Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study.

BACKGROUND: Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes. PATIENTS AND METHODS: This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS). RESULTS: No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported. CONCLUSIONS: ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course.

Mutations of the epidermal growth factor receptor tyrosine kinase domain and associations with clinicopathological features in non-small cell lung cancer patients.

Somatic tyrosine kinase (TK) domain mutations of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of non-small cell lung cancer (NSCLC) to tyrosine kinase inhibitors (TKI's), however their incidence in distinct populations is not clarified. We sequenced exons 18-21 of the EGFR TK domain from 60 Greek and Czech patients, enrolled in an adjuvant chemotherapy trial following total resection for stages I-IIIa disease. Somatic mutations were found in 9/60 patients (15.0%), several being novel. EGFR mutations were more common in Stage I tumors (p = 0.023), they were also more common in women and never smokers; however, no other significant association of clinicopathological features with mutations was found. Median TTP and OS of patients with and without mutations were 13.2 and 40 months compared to 22.9 and 43.2 months, respectively. These differences were not statistically significant. K-ras (5/60, 8%) and EGFR mutations were found to be mutually exclusive. We identified a wide spectrum of somatic EGFR TK mutations reporting a relatively high incidence (15%) in NSCLC patients of Greek and Czech origin. As ethnicity seems to be a factor for the origin of these mutations, further studies in distinct populations are warranted.

Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

PURPOSE: The aim of this study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival (DFS) and secondarily on overall survival (OS) in patients with high-risk operable breast cancer. PATIENTS AND METHODS: From June 1997 until November 2000, 604 patients with T1-3N1M0 or T3N0M0 tumors were randomized to three cycles of epirubicin 110 mg/m2 followed by three cycles of paclitaxel 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) (group A), or to four cycles of epirubicin followed by four cycles of CMF, as in group A (group B). All cycles were given every 2 weeks with granulocyte colony-stimulating factor support. RESULTS: A total of 595 patients were eligible. Median follow-up was 61.7 months for group A and 62 months for group B. The 3-year DFS was 80% in group A and 77% in group B. Survival rates were 93% and 90%, respectively. The effect of treatment on the hazard of death was different according to hormonal receptor status. More specifically, in patients with negative receptor status the hazard of death was significantly higher for group B (hazard ratio 2.42). Both regimens were well tolerated and severe acute side-effects were infrequent. No cases of severe cardiotoxicity or acute leukemia were recorded. CONCLUSIONS: The present study failed to demonstrate a significant difference in DFS or OS between the two treatment groups. However, our study has shown clearly that high-dose paclitaxel can be safely incorporated to dose-dense sequential chemotherapy.

Adjuvant cytotoxic and endocrine therapy in pre- and postmenopausal patients with breast cancer and one to nine infiltrated nodes: five-year results of the Hellenic Cooperative Oncology Group randomized HE 10/92 study.

SUMMARY: The present randomized phase III trial was designed to detect a 15% benefit in relapse-free survival (RFS) or overall survival (OS) from the incorporation of adjuvant tamoxifen to the combination of CNF [cyclophosphamide, 500 mg/m2; mitoxantrone (Novantrone), 10 mg/m2; fluorouracil, 500 mg/m2 chemotherapy and ovarian ablation in premenopausal patients with node-positive breast cancer and conversely from the incorporation of CNF chemotherapy to adjuvant tamoxifen in node-positive postmenopausal patients. From April 1992 until March 1998, 456 patients with operable breast cancer and one to nine infiltrated axillary nodes entered the study. Premenopausal patients were treated with six cycles of CNF chemotherapy followed by ovarian ablation with monthly injections of triptoreline 3.75 mg for 1 year (Group A, 84 patients) or the same treatment followed by 5 years of tamoxifen (Group B, 92 patients). Postmenopausal patients received 5 years of tamoxifen (Group C, 145 patients) or 6 cycles of CNF followed by 5 years of tamoxifen (Group D, 135 patients). Adjuvant radiation was administered to all patients with partial mastectomy. After a median follow-up period of 5 years, 125 patients (27%) relapsed and 79 (17%) died. The 5-year actuarial RFS for premenopausal patients was 65% in Group A and 68% in Group B (p = 0.86) and for postmenopausal patients 70% in Group C and 67% in Group D (p = 0.36). Also, the respective OS rates were 77% and 80% (p = 0.68) for premenopausal and 84% and 78% (p = 0.10) for postmenopausal patients. Severe toxicities were infrequently seen, with the exception of leukopenia (18%), among the 311 patients treated with CNF. In conclusion, the present study failed to demonstrate a 15% difference in RFS in favor of node-positive premenopausal patients treated with an additional 5 years of tamoxifen after CNF adjuvant chemotherapy and ovarian ablation. Similarly, six cycles of CNF preceding 5 years of tamoxifen did not translate to a 15% RFS benefit in node-positive postmenopausal patients.

Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-alpha and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer. PURPOSE: To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer. PATIENTS AND METHODS: From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m(2)/week x 6, followed by a 2-week rest) and LV (500 mg/m(2)/week x 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients). RESULTS: A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received > or =80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B. There were no treatment-related deaths. CONCLUSIONS: The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer.

Postoperative radiation and concomitant bolus fluorouracil with or without additional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: Randomized studies have shown that postoperative chemotherapy with or without radiation therapy (RT) improved local control and survival of patients with stages II or III rectal cancer. However, the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a highly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced colorectal cancer. However, this difference in response rate did not translate into a survival benefit. PURPOSE: To evaluate the impact on the disease-free survival (DFS) and overall survival (OS) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV. PATIENTS AND METHODS: From October 1989 until February 1997, 220 patients were randomized postoperatively to receive either one cycle of chemotherapy with FU (600 mg/m2/week x 6 followed by a two-week rest) and leucovorin (LV, 500 mg/m2/week x 6 as a two-hour infusion) followed by pelvic RT with concomitant FU (400 mg/m2) as a rapid intravenous injection during the first three and last three days of RT, and three more cycles of the same chemotherapy with FU and LV (standard, group A, 111 patients) or pelvic RT with concomitant FU only (experimental, group B, 109 patients). RESULTS: As of August 1998, after a median follow-up of 4.9 years, there was no significant difference in either three-year DFS (Group A, 70.3%; group B, 68.2%, P = 0.53) or OS (group A, 77%; group B, 73.3%. P = 0.75). Cox multivariate analysis revealed stage of disease, number of infiltrated nodes, tumor grade, presence of regional implants and perforation to be significant prognostic factors. The incidence of severe side effects was significantly higher in the patients in group A than in those in group B (32.4% vs. 4.6%, P < 0.0001). CONCLUSIONS: The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a > or = 10% three-year survival benefit over that of concomitant RT and bolus infusion of FU, and significantly increases toxicity in patients with stages II or III rectal cancer.

A randomized trial comparing adjuvant fluorouracil, epirubicin, and mitomycin with no treatment in operable gastric cancer.

Combination chemotherapy (CT) has, in some groups of patients with gastric cancer (GC), who are at a high risk for relapse, resulted in a small but measurable improvement in palliation and patient survival not reaching statistical significance and therefore remaining applicable in an investigational setting. Based on the above data, we studied adjuvant CT with FEM (5-fluorouracil (5-FU), epirubicin, mitomycin C) in a randomized study of patients with completely resected stage III GC and patients with stages T1-3 with a low histologic grade. CT was started 2-3 weeks after surgery. From August 1988 until February 1994, 84 patients with completely resected tumors and lymph nodes were randomized to either group A (FEM) or group B (no treatment). Patients were eligible for randomization if they had a Karnofsky score > 60, no postoperative evidence of residual tumor, and normal cardiac, hepatic and renal functions. Forty-two patients were randomized to each group, with no significant differences regarding: age distribution, group A 53 years (41-65), group B 57 years (35-66); sex, group A 32/10, group B 25/17 (men/women); site of primary tumor, group A 22/20, group B 25/17 (pylorus/antrum); histologic grade, group A 0/19/23, group B 0/25/17 (grades I/II/III); lymph node metastases, group A 30, group B 32, and surgical procedure, group A 33/9/6, group B 35/7/9 (total gastrectomy/partial gastrectomy/splenectomy). Group A received 5-FU 600 mg/m2/day i.v. on days 1, 8, 29 and 36, epirubicin 45 mg/m2/day i.v. on days 1 and 29, and mitomycin C 10 mg/m2 i.v. on day 1. The schedule was repeated every 56 days for 3 cycles. Group B received no treatment odd was only subjected to the regular follow-up. At the last follow-up at 66 months, 27/42 patients in group A (64%) had relapsed or died, compared to 34/42 patients in group B (81%). The differences in the relapse and the disease-free and the overall survival rates were not statistically significant. Only the subgroup of patients with histologic grade III tumors receiving adjuvant FEM demonstrated a trend towards improved survival (p = 0.085). Main therapy-related toxicities for the treatment group were grade I-II anemia, neutropenia, and throbocytopenia in 16, 45, and 22% of patients, respectively, and grade I-II nausea and vomiting in 29% of patients. Based on the present findings and those of previous studies, even if one considers the difference reaching statistical significance in the latter for histologic grade III tumors, it becomes evident that with current therapeutic modalities adjuvant therapy has no established role in the management of resectable GC. Studies of new-generation regimens, such as FAMTX (5-FU, Adriamycin and methotrexate) as well as ELF (etoposide, Leucoverin, and 5-FU), should be conducted in the adjuvant therapy setting with a nontherapy control group, in order to clarify the issue of adjuvant CT in resectable GC.

Cyclophosphamide, mitoxantrone, fluorouracil versus conventional CMF as adjuvant treatment in node-positive breast cancer patients. A Hellenic Cooperative Oncology Group Study.

362 evaluable node-positive patients with stage II breast cancer were randomized, receiving either 6 cycles of conventional CMF or 6 cycles of the combination of cyclophosphamide (500 mg/m2), mitoxantrone (Novantrone 10 mg/m2), and fluorouracil (500 mg/m2; CNF). After a median follow-up of 51 months, 64 (36%) patients relapsed in the CMF group and 60 (33%) in the CNF group (p=0.8276). By Cox multivariate analysis, tumor size, menopausal status and number of involved nodes were retained as independently significant variables. Toxicities were remarkably similar in both groups. It appears that after a median follow-up of 51 months there is no significant difference in relapse-free survival between node-positive patients with breast cancer who received either 6 cycles of the conventional CMF or the CNF combination as adjuvant treatment.

Cisplatin and continuous infusion of fluorouracil followed by radiation and weekly carboplatin in the treatment of locally advanced head and neck cancer: a Hellenic Cooperative Oncology Group study.

Induction chemotherapy followed by radiation has been extensively studied in an effort to improve local control and possibly overall survival of patients with locally advanced head and neck cancer. From June 1989 until May 1991, 39 patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with 3 cycles of induction chemotherapy, consisting of cisplatin (100 mg/m2 d 1) and fluorouracil (1000 mg/m2 d 2-6) followed by radiation potentiated by weekly administration of carboplatin (60 mg/m2). Surgery was performed in selected patients with residual disease after the combined modality approach. Four cycles of adjuvant chemotherapy with carboplatin (325 mg/m2) and bleomycin (15 u) were administered in those patients who demonstrated a partial response after locoregional treatment. There were 36 men and 3 women with a median age of 56 (range 39-74) years and Karnofsky performance status of 70 (range 60-100). The primary site of the tumor was nasopharynx (8), oropharynx (8), hypopharynx (3), oral cavity (4), larynx (13), paranasal sinus (2), and salivary glands (1). Thirty-two (82%) patients presented with stage IV disease. After the completion of induction chemotherapy, 14 (36%, 95% CI 21-53%) patients achieved a complete response (CR). This CR rate was increased to 56% (95% CI, 42-74%) after locoregional treatment. Main toxicities included nausea/vomiting (56%), leukopenia (40%), anemia (30%), thrombocytopenia (10%), stomatitis (28%), diarrhea (17%), and alopecia (12%). Median relapse-free survival was 18 (1-50) months, median time to progression was 13 (0.3-58.5) months, and median survival 19 (0.3-59) months. Induction chemotherapy with cisplatin and fluorouracil followed by radiation potentiated with carboplatin is feasible. However, this combined modality approach, as applied in the present study, does not appear to yield superior results than those reported with chemotherapy followed by radiation alone.

Carboplatin, continuous infusion fluorouracil and mid-cycle high-dose methotrexate as initial treatment in patients with locally advanced head and neck cancer. Hellenic Co-operative Oncology Group Study.

Forty-nine patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with 3 cycles of induction chemotherapy prior to definitive local treatment (surgery and/or radiation therapy). Chemotherapy consisted of carboplatin 300 mg/m2 on day 1, fluorouracil 1000 mg/m2 daily as a continuous infusion on days 1 to 5 and high-dose methotrexate 1.2 g/m2 with leucovorin rescue on day 14. After completing the induction chemotherapy, 9 patients (18%) achieved a complete remission (CR), 26 (54%) a partial remission (PR), 7 had stable disease and 7 a progression. The response rates increased to 53% CR and 18% PR following locoregional treatment. Survival at 12 months was 61% and its actuarial probability at 24 months 31%. Median time to progression was 14 months. Toxicity from chemotherapy was generally mild. Nausea was observed in 35%, vomiting in 26%, stomatitis in 57%, anemia in 22%, leukopenia in 36%, thrombocytopenia in 26% and diarrhea in 6% of the patients. In conclusion, the combination of carboplatin, 5-day continuous-infusion fluorouracil and mid-cycle high-dose methotrexate is a moderately effective, well tolerated regimen in patients with SCCHN but does not seem superior to the combination of carboplatin and fluorouracil only.

High-dose leucovorin, fluorouracil and oral dipyridamole in the treatment of advanced colorectal cancer.

Fifty-five patients with advanced colorectal cancer were treated with the combination of leucovorin (LV), fluorouracil (FU) and dipyridamole (DP). Two (4%) patients achieved a clinical complete remission, 4 (7%) a partial remission, 24 (44%) had stable disease while 25 (45%) patients progressed during the chemotherapy period. Median survival was 47 weeks and median time to progression 19.5 weeks. Major toxicities included diarrhea (66%), leukopenia (45%), anemia (50%) and nausea/vomiting (44%). In conclusion, the addition of oral DP does not appear to improve the efficacy of the standard LV/FU regimen in patients with advanced colorectal cancer.

Decreased oral toxicity with the local use of allopurinol in patients who received high dose 5-fluorouracil.

5-Fluorouracil (5FU) is the most effective drug in gastrointestinal cancer. Mucositis and bone marrow toxicity are the two major limiting side effects. In our effort to reduce mucositis we administered Allopurinol mouthwash in 42 patients who had experienced oral mucositis during prior treatment with 5FU. In all patients significant reduction of oral toxicity was noticed as well as prolonged pain relief.

Folinic acid plus high-dose 5-fluorouracil with allopurinol protection in the treatment of advanced colorectal carcinoma.

Protection by prolonged administration of allopurinol against high-dose 5-fluorouracil (5-FU) administered with folinic acid in 74 patients with colorectal cancer was investigated. The dose of 5-FU was 700 mg/m2 per day for 5 days. Of 41 patients without previous chemotherapy, 1 had a complete response and 4 had partial responses (total 12%), 15 remained stable and 21 progressed. Mean duration of response was 7.4 (1.8-12.6) months. The most frequent toxicities were decreased granulocytes (13%), diarrhoea (37%), and stomatitis (35%), which were similar to the frequencies of other studies with lower doses of 5-FU without allopurinol. Prolonged administration of allopurinol thus gives some protection to patients with colorectal cancer who receive folinic acid plus high-dose 5-FU but responses were not better than those with conventional doses.

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.