Ongoing clinical trials in lung cancer.
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Antineoplastic Agents↗
Biomedical subjects
M Tonato
Publications and source records attributed to M Tonato.
Induction chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (CAP) in a combined modality approach for locally advanced and inflammatory breast cancer. Long-term results.
Thirty-one patients with locally advanced and inflammatory breast carcinoma (stage IIIA and IIIB) were treated with a combined modality approach between 1985 and 1989. All patients received as induction chemotherapy a combination of cisplatin, doxorubicin, and cyclophosphamide (CAP). Responsive patients and patients with operable stable disease underwent modified radical mastectomy followed by concurrent radiotherapy and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) adjuvant chemotherapy. Thirty patients were evaluable for response to CAP. The rate of objective response to induction chemotherapy was 76.7% with 2 patients (6.7%) obtaining a complete response and 21 patients (70%) a partial response. Twenty-five patients were rendered disease-free after induction chemotherapy and surgery. Only 2 of these had pathological complete response (8%). The median overall survival was 48.7 months, the median time to progression was 22.4 months and the median disease-free survival was 29.1 months. The patients with noninflammatory breast tumor had a significantly better overall survival, disease-free survival, and time to progression. The overall survival and the time to progression were statistically superior in patients with primary tumor size < or = 8 cm. At a median follow-up of 6 years, 29% (95% CI, 13.05 to 45.01) of patients were alive and 28% (95% CI, 10.4 to 45.6) were disease-free. This combined modality treatment seems feasible with quite acceptable toxicity; the CAP combination is an effective alternative to the other standard chemotherapeutic regimens. Our results, although encouraging, are still poor, and new drugs and strategies are required to improve the long-term outcome.
Adenocarcinoma↗
Radiotherapy without steroids in selected metastatic spinal cord compression patients. A phase II trial.
A phase II trial was planned to investigate the feasibility of radiotherapy (RT) without steroids in 20 consecutive patients with metastatic spinal cord compression (MSCC), no neurologic deficits, or only radiculopathy, and no massive invasion of the spine at magnetic resonance imaging (MRI) or computed tomography (CT). Aiming at an early diagnosis, MRI or CT was prescribed for all cancer patients with back pain and osteolysis, even when there were no signs of neurologic spinal compression. All patients were given 30 Gy in 10 fractions over 2 weeks with no steroids. Back pain and motor capacity were the parameters adopted to verify response to RT. Sixteen of 20 patients (80%) were able to walk without support, and 14 (70%) had no radiculopathy. Seventeen of 20 cases (85%) achieved relief from back pain. Regarding motor function, all patients (100%) responded to RT because the 16 patients able to walk without support at diagnosis did not deteriorate and the other 4, who needed support, became ambulatory without motor impairment. Median survival time was 14 months. Eight of 20 (40%) treated patients are still alive (14 to 36 months after end of RT), fully ambulatory, and free from relapse in the treated spine. Acute side effects were documented in only 2 patients (10%) and were managed without steroids. The results of this study suggest that RT without steroids is a feasible regimen for MSCC patients with good motor function. Elimination of steroids from the standard treatment for MSCC avoids cortisone side effects above all in those patients with diabetes, hypertension, peptic ulcer, and other steroid-sensitive medical problems.
Adult↗
The role of neoadjuvant chemotherapy in NSCLC.
Neoadjuvant chemotherapy to reduce tumor size before surgery or radiologic treatment is now a feasible option in the treatment of non-small cell lung cancer (NSCLC). Patients in clinical stage IIIA N2 of the disease who were previously a poor prognostic subset when treated with surgery are now being treated with neoadjuvant chemotherapy, followed by surgery or radiotherapy, in an attempt to improve survival rates. Published trials of neoadjuvant chemotherapy report response rates of 50 to 80% and median survival of 18-27 months. Two small trials have reported striking benefits of neoadjuvant chemotherapy over surgery alone. Other larger ongoing trials should answer some of the questions raised by these two trials.
Carcinoma, Non-Small-Cell Lung↗
Preliminary results of a dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.
This ongoing phase I study sought to establish the maximum tolerated dose of the combination of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. Paclitaxel was administered as a 3-hour intravenous infusion. The carboplatin infusion was administered over 30 minutes immediately afterward. Patients were assigned sequentially to one of eight treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 185 mg/m2 and from 230 to 350 mg/m2, respectively. Twenty-four patients have been treated to date, and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2. The combination has an excellent safety profile, with only a few, short-lasting episodes of neutropenia observed and no evidence of infection. At the doses tested, thrombocytopenia has not occurred.
Adolescent↗
Safety profile of gemcitabine.
This paper reviews the toxicity profile of gemcitabine in a large group of patients (up to 790) from pivotal phase II studies, in which the drug was given intravenously as a 30 min infusion, in a schedule once a week for 3 weeks followed by a week of rest. The safety profile of gemcitabine is unusually mild for such an active agent in solid tumours. Haematological toxicity is mild and short-lived with modest WHO grades 3 and 4 for haemoglobin (6.4% and 0.9% of patients), leukocytes (8.1% and 0.5%), neutrophils (18.7% and 5.7%) and platelets (6.4% and 0.9%). The incidence of grade 3 and 4 infection associated with this level of myelosuppression was low (0.9% and 0.2%). Transaminase elevations occurred frequently, but they were usually mild, and rarely dose limiting. Mild proteinuria and haematuria were seen but were rarely clinically significant. There was no evidence of cumulative hepatic or renal toxicity. Nausea and vomiting was mild, rarely dose limiting, and generally well controlled with standard antiemetics. Flu-like symptoms were experienced in a small proportion of patients but were of short duration. Where oedema/peripheral oedema was experienced there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare, with WHO grade 3 alopecia reported in 0.5% of patients. There was no grade 4 alopecia. Furthermore, gemcitabine displayed minimal toxicity in elderly patients, and the side-effect profile does not seem to be affected by patient age. The adverse events typically experienced with cytotoxic agents, namely myelosuppression, nausea and vomiting and alopecia, are not seen to such a degree with gemcitabine, and this nonoverlapping toxicity profile suggests that gemcitabine is a promising agent for incorporation into combination chemotherapy regimens.
Age Factors↗
Effect of moisture content on the invertase activity of freeze-dried S. cerevisiae.
The invertase activity of intact Saccharomyces cerevisiae submitted to freezing-thawing was affected by pH, the chemical nature of the buffer, and the freezing cooling rate (CR), leading in some cases to a complete invertase inactivation (acetate buffer, pH 4.0, CR = 0.5 degree C/min). Once established under adequate freezing conditions the invertase activity remained unchanged after freeze-drying. Nevertheless, in some cases the cell-growing capability after freeze-drying diminished around 70%, mainly if the frozen cell suspension was attained through freezing carried out at CR = 0.5 degree C/min. Water sorption isotherms of freeze-dried samples (freeze-dryer Edwards L-4KR; 30 degrees C and 0.1 mB) were determined at 10 and 25 degrees C. The monolayer moisture content (MMC) at each temperature (12.7 and 3.71 for 10 and 25 degrees C, respectively) was calculated from isotherms by applying BET and GAB models. Freeze-dried yeast with water activity (Aw) between 0 and 0.33 (about the MMC value) maintained at 25 degrees C for 235 days and at 89 degrees C for 15 min retained at least 85% of its original invertase activity (IA), whereas samples with Aw > MMC lost at least 60% of its IA. X ray diffraction showed that the freeze-dried cake before and after storage presented an amorphous structure.
Buffers↗
Are there differences among the serotonin antagonists?
The serotonin-receptor (5-HT3) antagonists combined with dexamethasone are considered the antiemetic therapy of choice in the prevention of cisplatin-induced emesis. As there are now several compounds on the market, the dilemma of preference is particularly relevant. In preclinical studies some differences among the three marketed drugs (ondansetron, granisetron and tropisetron) have emerged. In particular, tropisetron and granisetron have a greater potency and duration of action and seem to have a greater selectivity toward the 5-HT3 receptor with respect to ondansetron. Furthermore, while with tropisetron and granisetron there is a linear dose/response relationship, this does not seem to be the case for ondansetron. These preclinical differences, however, do not seem to correlate with the clinical antiemetic activity of these compounds. In fact, although the number of comparative studies is small, with all of them presenting several shortcomings (small number of patients, not blinded studies, no association with steroids, sponsored trials), it seems that the antiemetic activity and tolerability of ondansetron, granisetron and tropisetron is very similar. If these data are confirmed, the least expensive of the 5-HT3 antagonists should be the drug of choice. We feel, however, that the answer to this rather difficult question of choice will come from very large, independent, methodologically correct studies designed to show small but clinically significant differences (i.e., less than 10% in complete protection from emesis). These trials, which require about 1000-1500 patients, are ongoing and the one carried out as a multicenter study by the Italian Group for Antiemetic Research is close to conclusion.
Animals↗
Antiemetics in cancer chemotherapy: historical perspective and current state of the art.
Chemotherapy-related nausea and vomiting can today be controlled with available antiemetics in a high percentage of patients but emesis remains a problem for some patients, with certain drugs and with repeated cycles of chemotherapy. The fundamental steps of clinical research in antiemetics towards the improvement of the control of nausea and vomiting with new drugs or combinations are presented. Special emphasis is given to cisplatin-induced nausea and vomiting because of the frequency and relevance of this phenomenon. The use of high-dose metoclopramide, its combination with steroids, and later the addition of lorazepam or diphenhydramine represented the evolving standard of the 1980s, with the level of complete protection from vomiting improving from 30%-40% to 60%-70% with the three-drug combination. The introduction of new agents such as the 5-hydroxytryptamine 3 (5-HT3) receptor antagonists has recently offered new possibilities because of their activity and lack of toxicity. In particular, the combination of ondansetron plus dexamethasone is today the most efficacious and least toxic antiemetic treatment for prevention of emesis in patients treated with a single high dose or low repeated doses of cisplatin. A comparison of different 5-HT3 antagonists, always in combination with steroids, is now considered necessary. For patients treated with moderately emetogenic chemotherapy the use of steroids can still be considered the standard treatment. In this setting, the role of 5-HT3 receptor antagonists, alone or in combination with steroids, has to be better defined through large, well-planned clinical trials, which should have a cost-effectiveness analysis as one of their goals.
Antiemetics↗
Cost and cost-effectiveness analysis of ondansetron versus metoclopramide regimens: a hospital perspective from Italy.
In a large double-blind study of antiemetic therapy conducted in Italy, 289 patients underwent 3 consecutive cycles of cisplatin chemotherapy. Antiemetic treatment with ondansetron plus dexamethasone was more efficacious and better tolerated, but also more expensive, than treatment with metoclopramide plus both dexamethasone and diphenhydramine. To evaluate the different costs of the 2 antiemetic regimens, we conducted a retrospective cost-effectiveness analysis from a hospital perspective. Direct costs of antiemetic therapy (acquisition cost of drugs, materials and time spent by nurses to prepare and administer therapies), cleanup after emesis, rescue medication and adverse events were evaluated. Antiemetic drug acquisition costs per patient were 5.23-fold higher for the ondansetron regimen than for the metoclopramide regimen. However, when the costs of materials and nursing time required to prepare and administer the antiemetic regimens were included, this ratio was 3.77. Furthermore, including the cost of emesis, rescue antiemetic treatments and medication used to treat adverse events, hospital costs per patient were 3.21-fold higher with the ondansetron regimen during the first cycle, 3.08-fold higher during second cycle and 2.89-fold higher during third cycle of chemotherapy. Complete protection from vomiting and from both vomiting and nausea with ondansetron occurred, respectively, in 78.7 and 69.1% of patients in the first cycle, 73.8 and 57.3% in the second cycle, and 74.2 and 58.1% in third cycle of chemotherapy. Corresponding figures for the metoclopramide regimen were 59.5 and 50.4%, 53.6 and 37.1%, and 46.8 and 27.3%, respectively. Thus, the cost per successfully treated (completely protected) patient was 2.43- and 2.34-fold higher, respectively, for ondansetron at the first cycle, 2.23- and 1.99-fold higher, respectively, at second cycle, and 1.82- and 1.36-fold higher, respectively, at third cycle. In conclusion, the study demonstrates that, while ondansetron has a greater acquisition cost than metoclopramide, the ondansetron regimen costs per successfully-treated patient substantially decrease when all direct hospital costs are taken into account.
Chemotherapy, Adjuvant↗
Expression of aphidicolin-induced fragile sites in lymphocytes of patients with breast cancer.
The expression of fragile sites induced by aphidicolin (APC) was evaluated on metaphase chromosomes obtained from the peripheral blood lymphocytes of 26 women with breast cancer and 15 sex- and age-matched normal controls. Both the proportion of damaged cells (P < 0.001) and the mean number of gaps and breaks per cell (0.02 < P < 0.05) were significantly higher in the patient group. There were no differences in either the age-related fragile site levels or the expression of single fragile sites between patients and controls. Our findings indicate an increased genetic instability in women with breast carcinoma.
Adult↗
Ondansetron.
Ondansetron is the first selective antagonist of the 5-hydroxytryptamine receptors (type 3) marketed for the prevention of emesis induced by antineoplastic agents. Ondansetron has been shown to be more active and less toxic than high-dose metoclopramide in patients submitted to cisplatin chemotherapy. Furthermore, when dexamethasone was added to ondansetron, its antiemetic efficacy increased significantly. In the prevention of emesis induced by a high single dose of cisplatin or by repeated low doses, ondansetron combined with dexamethasone has been shown to be the more efficacious and less toxic antiemetic treatment. However, in the prevention of delayed emesis from cisplatin, its role is still to be defined. In patients submitted to moderately emetogenic chemotherapeutic agents, ondansetron has shown an efficacy superior or equal to standard doses of metoclopramide, but is less toxic. Moreover, when compared with dexamethasone, its antiemetic efficacy and tolerability is similar; in this group of patients ondansetron should be used only when steroids fail. Ondansetron toxicity is generally mild; in particular, it does not induce extrapyramidal reactions. The most frequent side-effects are headache and constipation.
Antineoplastic Combined Chemotherapy Protocols↗
Reliability and validity of a quality of life questionnaire in cancer patients.
Two studies were sequentially conducted to validate a new questionnaire which takes into consideration the most important variables which could influence quality of life evaluation. Particular attention was given to the methodology employed to collect data and to the patients' characteristics. In the first study 80 consecutive cancer patients were randomised to twice fill in one of four different types of questionnaire, each one characterised by a different polarisation of semantic and syntactic extreme values of the visual linear analogue (for instance, "very much" always on the right, regardless of the semantic value of the answer; positive semantic value always on the right, regardless of whether it was "very much" or "not at all"; and so on). The second study, conducted on 60 lung cancer patients, consisted in testing the reliability (by measuring the reproducibility in different ways) and the validity (by performing a factor analysis) of the type of questionnaire indicated by the first study as the most reliable. The internal coherence was also evaluated by measuring the effects of physical and psychological conditions on the responses.
Adult↗
Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer.
BACKGROUND: High-dose radiation therapy is generally recommended as standard treatment in regionally advanced unresectable non-small-cell lung cancer (NSCLC), but median- and long-term survival remain poor. Some reports have recently shown an improvement of results in advanced NSCLC when cisplatin was included in the chemotherapy regimens. Therefore, we designed a randomized trial to determine whether induction chemotherapy before high-dose radiotherapy improves response rate and survival in stage III NSCLC over that achieved with radiotherapy alone. PATIENTS AND METHODS: From March, 1984 to December, 1988, 66 consecutive patients with stage III unresectable NSCLC were randomized to one of two treatment arms; 61 were evaluable for survival and 58 for response and toxicity. Patients randomly assigned to arm A received cisplatin (CDDP 100 mg/m2 on day 1) and etoposide (VP 16 120 mg/m2 on days 1, 2, 3) every 3 wks for 3 courses followed by radiotherapy 56 Gy on pre-treatment tumor volume and 40 Gy on mediastinum and bilateral supraclavicular nodes. Patients assigned to arm B received only the same radiotherapy. The 61 eligible patients were comparable in terms of age, performance status, histology and treatment. RESULTS: Response rate was 53% in arm A and 32% in arm B. The median survival was 52 wks for the combined treatment arm and 36 wks for the radiation therapy arm. At six years of follow-up all the patients were dead. Toxicity was mild and no treatment-related deaths were recorded. CONCLUSION: Induction chemotherapy produced a better response rate and a trend of improved survival (4 months) but a significant survival advantage was not achieved (p < 0.11), probably because of the small number of patients enrolled in the trial.
Aged↗
A prospective analysis of chemotherapy following surgical resection of clinical stage I-II small-cell lung cancer.
Thirty-seven (37) consecutive patients with clinical Stage I (T1-2NO, Mo), and Stage II (T1-2N1 Mo) central small-cell lung cancer (SCLC) underwent complete surgical resection of the primary tumor. Ten patients were subsequently pathologically Stage I, 14 patients were Stage II, and 8 were Stage III (T3;N2). The pathologically Stage I, II, and III patients were then treated with chemotherapy consisting of cyclophosphamide (1 g/m2), doxorubicin (50 mg/m2), and vincristine 2 mg (CAV) every 3 weeks for six courses followed by prophylactic cranial irradiation (2000 cGy in 10 fractions). Median survival in Stage I patients is 162 weeks and calculated 5-year survival is 50%; for Stage II patients, median survival is 86 weeks and calculated 5-year survival is 35%. T3;N2 patients have a median survival of 63 weeks; calculated 5-year survival is 21%. Our data suggest surgery plus adjuvant chemotherapy and cranial irradiation results in long-term survival in early central SCLC. These data support the need for randomized surgical trials in Stage I, II, and III central SCLC.
Adult↗
Reducing chemotherapy-induced nausea and vomiting. Current perspectives and future possibilities.
Nausea and vomiting are among the most distressing adverse effects of cancer chemotherapy. In the last 10 years considerable advances in the prevention of chemotherapy-induced emesis have been made. From an analysis of the results obtained in patients receiving moderately- to severely-emetogenic drugs the following guidelines in choosing the best antiemetic treatment can be given: 1. For the prevention of acute emesis induced by a high single dose of cisplatin (> or = 50 mg/m2) or by low doses (20 to 40 mg/m2) repeated for 4 to 5 days, the combination of ondansetron plus dexamethasone is the most efficacious and least toxic antiemetic therapy. 2. For the prevention of delayed emesis the combination of oral dexamethasone plus metoclopramide seems to offer the best protection, although over 40% of patients still experience delayed nausea and vomiting. 3. For the prevention of acute emesis induced by moderately emetogenic drugs, corticosteroids (dexamethasone or methylprednisolone) are efficacious and safe antiemetic agents. Although equally efficacious, the serotonin (5-HT)3 receptor antagonists, due to their higher acquisition costs, are indicated only in patients refractory to corticosteroids or in those who cannot use them. Unresolved problems in antiemetic research include: (i) identification of the best antiemetic treatment for those areas of cancer chemotherapy where adequate data are lacking, such as high dose regimens for bone marrow transplantation; (ii) optimisation of treatment for the most widely used chemotherapy regimens; and (iii) identification of the best rescue treatment for patients who fail to respond to antiemetic prophylaxis. Although many new 5-HT3 antagonists are currently being studied, the possible improvement in efficacy and tolerability brought about by these agents will probably only be marginal.
Antiemetics↗
Prevention of cisplatin-induced emesis. The Italian Group for Antiemetic Research.
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Cisplatin↗
Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen.
BACKGROUND: Endocrine factors may affect the clinical course of malignant melanoma and the response to the treatment of this disease. The presence of estrogen receptors in melanomas has been suggested, and occasional responses to antiestrogen therapy have been reported. METHODS AND RESULTS: We randomly assigned 117 patients with metastatic malignant melanoma to treatment with dacarbazine alone or dacarbazine in combination with tamoxifen. The overall rate of response, measured objectively, was higher (28 percent vs. 12 percent, P = 0.03) and survival was longer (median, 48 vs. 29 weeks, P = 0.02) among the patients who received dacarbazine plus tamoxifen than among those who received dacarbazine alone. Among women, both the response rate (38 percent vs. 10 percent, P = 0.04) and the median survival (69 vs. 30 weeks, P = 0.008) were better with dacarbazine plus tamoxifen than with dacarbazine alone, whereas among men the differences were smaller and not statistically significant. Among the patients given dacarbazine alone, there were no significant differences between women and men in response rate (10 percent vs. 13 percent) or survival (30 vs. 27 weeks), whereas among those given dacarbazine plus tamoxifen, women had better outcomes, as indicated by both response rate (38 percent vs. 19 percent, P = 0.15) and survival (69 vs. 31 weeks, P = 0.02). When we analyzed the Quetelet body-mass index (the weight in kilograms divided by the square of the height in meters) as an indirect indicator of the levels of endogenous estrogens in postmenopausal women and in men, survival was not affected by the body-mass index in the group given dacarbazine alone, whereas in the group given dacarbazine plus tamoxifen, survival was longer among patients whose Quetelet index was above the median value than among those with a Quetelet index lower than the median value (60 vs. 26 weeks, P less than 0.001). CONCLUSIONS: In the treatment of metastatic malignant melanoma, dacarbazine plus tamoxifen is more effective than dacarbazine alone, as indicated by both the response rate and the median survival; the difference in efficacy is among women.
Adult↗