Publications by Year: 1998

1998
Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs M, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Journal of Clinical Oncology [Internet]. 1998;16(2):593 - 602. WebsiteAbstract
Purpose: To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. Patients and Methods: Patients with stage III myeloma and at least one lyric lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. Results: The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P= .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. Conclusion: Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.
Georgoulias V, Androulakis N, Dimopoulos AM, Kourousis C, Kakolyris S, Papadakis E, Apostolopoulou F, Papadimitriou C, Vossos A, Agelidou M, et al. First-line treatment of advanced non-small-cell lung cancer with docetaxel and cisplatin: A multicenter phase II study. Annals of Oncology [Internet]. 1998;9(3):331 - 334. WebsiteAbstract
Purpose: To evaluate the efficacy and safety of the docetaxel-cisplatin combination in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Chemotherapy-naive patients with histologically confirmed, measurable stage IIIB or IV NSCLC, a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow, renal, hepatic and cardiac function were eligible for the study. Patients received docetaxel (100 mg/m2) as an one-hour infusion on day 1 and cisplatin (80 mg/m2) as a 30-min infusion with appropriate hydration on day 2. Granulocyte colony- stimulating factor (G-CSF; 150 μg/m2, SC) was given on days 3 to 13. Treatment was repeated every three weeks. Results: Fifty-three patients were enrolled (28 with stage IIIB and 25 with stage IV). One complete and 23 partial responses were observed (overall response rate (OR): 45%; 95% CI: 34,1%-61.8%). The response rate was 57% and 32% in patients with stages IIIB and IV disease (P = NS). The median time to progression was 36 weeks and the median survival 48 weeks; the one-year survival was 48%. Grade 3-4 neutropenia occurred in 23 patients, 15 of whom were hospitalized for neutropenic fever; two patients died of sepsis. Grade 2 neurotoxicity was observed in six patients and grade 3 in five patients; grade 3 fatigue occurred in seven patients, grade 3-4 mucositis in four patients and grade 3- 4 diarrhea in six patients. Mild allergic reactions and oedema were observed in five and four patients, respectively. The median dose intensity was 30 mg/m2/week for docetaxel and 24 mg/m2/week for cisplatin, corresponding to 91% and 89% of the specified protocol doses, respectively. Conclusions: The docetaxel-cisplatin combination is an active regimen in advanced NSCLC, but hematologic toxicity remains high despite the prophylactic use of G-CSF.
Weber DM, Dimopoulos MA, Moulopoulos LA, Delasalle KB, Smith TL, Alexanian R. Prognostic features of asymptomatic multiple myeloma. Cancer Research Therapy and Control [Internet]. 1998;6(1-4):113. Website
Papadimitriou CA, Dimopoulos MA, Ampela C, Louvrou-Fertaki A, Anagnostopoulos A, Athanassiades P, Stamatelopoulos S, Keramopoulos A. Sequential administration of doxorubicin and paclitaxel followed by cyclophosphamide, methotrexate and 5-fluorouracil combination (CMF) in women with metastatic breast cancer. Oncology [Internet]. 1998;55(6):533 - 537. WebsiteAbstract
Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer.
Fountzilas G, Dimopoulos A-M, Papadimitriou C, Kalogera-Fountzila A, Aravantinos G, Bafaloukos D, Athanassiades A, Nicolaides C, Keramopoulos A, Pavlidis N, et al. First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): A phase II study conducted by the Hellenic Cooperative Oncology Group. Annals of Oncology [Internet]. 1998;9(9):1031 - 1034. WebsiteAbstract
Purpose: To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first- line chemotherapy in patients with advanced breast cancer (ABC). Background: Paclitaxel is an active agent in ABC. Furthermore, our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC. Patients and methods: From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. Results: A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1,5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07- 24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07- 23+) months and median survival 20.4 (range 0.07-24.5+) months. Conclusions: The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.
Dimopoulos MA, Deliveliotis C, Moulopoulos LA, Papadimitriou C, Mitropoulos D, Anagnostopoulos A, Athanassiades P, Dimopoulos C. Treatment of patients with metastatic urothelial carcinoma and impaired renal function with single-agent docetaxel. Urology [Internet]. 1998;52(1):56 - 60. WebsiteAbstract
Objectives. To evaluate the efficacy and toxicity of single-agent docetaxel in patients with metastatic urothelial carcinoma and impaired renal function. Methods. Eleven consecutive patients previously untreated for metastatic disease with renal impairment (median serum creatinine level of 2.6 mg/dL) were treated with intravenous docetaxel 100 mg/m2 for 1 hour every 21 days. Granulocyte colony-stimulating factor was administered at a dose of 5 μg/kg/day subcutaneously from days 5 to 14. Results. Five of 11 patients achieved a partial response, with time to progression of responding patients ranging from 5 to 22 months or more. The median overall survival rate was 11 months. Renal function improved in 5 of 8 patients with tumor- related renal impairment. Toxicity was primarily hematologic, with 5 patients developing grade 3 or 4 neutropenia; nonhematologic toxicities were manageable. Conclusions. Our preliminary data indicate that single-agent docetaxel therapy may represent an effective therapeutic alternative for patients with advanced urothelial carcinoma and renal insufficiency precluding cisplatin-based combination chemotherapy.
Dimopoulos MA, Papadopoulou M, Andreopoulou E, Papadimitriou C, Pavlidis N, Aravantinos G, Aspropotamitis A, Anagnostopoulos A, Fountzilas G, Michalas S, et al. Favorable outcome of ovarian germ cell malignancies treated with cisplatin or carboplatin-based chemotherapy: A hellenic cooperative oncology group study. Gynecologic Oncology [Internet]. 1998;70(1):70 - 74. WebsiteAbstract
Purpose. To evaluate the outcome and the prognosis of patients with ovarian germ cell malignancies who were treated with platinum-based chemotherapy immediately after initial surgery. Methods. We conducted a retrospective review of patients with ovarian germ cell tumors who were referred for consideration of treatment to the Departments of Medical Oncology participating in the Hellenic Cooperative Oncology Group. Results. Over a 14-year period 53 patients were included in our study. There were 13 patients with dysgerminoma and 40 patients with nondysgerminomatous tumors. Forty percent of patients underwent complete resection of their tumors. Platinum-based chemotherapy consisted primarily of cisplatin, vinblastine, and bleomycin (PVB) in 9 patients; bleomycin, etoposide, and cisplatin (BEP) in 15 patients; and bleomycin, etoposide, and carboplatin (BEC) in 25 patients. With a median follow-up of 39 months, 5 patients developed progressive disease and died of their tumor and 1 patient died of bleomycin- induced lung toxicity with no evidence of active tumor. The 5-year overall survival was 100% for patients with dysgerminoma and 85% for patients with nondysgerminomatous tumors. Eighty percent of patients with advanced nondysgerminomatous tumors and residual disease after surgery remain disease free. Conclusion. With this study we confirm that patients with ovarian germ cell malignancies have a favorable outcome when treated with platinum-based chemotherapy.
Seong C, Delasalle K, Hayes K, Weber D, Dimopoulos M, Swantkowski J, Huh Y, Glassman A, Champlin R, Alexanian R. Prognostic value of cytogenetics in multiple myeloma. British Journal of Haematology [Internet]. 1998;101(1):189 - 194. WebsiteAbstract
Karyotypic studies of bone marrow were conducted in 79 previously untreated patients with multiple myeloma who received a standard programme of chemotherapy. An abnormal karyotype was observed in 46% of patients, virtually all showing multiple abnormalities consistent with a long period of preclinical clonal evolution. Patients with an abnormal pattern showed various aberrations with hyperdiploidy in 64%, pseudodiploidy in 5% and hypodiploidy in 31%. The number of chromosomes affected ranged from two to 19 (median 10), with at least one trisomy in 83%, one monosomy in 75%, and one translocation in 42% of patients. Lymphoma-like karyotypes were present in 17% of patients with an abnormality but were not associated with atypical clinical features, such as an extramedullary mass, leukaemia, or increased serum lactate dehydrogenase. Monosomy or deletion of chromosome 13 was present in 47% of patients with an abnormal pattern, who lived for a shorter duration (median 10 months) than patients with other abnormalities (median 34 months) or with diploidy (median 35 months). The cause of the short survival of patients with monosomy or deletion of chromosome 13 was not clear, but further studies on the relationship with specific oncogenes are indicated.
Sfikakis PP, Dimopoulos MA, Souliotis VL, Charalambopoulos D, Mavrikakis M, Panayiotidis P. Effects of 2-chlorodeoxyadenosine and gold sodium thiomalate on human bcl-2 gene expression. Immunopharmacology and Immunotoxicology [Internet]. 1998;20(1):63 - 77. WebsiteAbstract
Aberrant expression of apoptosis-related genes including the 'cell death suppressor gene' bcl-2, may play an important pathogenetic role in cancer expression by 2-CdA, and or GST would provide a basis for their efficacy in suppressing arthritis by interfering with the upregulation of bcl-2 mRNA in the synovial lining cells (Muller-Laduer et al., 1995). However, the lack of a direct inhibitory effect on the induction of bcl-2 biosynthesis at the relatively high concentrations tested suggests that both GST and 2-CdA exert their beneficial effects in these patients through a bcl-2 independent mechanism.
Dimopoulos MA, Moulopoulos LA. Role of adjuvant chemotherapy in the treatment of invasive carcinoma of the urinary bladder. Journal of Clinical Oncology [Internet]. 1998;16(4):1601 - 1612. WebsiteAbstract
Purpose: The standard treatment for patients with muscle-invasive carcinoma of the urinary bladder is radical cystectomy. While radical cystectomy cures many patients with this tumor, almost 50% of them will develop metastatic disease. Adjuvant chemotherapy has been proposed for these patients in an attempt to reduce the probability of relapse and to improve survival. To assess whether adjuvant chemotherapy does benefit patients with muscle-invasive bladder cancer, we reviewed all phase II and III studies published in the English literature over the last 20 years. Methods: A review of all published reports was facilitated by the use of Medline computer search and by manual search of the Index Medicus. Results: Several comparative, nonrandomized studies have indicated that adjuvant chemotherapy may prolong disease-free survival. Four randomized studies have been conducted and all had a suboptimal patient accrual. Three studies used a cisplatin-containing combination chemotherapy and included primarily patients with non-organ-confined transitional-cell carcinoma (TCC) of the bladder. All three studies indicated that adjuvant chemotherapy improve disease-free survival and two of them also showed improvement in event-free survival and overall survival, respectively. Conclusion: Published series have been unable to establish an undisputed benefit of adjuvant chemotherapy over radical cystectomy alone for muscle-invasive bladder cancer. The interpretation of the available data is compromised by several methodologic and statistical problems. Thus, adjuvant chemotherapy cannot be considered as a standard treatment for all patients with muscle-invasive carcinoma of the bladder. Well-designed prospective randomized studies are needed to clarify the rob of adjuvant chemotherapy in this disease. However, outside a protocol setting, there is some evidence that patients with extravesical disease or with lymph node involvement may benefit from adjuvant treatment with cisplatin-based combination chemotherapy. No data support such an approach for patients with muscle-invasive but organ-confined bladder cancer.
Fountzilas G, Athanassiades A, Papadimitriou V, Dimopoulos M-A, Bafaloukos D, Aravantinos G, Nicolaides C, Kalofonos H, Papakostas P, Xiros N, et al. Paclitaxel and carboplatin as first-line chemotherapy for advanced breast cancer. ONCOLOGY [Internet]. 1998;12(1 SUPPL.1):45 - 48. WebsiteAbstract
In a phase II study, 66 patients with advanced breast cancer (median age 56 years; range, 28 to 75 years) were treated with paclitaxel (Taxol), 175 mg/m2 infused over 3 hours, and carboplatin (Paraplatin), dosed to attain an area under the concentration-time curve (AUC) of 6 mg x min/mL; treatment was repeated every 3 weeks. A total of 38 (58%) patients had received prior adjuvant chemotherapy, 21 with a regimen containing an anthracycline or mitoxantrone (Novantrone). As of May 1997, 295 cycles of paclitaxel- carboplatin have been administered, 248 (84%) at full dose. The relative dose intensity of paclitaxel is 0.9 (range, 0.5 to 1.2). Of the 66 patients, 8 (12%) have achieved a complete response and 27 (41%) a partial response, for a total response rate of 53%. Grade 3 to 4 toxicities have included anemia (5%), leukopenia (25%), thrombocytopenia (5%), nausea/vomiting (7%), myalgias/arthralgias (4%), allergic reaction, neurotoxicity, and infection (2% each). Alopecia has been universal. Median time to progression is 8.9 months; median survival has not yet been reached. We conclude that the combination of paclitaxel and carboplatin has significant activity in advanced breast cancer and can easily be administered on an outpatient basis with manageable toxicity.
Nakopoulou L, Vourlakou C, Zervas A, Tzonou A, Gakiopoulou H, Dimopoulos M-A. The prevalence of bcl-2, p53, and Ki-67 immunoreactivity in transitional cell bladder carcinomas and their clinicopathologic correlates. Human Pathology [Internet]. 1998;29(2):146 - 154. WebsiteAbstract
The aim of this study was to investigate the expression of bcl-2, p53 oncoproteins, and Ki-67 antigen in a series of transitional cell bladder carcinomas and its relation to the traditional prognostic indicators and patient's survival. One hundred six cases with transitional cell carcinoma (TCC) were examined for detection of bcl-2, p53 proteins, and Ki-67 antigen (MIB1 antibody). Bcl-2 immunohisto-chemical positivity was observed in 52% of TCCs and in 577% of low-grade and 44% of high-grade TCCs. Bcl-2 was also detected in normal urothelium and dysplastic lesions with basal cell expression, showed a significant inverse correlation with overall bcl-2 positivity. The loss of bcl-2 protein expression in higher-stage TCCs was statistically significant (pt = .01). P53 protein was overexpressed in 50% of TCCs and more frequently in invasive and in carcinomas in situ than in superficial TCCs (Pt = .03). In contrast, detection of p53 was not observed in normal and dysplastic urothelium. P53 positivity was related to the degree of differentiation and to the stage of the disease (Pf = .01 and Pt = .03, respectively). Concerning Ki-67 antigen, its expression was found in 57.5% of TCCs. There was a strong overall correlation of Ki-67 with tumor stage (Pt = .002) and grade (Pf = .002). Univariate statistical analysis showed that the expression of p53 and Ki-67 was significantly correlated to poor prognosis (p = .02, P = .02, respectively). On multivariate analysis, none of these markers but only stage and grade were significantly correlated to prognosis (P = .02, respectively). These findings suggest that overexpression of bcl-2 protein may be an early event in tumorigenesis. Tumors with loss of bcl-2 positivity and overexpression of p53 and Ki-67 had an unfavorable prognosis; however, in multivariate analysis, they had no independent prognostic value.
Dimopoulos MA, Moulopoulos LA, Weber D, Delasalle K, Alexanian R. Magnetic resonance imaging of the bone marrow in plasma cell dyscrasias. Cancer Research Therapy and Control [Internet]. 1998;6(1-4):91 - 92. Website