intensive induction chemotherapy administered before loco-regional treatment would improve survival of patients with advanced disease. METHODS: Patients had previously untreated, advanced nonmetastatic (stages III and IV) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and paranasal sinuses. The study design was a randomized, multi-institutional, phase III trial. Eligible patients (n = 237) were randomly assigned to receive either initial chemotherapy (cisplatin and infusional fluorouracil) followed by loco-regional treatment (group A, n = 118) or loco-regional treatment alone (group B, n = 119). For operable patients (group A, n = 34; group B, n = 32), loco-regional treatment included resection followed by adjuvant radiotherapy. For inoperable patients, radical irradiation was performed with a planned dose of 65-70 Gy to involved areas. A dose of 45-50 Gy was also planned to the uninvolved neck or postoperatively. The statistical (log-rank) test was performed no earlier than 2 years after the randomization of the last patient. RESULTS: Seventy-one patients (60%) in group A and 67 patients (56%) in group B were considered free of disease after they completed the treatment sequence. The analysis of time to distant metastases showed an advantage for group A patients. (Respective 2- and 3-year values for inoperable patients were 15% and 24% for group A versus 36% and 42% for group B, P = .04; only one operable group A patient had distant metastases after 49 months versus 26% [2 years] and 31% [3 years] for operable group B patients, P = .01.) For inoperable patients, the combined treatment was significantly associated with an increase in complete remission rate (group A, 44%) as compared with radiotherapy alone (group B, 30%) (P = .037). Inoperable patients also benefitted from induction chemotherapy in terms of disease-free survival (49% and 34% for group A versus 28% and 26% for group B; P = .06) and of overall survival (30% and 24% for group A versus 19% and 10% for group B; P = .04). CONCLUSIONS: When all 237 randomly assigned patients were analyzed, there were no significant differences in the two treatment strategies in loco-regional failure or in disease-free or overall survival, although the development of distant metastases was reduced. For operable patients, the only benefit from neoadjuvant chemotherapy was a significant reduction in the incidence of distant metastases. For inoperable patients, neoadjuvant chemotherapy improved local control, decreased the incidence of distant metastases, and improved the complete remission rate and overall survival. IMPLICATIONS: Confirmatory studies with effective chemotherapy regimens delivered for an adequate number of cycles are required.

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.

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.

Psoriasis and tamoxifen therapy: a case report.

A case of chronic plaque psoriasis in a woman with advanced breast cancer is reported. Treatment of the breast cancer with tamoxifen cleared the psoriatic skin lesions for several months, even after suspension of the hormonal treatment.

Tamoxifen efficacy in advanced breast cancer previously treated with endocrine and cytotoxic therapy.

Sixty-nine postmenopausal women with disseminated breast cancer previously treated with endocrine and cytotoxic therapy were treated with tamoxifen (20 mg/day). Complete plus partial response (CR+PR) was observed in 29 % (CR 16 %) and stable disease in 28 %. The objective response was higher in soft tissue sites (52 %) compared to osseous (12 %) and visceral (13 %) disease. No regression or disease stabilization was observed in the presence of liver involvement. Free-interval, length and type of menopause, and estrogen receptor status (carried out only 26 patients) did not statistically influence the percent of objective response. Only 1 of 16 patients (6 %) who did not respond to previous endocrine therapy responded to tamoxifen, while 3 of 9 previous hormonal responders (33 %) achieved objective regression with antiestrogen therapy. On the contrary, the response to previous chemotherapy failed to influence the subsequent response to tamoxifen. The median duration of the response was more than 12 months and the median survival more than 18 months. Treatment was generally very well tolerated and in only one patient was temporarily discontinued because of thrombocytopenia.

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.

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.

Survey on the use of questionable methods of cancer treatment. GOCS. Grupo Oncólogico Cooperativo del Sur República Argentina.

BACKGROUND: Despite the improvement of cancer treatments, unproven and useless therapies are widely adopted among cancer patients and their families. Little information is available on the actual magnitude of such a phenomenon. METHODS: Two anonymous, similarly aimed surveys were independently carried out in Italy and Argentina on cancer patients and their families by two research groups. RESULTS: Respectively 563 and 400 questionnaires were distributed. The percentage of patients and/or families involved in unsound care (17%) was similar in both surveys. Of these treatments, 20%-38% were proposed by physicians, but relatives, friends, and mass-media had an equally important role. The costs of such care was difficult to estimate. CONCLUSIONS: Real and exhaustive efforts are needed by Health Care Organizations, which must execute a policy of information and education towards the public and professionals, as well as declare unethical the use of unproven therapies which claim cancer cure but simply create false hopes. All oncologists should be aware of the use of these treatments for cancer patients, even concomitantly with conventional care.

Mitomycin C in metastatic breast cancer resistant to hormone therapy and conventional chemotherapy.

Mitomycin C was administered to 22 patients with metastatic breast cancer, refractory to hormonal therapy and conventional chemotherapy. Treatment was given by intravenous bolus injection at 20 mg/m2 of the drug and repeated at 6-week intervals. The overall response rate was 23%. Two complete remissions were seen in soft tissue lesions. Leukopenia occurred in 68% of the patients, thrombocytopenia in 36%, and anemia in 14%. One case of cardiotoxicity after previous treatment with adriamycin was observed. We conclude that mitomycin C is an active agent in disseminated breast cancer resistant to hormone therapy and chemotherapy. Combination of mitomycin C with other chemotherapeutic drugs will be tested.

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 (T 1/2 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 usefulness is probably confined to patients with minimal abdominal disease.

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.

4'epidoxorubicin plus verapamil in anthracycline--refractory cancer patients.

Four patients refractory to doxorubicin (DX) and 9 patients refractory to 4'epidoxorubicin (4'EpiDX) were treated with verapamil (VRP) (120 mg every 6 h for 3 days) plus 4'EpiDX (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 4'EpiDX, can induce objective responses in some patients refractory to anthracyclines.

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.

[Approach to the problem of economic costs of the medical therapy of tumors]. / Approccio al problema dei costi economici della terapia medica dei tumori.

The use of antitumoral drugs is increasing constantly. The economic cost pro capite of the commonest oncotherapeutic treatments has been analysed. The calculation is carried out on the basis of out-patient as well as in-patient treatment. The costs were identical in the hospital where the study was carried out due to the application of the recent regional health legislation. A number of considerations are made regarding the implications of unqualified use of the medical treatment of cancer.