Phase II studies of anticancer chemotherapy: indirect evidence of poor quality.
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Antineoplastic Agents↗
Biomedical subjects
G Facchini
Publications and source records attributed to G Facchini.
Docetaxel induces p53-dependent apoptosis and synergizes with farnesyl transferase inhibitor r115777 in human epithelial cancer cells.
Docetaxel (Taxotere, DTX) is a promoter of apoptosis in cancer cells. Since cytotoxic mechanisms of DTX are not yet fully understood, we have investigated the effects of DTX on apoptosis and ras-->Erk-mediated signal transduction in human epidermoid KB, colon HT-29 and breast HCC1937 cancer cells. We have found that the exposure to 0.78 or 1.56 or 2.5 ng/ml DTX for 48 h induced apoptosis and growth inhibition in about 50 % of KB, HCC1937 and HT-29 cell population, respectively. In these experimental conditions, PARP and caspase 3 cleavage was also showed in all cell lines. KB and HCC1937 cells express a wild type p53 while HT-29 display a mutated form. Interestingly, we have found that DTX reduces the expression of mutated p53 in HT-29 and increases the expression of wild type in KB and HCC1937 cells. Moreover, DTX reduces ubiquitination of the wild type p53 in KB and HCC1937 cells and increases the ubiquitin-conjugated form of mutated p53 in HT-29 cells. Furthermore, exposure of cancer cells to DTX for 48 h increases the expression and activity of Ras and up-regulates Raf-1 and the phosphorylated isoforms of Erk-1/2. On the bases of these data, we have hypothesized that the increased activity of the ras-->erk-dependent pathway induced by DTX could be a protective signalling from the apoptosis caused by the drug. Therefore, we have used R115777, a farnesyl transferase inhibitor that inactivates ras, in combination with DTX. The combined treatment with DTX and R115777 resulted in a strong synergism in growth inhibition in the three cell lines. These data suggest the use of the combination in these therapeutic settings even if further experiments are required for the clinical translation.
Animals↗
A liver angioma colonized by colon cancer cells in a patient with two primitive localizations by colon adenocarcinoma: biologic, diagnostic and therapeutic implications.
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Adenocarcinoma, Mucinous↗
Stop-flow technique for loco-regional delivery of high dose chemotherapy in the treatment of advanced pelvic cancers.
AIM: To verify the rationale of a pelvic stop-flow technique for the perfusion of high-doses of mitomycin C and anthacyclines in patients with inoperable, recurrent pelvic cancer. METHODS: The stop-flow technique was realized by using percutaneous double-balloon arterial-venous catheters that selectively isolate the pelvic vascular section and a perfusion provided by an extracorporeal pump for 20 min. Ten patients (pts) with unresectable pelvic recurrence from colon-rectal cancer were treated with a combination of Mitomycin C (MMC, 20 mg/sqm) plus doxorubicin (DOXO, 75 mg/sqm; 8pts) or epirubicin (EPI, 75 mg/sqm; 2pts) infused into the isolated pelvic compartment. Blood samples were collected from the extracorporeal vascular flow and from peripheral plasma, and analysed for drug quantitation. RESULTS: During the procedure, there were no technical or hemodynamic complications, and no deaths occurred during surgery or in the postoperative period. MMC and DOXO peak levels measured in the extracorporeal system which irrotates the tumor area, were on average 21.6 (range: 4.3-44.3, MMC) and 17.2 (range: 1.8-48.4, DOXO) times higher than those observed in the peripheral blood. Similarly; the area under concentration (AUC) versus time curves measured in the pelvic compartment during stop-flow perfusion were 19.9 (range: 3.8-45.0, MMC) and 13.4 (range: 1.2-26.6, DOXO) times higher than the corresponding value in peripheral circulation. The drug percentage eliminated in the ultra filtrate was only 7.7% (MMC) and 0.9% (DOXO), and the plasmatic AUC(0-24) were similar to those observed with iv bolus of equivalent drug doses. Minimal systemic and local toxicities were observed. One complete pathological and 2 partial responses were observed; pain remission in 8/10 patients. median survival was 12 months (8-31). CONCLUSION: The endo-arterial administration into the local vasculature produces high pelvic-systemic concentration gradients during the stop-flow perfusion with limited local and systemic toxicity. The encouraging clinical results suggest further evaluation.
Adolescent↗
Percutaneous ethanol injection efficacy in the treatment of large symptomatic thyroid cystic nodules: ten-year follow-up of a large series.
We present a prospective study on the long-term efficacy of percutaneous ethanol injection (PEI) treatment of a large series of symptomatic thyroid cystic nodules (STCN). Ninety-eight patients (72 females and 26 males) were treated. The mean basal volume of the STCN was 35.3 mL. In 92 of 98 patients PEI treatment induced a greater than 50% nodule shrinkage, only 6 of 92 responder patients relapsed at a follow-up of 9 years. Moreover, all the patients had a significant clinical benefit because a significant reduction of the cyst-associated symptoms was recorded. Furthermore, a limited number of sessions was required for the treatment of cysts larger than 40 mL (mean +/- standard deviation [SD]: 2.7 +/- 0.75) demonstrating the feasibility of the procedure also in the treatment of large cysts. In conclusion, PEI is an effective and inexpensive procedure with a high patient compliance and long-lasting effects in the treatment of cysts larger than 40 mL.
Administration, Cutaneous↗
Phase I-II study of gemcitabine and paclitaxel in pretreated patients with stage IIIB-IV non-small cell lung cancer.
Gemcitabine and paclitaxel are among the most active new agents in non-small cell lung cancer (NSCLC) and are worth considering for second-line chemotherapy. In this phase I-II study, we combined gemcitabine and paclitaxel for second-line treatment of advanced NSCLC. Gemcitabine doses were kept fixed at 1000 mg/m2 on day 1 and 8, and paclitaxel doses were escalated from 90 mg/m2 on day 1 of the 21-day cycle. Thirty-seven patients were treated at six different dose levels. Grade 4 neutropenia was dose-limiting toxicity (DLT), since it occurred in two out of six patients treated at paclitaxel 240 mg/m2; the paclitaxel dose level just below (210 mg/m2) was selected for phase Il evaluation. Non-hematologic toxicity was mild. One complete response (CR) (3%) and 13 partial responses (PR) (36%) were observed in 36 evaluable patients for an overall response rate of 39% (95% C.I., 23-57%). Median duration of response was 35 weeks (range, 8-102). All of the observed objective responses occurred in the 19 patients who had previously responded to the first-line therapy. Median survival was 40 weeks (range, 8-108 weeks). The combination of gemcitabine and paclitaxel is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC; further evaluation, at least in selected patients, such as those previously responding to first-line chemotherapy, is definitely warranted.
Adult↗
[Extramedullary primary cutaneous plasmacytoma. Description of a case] .
Primary cutaneous plasmacytomas of the chest wall are very rare. In this report we describe a case of a 70-years old man, affected by chronic obstructive pulmonary disease and renal failure. He was admitted because of a painful tumor on the right lateral chest wall: a transcutaneous fine needle aspiration and excisional biopsy revealed as a metastasis from lung cancer without clinical and or radiological evidence of pulmonary tumors and or other neoplasms. Because of failure of chemotherapy, the patient had undergone to bone marrow biopsy that it revealed medullary plasmacytosis < 5% plasma cells with a beta 2 microglobulin elevated. An other following excisional biopsy of a chest wall with immunocytochemistry revealed to be a cutaneous plasmacytomas. The patient was treated with local irradiation for a total dose of 40 cGy and systemic chemotherapy, stopped because of death by myocardial infarction. Cutaneous plasmacytomas appear to be more aggressive than non cutaneous extramedullary plasmacytomas; they should be separately categorized from them in future studies.
Aged↗
Phase I-II study of gemcitabine and carboplatin in stage IIIB-IV non-small-cell lung cancer.
PURPOSE: Platinum-based chemotherapy currently represents standard treatment for advanced non-small-cell lung cancer. Gemcitabine is one of the most interesting agents currently in use in advanced non-small-cell lung cancer, and high response rates have been reported when it is administered in combination with cisplatin. The aim of the present study was to evaluate the combination of gemcitabine and carboplatin in a phase I-II study. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non-small-cell lung cancer received carboplatin at area under the concentration-time curve (AUC) 5 mg/mL/min and gemcitabine at an initial dose of 800 mg/m2, subsequently escalated by 100 mg/m2 per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of the 28-day cycle. Dose escalation proceeded up to dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 nonhematologic toxicity. RESULTS: Neutropenia was DLT, inasmuch as it occurred in three of five patients receiving gemcitabine 1,200 mg/m2. Nonhematologic toxicities were mild. Gemcitabine 1,100 mg/m2 plus carboplatin AUC 5 was recommended for phase II studies. An objective response was observed in 13 (50%) of 26 patients, including four complete responses (15%) and nine partial responses (35%). Median duration of response was 13 months (range, 3 to 23 months). Median overall survival was 16 months (range, 3 to 26 months). CONCLUSION: The combination of gemcitabine and carboplatin is well tolerated and active. Neutropenia was DLT. The observed activity matches that observable in cisplatin-gemcitabine studies, whereas duration of response and survival are even higher. A phase II trial is under way.
Adult↗
Phase I/II study of paclitaxel and vinorelbine in metastatic breast cancer.
Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer. Both in vitro and in vivo studies have shown that the combined administration of these two microtubule-targeting agents is feasible and worthwhile. Based on the promising preclinical data, patients with metastatic breast cancer no longer amenable to conventional treatment were entered into a phase I/II study in which the vinorelbine dose was fixed at 30 mg/sqm and paclitaxel was started at 90 mg/sqm and then subsequently escalated by 30 mg/sqm per step. Cycles were repeated every 21 days. Hematopoietic growth factor support was provided from the 4th dose level onwards. Grade III neutropenia was observed only in 2 patients treated at the 5th dose level. Thrombocytopenia never reached grade 3. Neurotoxicity was considered dose-limiting, since grade 3 peripheral neuropathy occurred in all three patients treated at the 6th dose level. Other toxicities were mild. Paclitaxel 210 mg/sqm and vinorelbine 30 mg/sqm was the selected combination for phase II. Overall response rate in 34 evaluable patients was 38% (95% confidence interval (C.I.), 22% to 54%). In particular, 3 complete responses (9%) and 10 partial responses (29%) were observed. The observed level of antitumor activity, with an overall response rate of 38% and a median duration of response of 12 months, is of interest, since the study was targeted only to anthracycline-pretreated patients, most of whom had adverse prognostic features. The evaluation of a combination of vinorelbine and paclitaxel as first-line therapy in metastatic breast cancer seems worthwhile and is currently undergoing.
Adult↗
Phase I study of vinorelbine and paclitaxel in small-cell lung cancer.
BACKGROUND: Vinorelbine and paclitaxel interfere with mitotic spindle function through different mechanisms of action. Both of the drugs show antitumor activity in small-cell lung cancer when used as single agents; furthermore, in vitro and in vivo studies have shown a synergistic activity between the two drugs. PATIENTS AND METHODS: Patients with small-cell lung cancer no longer amenable to conventional treatment were entered into a phase I study in which vinorelbine was given at a fixed dose of 30 mg/m2 by 15-min intravenous infusion, whereas paclitaxel was given by 3-h infusion starting 1 h after vinorelbine at an initial dose of 90 mg/m2, which was subsequently escalated by 30-mg/m2 steps. Cycles were repeated every 21 days. RESULTS: Grade 3 neutropenia was observed only in three patients treated at the fifty dose level. Thrombocytopenia never reached grade 3. Neurotoxicity was considered dose-limiting, since grade 3 peripheral neuropathy occurred in three of five patients treated at the fifth dose level (paclitaxel 210 mg/m2). Other side effects were generally mild. The overall response rate in 22 evaluable patients was 32% (95% CI 13-51%); in particular, 1 complete response (4.5%) and 6 partial responses (27.3%) were observed. The maximally tolerated doses recommended for phase II studies are 180 mg/m2 for paclitaxel and 30 mg/m2 for vinorelbine. The observed myelosuppression was less severe than anticipated on the basis of the effects of each drug alone. CONCLUSIONS: The promising activity of this drug combination warrants a phase II study in untreated patients with extensive-stage small-cell lung cancer.
Adult↗
Primary pulmonary hypertension: a continuing diagnostic and therapeutic challenge.
Primary pulmonary hypertension (PPH) continues to present both diagnostic and therapeutic challenges to the physician, reflecting the lack of understanding about the basic mechanism of the disease. The onset of the condition is usually insidious, the main symptoms of dyspnoea, syncope and angina often being ascribed to functional or emotional causes. As a result, delay in diagnosis is the norm, with an interval from onset of symptoms to diagnosis of up 2 yrs. The ability of the vasodilator drugs that are now available to produce sustained improvement in patients with PPH is limited by a number of factors. The prognosis is generally severe; however, despite the overall dismal prognosis, duration of survival ranges up to 10 years or more. It is important to consider the possibility of an early stage, when functional changes are prevalent in a substantial number of patients with primary pulmonary hypertension. At this stage, an optimized therapy would be expected to interrupt the course of pulmonary hypertension or, at the very least, retard its progression.
Administration, Inhalation↗
Accelerated split-course (type B) thoracic radiation therapy plus vinorelbine/carboplatin combination chemotherapy in stage III inoperable non-small cell lung cancer.
43 patients with stage III NSCLC (non-small cell lung cancer) entered a phase II study aimed at evaluating the toxicity and the activity of a combined modality programme including an accelerated split-course schedule (type B) of thoracic radiation therapy and a combination chemotherapy with vinorelbine and carboplatin. An objective response was achieved in 18/42 evaluable patients (5 complete and 13 partial responses), for an overall response rate of 43% (95% confidence interval, 28-58%). Four complete responses had a duration which exceeded 16 months. Treatment was well tolerated; grade III myelotoxicity occurred in only 14% of patients and treatment was delayed in only 2 cases because of grade 3 oesophagitis. Both tolerability and efficacy data suggest that this regimen holds promise for the treatment of patients with stage III NSCLC.
Adult↗
Paradoxical bronchospasm and cutaneous rash after metered-dose inhaled bronchodilators.
The authors describe a case of paradoxical bronchospasm with laryngospasm and cutaneous rash occurring in an asthmatic woman after the use, via metered-dose inhaler, of different bronchodilators containing soy-derived excipients. It is noteworthy that the patient was not affected by soy allergy. After a short review of the relevant literature, the authors consider the possible aetiopathogenetic factors and outline the importance of this rare adverse reaction in the care of asthmatic patients.
Aerosols↗
Modulation of chemosensitivity by alpha interferon in multiple myeloma and non-Hodgkin's lymphoma.
Low-grade non-Hodgkin's lymphoma and multiple myeloma are chemosensitive malignancies, but are rarely curable because of primary or acquired drug resistance. Interferon has been shown to modulate the multidrug resistance phenotype and to reinduce chemosensitivity in patients with chemoresistant tumors. Fifteen patients with multiple myeloma and 64 patients with low/intermediate grade non-Hodgkin's lymphoma unresponsive to initial chemotherapy were treated with alpha 2b interferon for 2 months. In case of an objective response, treatment was continued until disease progression; non-responding patients received the same chemotherapy to which they were resistant, preceded by a 5 day course of interferon. Interferon salvage monotherapy induced an objective response in 1/15 patients with multiple myeloma and in 7/64 patients with non-Hodgkin's lymphoma. An objective response was achieved after retreatment with first-line chemotherapy preceded by interferon in 4/14 patients (28.6%) with multiple myeloma and in 20/56 evaluable patients (35.7%) with non-Hodgkin's lymphoma. Toxicity was moderate, predictable, manageable, and never caused interruption of the treatment. Interferon appears to be able to modulate chemosensitivity of tumors refractory to chemotherapy with several potential mechanisms, including an effect on drug accumulation; its utilization in this setting warrants further evaluation.
Adult↗
Phase II study of high-dose epirubicin, lonidamine, alpha 2b interferon in advanced breast cancer.
44 patients with advanced breast cancer were treated with high-dose epirubicin (130 mg/sqm), because of its steep dose-response curve. Lonidamine and alpha interferon were administered as well with the aim of increasing epirubicin uptake and overcoming drug resistance. Granulocyte-colony stimulating factor support was provided. 14 complete responses and 22 partial responses were observed in 40 evaluable patients for a 90% overall response rate. Median duration of response was 12 months for complete responders, 7 months for partial responders. In two cases the complete response has lasted for more than two years. Myelosuppression, infection, and cardiac toxicity were the main treatment-related toxic effects. These results are encouraging enough to justify a randomized comparison of our chemotherapy program with standard regimens used in advanced breast cancer.
Adult↗
A phase II study of carboplatin and vinorelbine as second-line treatment for advanced breast cancer.
Forty-one patients with advanced breast cancer were given carboplatin and vinorelbine as second-line therapy. Overall objective response rate was 46% (95% confidence interval 26-56%). Myelotoxicity was the most frequently observed toxic effect; grade III-IV leucopenia occurred in 46% of the patients. Our regimen is active as second-line chemotherapy for advanced breast cancer and warrants further evaluation.
Adult↗
Chlorambucil, vincristine and cytarabine (COA) treatment of low grade lymphomas.
Forty-five patients with stage III-IV low grade non-Hodgkin's lymphoma (NHL) were treated with a non-intensive polychemotherapy regimen including chlorambucil-vincristine and cytarabine (Ara-C), termed COA, for a total of 366 courses, beginning in June 1986. Grade 4 myelotoxicity occurred in only 4/45 patients. No treatment related death was observed. All patients were evaluable for response. Overall, 38 (84%) objective responses, including 31 (69%) complete responses (CR), were observed. At a median follow-up of 57 (21-84+) months, only 8 deaths occurred. Twenty-seven (60%) patients are still disease-free. All disease-free patients were in their first CR. The seven-year estimated survival is 71% and the estimated 7-year progression-free survival (PFS) was 48%. The estimated probability of complete responders to be disease-free at 6 years is 78%. Pretreatment laboratory parameters (serum levels of thymidine kinase, LDH and TNF-alpha showed a good prognostic relevance at using univariate analysis. At multivariate analysis, only the pretreatment serum levels of TNF-alpha were significantly associated with a higher CR achievement probability (p = 0.02) and a longer PFS (p = 0.02). We established a risk model for clinical outcome based on these 3 parameters. Patients having all parameters within the normal range at diagnosis, showed a very good prognosis (100% 7-year PFS and survival), while patients with all parameters increased had a very poor prognosis (0% 7-year PFS and 22% 7-year survival). In conclusion, COA treatment appears to be a non-toxic and very effective treatment for low-grade non-Hodgkin's lymphomas.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Carboplatin and alpha-2b interferon intraperitoneal combination as first-line treatment of minimal residual ovarian cancer. A pilot study.
21 untreated ovarian cancer patients with stage III and minimal tumour size, were given weekly intraperitoneal (i.p.) carboplatin (150 mg/m2) and alpha-2b interferon (IFN) (30 million U/m2) for a total of 12 courses, from June 1989 to February 1993. To date, a total of 248 courses have been administered. Toxicity was seldom severe, although fever (179 courses), fatigue (141 courses) and other IFN-related side-effects were very frequent. No patient refused to continue treatment, but in 5 patients IFN dose had to be reduced, and in 1 it was discontinued. The IFN mean delivered dose intensity was 19.8 million U/m2 week. Grade 3-4 myelotoxicity occurred in 7 patients (39 courses), but no deaths related to treatment occurred. The actual mean dose intensity of carboplatin was 121.5 mg/m2 week. To date, 20 patients have completed treatment and are evaluable for response. Of 11 patients with tumour size < or = 5 mm, 10 (91%) achieved a pathological complete response (pCR) as did 4/9 (44%) of those with tumour > 5 mm at entry, for a 70% (95% confidence interval 50-90) overall pCR rate. At a median follow-up of 21 months (range 4-46), only one death occurred. The probability of being alive at almost 4 years was 91% in the entire group (100% in those with tumour size less than 5 mm). Only 1 of 14 patients who achieved a pCR relapsed. This i.p. combination seems a feasible approach to previously untreated ovarian cancer patients with minimal tumour burden. IFN dosage should be reduced to improve tolerance. In view of the very high pCR rate achieved in the group of patients with smaller tumours, a randomised trial is warranted to compare this approach to standard treatment in these patients.
Adult↗