Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: Paclitaxel (Taxol) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer. PATIENTS AND METHODS: Chemotherapy-naive patients, stage IIIbwet and IV with performance status (0-1), were randomized to receive paclitaxel 200 mg/m(2) on day 1 plus gemcitabine 1 gm/m(2) (group A) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m(2) plus vinorelbine 22.5 mg/m(2) (group B) on days 1, 8 and 15 every 4 weeks. RESULTS: A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0 months [95% confidence interval (CI) 4.3-5.6] and 4.4 months (95% CI 3.7-5.2) for groups A and B respectively (P=0.365). Median survival was 11.1 months (95% CI 9.2-13.0) and 8.6 months (95% CI 7.0-10.2) for groups A and B respectively (P = 0.147). Grade 3/4 neutropenia and leukopenia were worse in group B (P<0.001, in both cases). Febrile neutropenia and severe infections were more prominent (P<0.001, P=0.029 respectively) in group B. CONCLUSION: Although response rate, PFS and survival were non-different in both groups, toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value.

Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group.

BACKGROUND: This phase III study was designed to compare the combination paclitaxel (Taxol)-gemcitabine (PG) versus carboplatin-gemcitabine (CG) in patients with advanced inoperable non-small-cell lung cancer. METHODS: Chemotherapy-naive patients with performance status of zero or one were randomized to gemcitabine 1 gm/m(2) on days 1 and 8 plus either paclitaxel 200 mg/m(2) on day 1 (arm A) or carboplatin at an area under the concentration-time curve of 6 mg on day 1 (arm B) every 3 weeks. Primary end point was overall survival (OS). Secondary end points included objective response (OR), time to progression and toxicity. RESULTS: A total of 512 patients were enrolled and 452 eligible (arm A, 225; arm B, 227) were analyzed. All characteristics were well balanced with the exception of vena cava obstruction symptoms and lymph node involvement. Median survival was 9.97 months [95% confidence interval (CI) 8.74-12.0] for group A and 10.49 (95% CI 9.04-11.94) for group B. There was no difference in the OS, 1-year survival, OR and TtP. However, statistically significant differences were seen in toxicity. CONCLUSION: The two regimens are equally active. Myelotoxicity is worse in the CG group whereas alopecia, myalgia and neurotoxicity worse in the PG group.

hMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients.

Germline mutations in genes encoding proteins involved in DNA mismatch repair are responsible for the autosomal dominantly inherited cancer predisposition syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We describe here analysis of hMLH1 and hMSH2 in nine Greek families referred to our centre for HNPCC. A unique disease-causing mutation has been identified in seven out of nine (78%) families. The types of mutations identified are nonsense (five out of seven) (hMLH1: E557X, R226X; hMSH2: Q158X, R359X and R711X), a 2 bp deletion (hMSH2 1704_1705delAG) and a 2.2 kb Alu-mediated deletion encompassing exon 3 of the hMSH2 gene. The majority of mutations identified in this cohort are found in hMSH2 (77.7%). Furthermore, four of the mutations identified are novel. Finally, a number of novel benign variations were observed in both genes. This is the first report of HNPCC analysis in the Greek population, further underscoring the differences observed in the various geographic populations.

Novel mutations of the APC gene in familial adenomatous polyposis in Greek patients.

Familial adenomatous polyposis (FAP), a premalignant clinical entity inherited as an autosomal dominant trait, is characterized by the development thousands of adenomatous polyps of the colorectum during the 2nd and 3rd decade of life. Approximately 80% of patients with FAP harbor truncating germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. We tested 24 members of six Greek families. All patients had the FAP phenotype, and one patient had an extracolonic tumor (medulloblastoma). Our method for testing was the polymerase chain reaction (PCR) amplification from genomic DNA extracted from whole blood, followed by automated DNA sequencing. Two novel truncating mutations (2601delGA and R923X) and three already-known mutations (R876X, Q1045X, and D1822V) were found. Other polymorphisms were also found. We identified the inactivating APC mutation in 12 of 13 of our FAP patients. Our results suggest that PCR sequencing is a reliable method for screening the APC gene for germline mutations.

Paclitaxel and carboplatin in inoperable non-small-cell lung cancer: a phase II study.

BACKGROUND: Based on the high activity of single-agent paclitaxel and the superior one-year survival rates of patients with non-small-cell lung cancer (NSCLC) treated with carboplatin, a phase II trial was initiated using both agents in patients with inoperable stages III and IV disease to investigate the efficacy and toxicity of the combination. PATIENTS AND METHODS: Since July 1995, 60 patients fulfilling all eligibility criteria entered this study. All patients received paclitaxel 175 mg/m2 as a three-hour infusion, and carboplatin dosed to an area under the concentration-time curve of seven, every three weeks. No granulocyte colony-stimulating factor was given. Of the 56 male and four female patients, the median age was 57 years (range 29 to 75 years) and the median Eastern Co-Operative Oncology Group performance status was one. Most of the patients had stage IV (34) adenocarcinoma (31) with low differentiation (28). The median number of chemotherapy cycles was three, with a range of one to eight. RESULTS: Of 55 evaluable patients, 15 (27.3%) achieved partial responses, 15 (27.3%) had stable disease, and 25 (45.4%) had progressive disease. The median survival was 8.95 months and 21.6% of the patients survived more than one year. Grade 2/3 nonhematologic toxicity included alopecia (59%), neurotoxicity (3%), and myalgia/arthralgia (10%). Grade 2/3 neutropenia occurred in 14% of patients, whereas grade 3/4 thrombocytopenia was seen in only 4%. One patient died of complications of a severe allergic reaction. CONCLUSION: Combination treatment using paclitaxel and carboplatin is active and well tolerated in patients with inoperable non-small-cell lung cancer. The dose-response relationship to paclitaxel and results of comparison with other platinum-based regimens remain to be determined.

5-Fluorouracil, interferon-alpha-2b and cisplatin (FAP) for advanced urothelial cancer. A phase II study. Hellenic Co-operative Oncology Group.

PURPOSE: To evaluate the efficacy and toxicity of the FAP combination chemotherapy as first-line treatment in advanced urothelial cancer. PATIENTS AND METHODS: Thirty-four patients with histologically confirmed advanced urothelial cancer, with measurable disease and without previous chemotherapy entered the study; all 34 are evaluable. The 28 males and 6 females had a median age of 65 (19-75) and a median ECOG performance status of 1 (0-2). Twenty-eight patients had bladder cancer, four had renal pelvic cancer and two ureteral cancer. Thirty patients had transitional cell carcinoma and four mixed, mostly of grade 3. Sites of disease included lymph nodes (18), bladder (9), liver (9), pelvic mass (9), lung (7), etc. The treatment plan was as follows: 5-fluorouracil 500 mg/m2 continuous infusion D1-D5 and D22-D26; interferon-alpha-2b 5 million i.u./m2 D1-D5 followed by 3x/week and then D22-D26; cisplatin 25 mg/m2 D1, D8, D15, D22. Cycles were repeated every 36 days. RESULTS: The median number of cycles administered was 3 (1-6). The relative dose intensities for 5-fluorouracil, interferon and cisplatin were 76%, 71% and 75%, respectively. Twenty-two of 34 patients (65%, 95% confidence interval [95% CI], 46% to 80%) had objective responses, including six complete clinical responses (CR) (18%, 95% CI, 7% to 35%) and 16 partial responses (PR) (47%, 95% CI, 30% to 65%). Three patients had stable disease and seven progressed. Two patients discontinued treatment after the first cycle because of toxicity. The median survival is 15.30 months (1.40-37.60), the median time to progression 11.60 months (4.13-37.60), and the median survival of complete responders 20.75+ months (8+ to 38+). The only significant hematologic toxicity was the grade 3-4 neutropenia in 44%. Non-hematologic toxic effects were unremarkable. CONCLUSION: The FAP combination as first-line chemotherapy is highly active in the treatment of advanced urothelial cancer, and has limited toxicity. Further phase III studies are in progress to compare FAP and M-VAC.

A multicenter study of recombinant human erythropoietin (epoetin alpha) in the management of anemia in cancer patients receiving chemotherapy.

Current evidence suggests that epoetin alpha administration is well tolerated and effective in the management of anemia of cancer and cancer chemotherapy. An open-label, multinational, non-comparative study was conducted in 215 cancer patients with anemia secondary to chemotherapy with platinum- or non-platinum-based combinations. Epoetin alpha was administered s.c. (150 IU/kg three times/week) for a planned period of 16 weeks. The response rate of epoetin alpha, defined as an increase in hemoglobin level of 2 g/dl or more from baseline, was 67%. The rate of response was not related to the chemotherapy regimen administered (platinum or non-platinum based). The percentage of patients transfused and the transfusion rate during epoetin alpha treatment were reduced. Transfusional need was eliminated in 64 (75%) of the 85 patients transfused before the study start, after 1 month of therapy. Quality of life, assessed using a visual analog scale, improved markedly in patients who experienced a hematological response. These patients also experienced a statistically significant (p < 0.0001) improvement in mean WHO performance score. These findings indicate that epoetin alpha is a well tolerated and effective agent which increases hemoglobin concentration and reduces transfusion requirements in anemic cancer patients receiving chemotherapy.

Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group.

PURPOSE: To investigate if double modulation of fluorouracil (5-FU) with leucovorin (folinic acid [FA]) and interferon alfa-2b (IFN 2b) improves responses and survival in comparison to single modulation of 5-FU with FA. PATIENTS AND METHODS: One hundred six patients with histologically confirmed advanced colorectal cancer, measurable disease, and without previous chemotherapy were prospectively randomized into two groups. Patients in group A received 5-FU 450 mg/m2 as an intravenous bolus in the midinfusion of FA weekly. FA was given at a dose of 200 mg/m2 in 500 mL 0.9% normal saline solution in 2-hour infusion. Patients in group B received exactly the same regimen plus IFN 2b 5 million units subcutaneously three times weekly. RESULTS: All patients were well balanced in both groups regarding age, sex, performance status, number, and site of metastasis. One hundred two patients were assessable. All patients have died. There was no difference in response between the two groups (7.8% v 9.8%). Median survival was 10.1 months in group A, and 7.2 months in group B (P = .00189). Median time to progression was 8.4 and 5.2 months, respectively (P = .00196). Overall, better performance status and older age had a positive impact on survival. Toxicity was the most important and catastrophic aspect of this study. Patients who received IFN 2b had significantly worse anemia, neutropenia, diarrhea, anorexia, weight loss, flu-like syndrome, and psychological reactions. CONCLUSION: Based on this final analysis, the addition of IFN 2b to the combination of 5-FU and FA enhances toxicity and contributes to decreased survival.

Cisplatin/etoposide versus carboplatin/etoposide chemotherapy and irradiation in small cell lung cancer: a randomized phase III study. Hellenic Cooperative Oncology Group for Lung Cancer Trials.

The efficacy and toxicity of cisplatin/etoposide and carboplatin/etoposide combinations along with thoracic irradiation were prospectively assessed in patients with small cell lung cancer. Both combinations were equally effective. However, the carboplatin/etoposide regimen caused significantly less nausea, vomiting, nephrotoxicity, and neurotoxicity, and it was easier to administer. Dose intensity and treatment delays were similar in both groups. Thoracic irradiation given concurrently with chemotherapy is feasible and seems to offer a survival advantage. The relapse rate also is lower among patients who have received radiation therapy, and recurrences tended to be outside of the lung. Overall, a survival benefit was identified for patients aged between 50 and 65 years who had limited disease, good performance status, and only one metastatic site. Prophylactic brain irradiation in a subset of patients reduced brain metastasis, but the difference did not reach significance. From this trial, it is concluded that carboplatin/etoposide combination therapy is highly effective and is well tolerated by patients with small cell lung cancer. In limited disease, this combination can be given concurrently with thoracic irradiation and offers a survival advantage.

The prognostic significance of immune changes in patients with renal cell carcinoma treated with interferon alfa-2b.

PURPOSE: To evaluate the response rate and the immunorestorative properties of subcutaneously administered interferon alfa-2b (IFN-A2b) in patients with advanced renal cell carcinoma (RCC) and to correlate the immune status with the clinical responses. PATIENTS AND METHODS: Twenty-six patients with advanced RCC were treated with recombinant IFN-A2b. The dose was increased progressively from 5 x 10(6) IU the first week to 10 x 10(6) IU the second week, and thereafter to 15 x 10(6) IU subcutaneously. RESULTS: Four patients (15%) achieved partial responses (PRs), and five patients (19%) had stable disease (S), whereas 17 patients (65%) progressed. In all patients, blood was withdrawn before IFN treatment and monthly thereafter. T lymphocytes after isolation from peripheral blood were tested for proliferation in the autologous mixed lymphocyte reaction (autoMLR) and allogeneic mixed lymphocyte reaction (alloMLR), interleukin-2 (IL-2) production, expression of IL-2 receptors during the alloMLR, and the production of interleukin-1 (IL-1) by peripheral-blood monocytes. Twelve patients were assessable, four patients had a PR, one patient had S, and seven patients had progressive disease. Striking increases were demonstrated in all parameters 1 month after treatment with IFN-A2b in the four patients who responded and the patient with S. Namely, the autoMLR responses showed a mean increase of 250%, the IL-2 production 247%, the expression of IL-2-specific receptors 446%, the alloMLR responses 160%, and the production of IL-1 262%. On the contrary, the nonresponders did not show any change in their overall immune status, and in some, deterioration of the already depressed immunologic functions was observed. CONCLUSIONS: Administration of IFN-A2b results in a marked potentiation of deficient cellular immune response in vitro in those patients with RCC who respond to the treatment. This may have prognostic significance, and certainly more patients are required to be studied for definite conclusions.

Combination chemotherapy with cis-platinum, adriamycin, mitomycin-C (PAM) in patients with advanced bladder cancer.

Thirty patients with advanced bladder cancer received combination chemotherapy with cis-platinum, adriamycin and mitomycin C. Two patients (6.6%) responded completely and survived 24 and 30 months. Partial response was noted in 14 patients (46.6%) who had a median survival of 9.6 months. Eight patients (26.6%) had stable disease with a median survival of 5 months whereas in 6 patients (20%) their disease progressed with a median survival of 3 months. The amelioration of hematuria, regardless of response, was impressive. Nausea and vomiting were the commonest side effects. Myelotoxicity was mild and reversible. We conclude that PAM chemotherapy is effective and well tolerated in patients with advanced bladder cancer.

Salvage chemotherapy for breast cancer patients treated with adjuvant adriamycin-containing regimen.

Purpose of this study was to evaluate the efficacy of salvage chemotherapy given to women with breast cancer in relapse who had in the past received adjuvant treatment including adriamycin. Fourty-nine evaluable patients had an adjuvant chemotherapy with CMFAV in 6 or 12 cycles. On relapse these patients received either adriamycin 40 mg/m2, mitomycin 8 mg/m2 and vinblastine 6 mg/m2 (group A) or dibromodulcitol 500 mg, mitomycin 8 mg/m2 and vinblastine 6 mg/m2 (group B). In Group A, 22 patients with a mean age of 49.2 years relapsed 14 months on average after the end of adjuvant treatment. In 11 of them the main site of relapse was visceral. In group B, 27 patients with a mean age 49.5 years relapsed 6.5 months on average after the end of adjuvant treatment. In 15 of them the main site of relapse was visceral. According to the disease-free interval (DFI), in group A with DFI less than 12 months 3 patients (23%) responded partially whereas in patients with DFI longer than 12 months 4 patients (44.4%) had a partial response. In group B with DFI less than 12 months 4 patients (21%) responded partially, whereas 2 (25%) responded with DFI longer than 12 months. We conclude that salvage chemotherapy in this group of patients with an adriamycin-containing regimen is superior to a non-adriamycin regimen only if the DFI is longer than 12 months.

Correlation of histoenzymological studies with the response to chemotherapy and survival in breast cancer patients.

The enzyme activity of cancerous tissue and the adjacent normal epithelium of 40 patients with breast cancer was determined. This enzymatic activity was correlated with the responsiveness of those tumors to the chemotherapy. It was found that the presence of cytochrome oxidase and alkaline phosphatase and the absence of leucine aminopeptidase, beta-glucuronidase and dehydrogenases in cancerous tissues was related to good response. On the contrary, the absence of alkaline phosphatase and cytochrome oxidase and the presence of leucine aminopeptidase, beta-glucuronidase and dehydrogenases in the cancerous tissues was related to poor response and therefore to poor survival.

Combination of hyperthermia and methotrexate in the treatment of transplanted Walker sarcoma.

The purpose of this experimental study was to evaluate the possible synergistic effect of hyperthermia (HPT) and methotrexate (MTX) in Wistar rats transplanted with Walker sarcoma. HPT was induced by microwaves of 432 MHZ frequency transmitted through a source of 2 x 5.5 cm2 surface. The temperature in the tumor was maintained at 43 degrees C which was controlled by an intratumor thermocouple connected with an electronic thermometer. Three experiments were performed. First, in 5 rats HPT only was applied and one rat was used as control. Second, HPT and MTX in combination were given to 6 rats. Third, MTX alone was given to 6 rats. In the first experiment all 5 rats had 50% reduction of their tumors compared to control. In the second experiment complete disappearance of the tumor was noticed and in the third experiment the tumor increased in size. Histologically, in the responding tumors extensive necrosis was seen with thrombosed vessels. We conclude that HPT and MTX are synergistic in treating Walker sarcoma in Wistar rats.

Combination chemotherapy with cyclophosphamide, adriamycin, and vincristine in malignant thymoma and myasthenia gravis.

Malignant thymoma (MT) is a rare tumor that is often associated with myasthenia gravis (MG). This tumor is considered resistant to chemotherapy. We had the opportunity to treat five patients with MT with cyclophosphamide 800 mg/m2, Adriamycin 50 mg/m2, and vincristine 1.4 mg/m2 (CAV) in cycles of 21 days. Two patients with MG that was resistant to antimyasthenic drugs immediately responded to this combination. One patient with only MT had a complete response, and two patients with only MT had a partial response. Two out of the five patients are still alive and free of disease. Two patients died of disease, and one died from a neutropenia-induced respiratory tract infection. It is concluded that this combination chemotherapy is active in MT and MG and deserves additional trials.

Combination chemotherapy with prednimustine, adriamycin, vincristine (VAP) in advanced breast cancer. A phase II study.

The purpose of this study was to evaluate VAP combination chemotherapy in advanced breast cancer: prednimustine 80 mg/m2 p.o. days 1-5, adriamycin 40 mg/m2 and vincristine 1.4 mg/m2 1st day in cycles of 3 weeks. Twenty-one women entered the study and 19 were evaluable. The mean age was 54.5 years (25-69) with an average performance status of 60 according to Karnofsky. Hormonal receptors were unknown in 10, positive in 6 and negative in 3. The dominant site of disease was soft tissues in 11, bones in 1, liver in 3 and lung in 4. Fourteen patients had as prior treatment cyclophosphamide, methotrexate and 5-fluorouracil (CMF), two had tamoxifen and three none. Ten patients (52.6%) had a partial response with a mean survival of 7.8+ months, 5 patients (26.3%) had stable disease with a mean survival 6.6+ months and 4 patients (21.1%) had progressive disease with a mean survival of 3 months. Regarding toxicity all patients had alopecia, most of the patients had nausea grade I, whereas 5 patients developed mild leukopenia. We conclude that VAP is an effective, well tolerated chemotherapy combination in patients with advanced breast cancer which deserves further clinical trials.

Diffuse purely osteolytic lesions in myelofibrosis.

In myelofibrosis, the skeletal bones present radiologically as normal or with osteosclerotic or osteoporotic changes. Lytic lesions are very rare and when present are usually associated with osteosclerosis. We report on a case of a patient with myelofibrosis exhibiting diffuse purely osteolytic lesions.