T. Economopoulos

Paclitaxel Plus Carboplatin Versus Gemcitabine Plus Paclitaxel in Advanced Non–Small-Cell Lung Cancer: A Phase III Randomized Trial

PURPOSE We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m(2) on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m(2) on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Students t test to compare independent samples between groups. RESULTS A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P =.32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P =.12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A (euro; 7,612.64) versus group B (euro; 7,484.77) was not statistically significant (P <.66). CONCLUSION The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC.

Carboplatin and paclitaxel in advanced or metastatic endometrial cancer

OBJECTIVES The purpose of this study was to evaluate the activity and toxicity of carboplatin and paclitaxel combination in advanced or recurrent endometrial carcinoma. METHODS Forty-seven eligible patients with measurable advanced or recurrent endometrial carcinoma were treated with carboplatin [area under the curve (AUC) 5] and paclitaxel 175 mg/m(2) every 3 weeks for 6-9 cycles or until disease progression or unacceptable toxicity. RESULTS There were 10 complete responses (CRs) (21%) and 19 partial responses (PRs) (41%) for an overall response rate (RR) of 62% (29 patients) (95% confidence interval [CI], 47-76%). The median progression-free survival (PFS) was 15 months (95% CI, 7.3-22.7 months) and the median overall survival (OS) was 25 months (95% CI, 19.0-31.0 months). No difference was found in RR and OS in patients with primary advanced disease and those with recurrent tumors. Similarly, no difference was found in PFS and OS for patients with serous/clear tumors and those with endometrioid tumors. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 36% of patients and 6% experienced febrile neutropenia. One patient each developed grade 4 thrombocytopenia and anemia. Grade 3 sensory neuropathy was recorded in 6% of patients. CONCLUSION The combination of carboplatin and paclitaxel appears to have activity in advanced or recurrent endometrial carcinoma with an acceptable toxicity profile.

Myelodysplastic syndromes: Analysis of 131 cases according to the FAB classification

The clinical and haematological findings in 131 patients with myelodysplastic syndromes (MDS), none of which had previously received chemotherapy or radiotherapy, classified according to the FAB criteria, were analysed. The distribution among the 5 subgroups was: RA 31 patients, RAS 19, RAEB 23, CMML 29 and RAEBT 29 patients. There were difficulties in the classification of 24 patients. These included, first, 8 cases with myeloid hyperplasia of the bone marrow (BM) but without mono‐cytosis or excess of blasts of the BM. They were classified as RA. Second, 8 cases with sideroblastosis but with monocytosis or excess of blasts of the BM were classified 3 as RAEB, 2 as CMML and 3 as RAEBT. Finally, 8 cases with absolute monocytosis and BM blasts 15–30% were classified as CMML. 37 of 82 dead patients (45.1%) had transformed to acute non‐lymphoblastic leukaemia (ANLL). The incidence of evolution to ANLL was low for RA and RAS (6.30% and 12.5% respectively), while it was 37.5% for RAEB, 57.1% for CMML and 77.2% for RAEBT. The median survival for each subgroup was: RA 18 months; RAS 25; RAEB 13; CMML 14 and RAEBT 10 months. It is concluded that the FAB classification with some modifications recognises group of MDS with different prognosis.

Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) study

The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT–PCR). The overall concordance between kRT–PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT–PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.

Primary extranodal non-Hodgkin's lymphoma of the head and neck

Primary extranodal NHL of the head and neck (HN-NHL) accounts for 10-20% of all cases of NHL. Despite their frequency, the natural history and biological behaviour of these lymphomas is poorly understood. In this study we analysed the data 116 cases of HN-NHL. There were 65 males and 51 females with a median age of 56 years. The distribution among different anatomical sites was: tonsils 56 cases (48.3%), nasopharynx 15 (12.9%), mandible/gingiva 9 (7.8%), hard palate 7 (6%), parotis 6 (5.2%), nasal cavity 6 (5.2%), hypopharynx/larynx 6 (5.2%), thyroid 5 (4.3%), ocular adnexa 4 (3.5%), paranasal sinuses 2 (1.7%). The patients were treated with radiotherapy alone (14 cases), combined chemotherapy (52 cases) and combined modality (50 cases). According to the WF histological classification 73 cases (62.9%) had intermediate, 32 (27.6%) high and 11 (9.5%) low grade. Patients were separated in two groups: Tonsillar NHL (56 cases) and NHL of all other sites (non-tonsillar group-60 cases). A comparison between the two groups showed that there was no statistically significant difference with respect to age, sex, and histological subtypes. Also treatment response was similar (82.1% for the tonsillar vs 83.3% for the non-tonsillar). The two groups differed in stage distribution, survival and pattern of relapse. Stage I was more frequent in the non-tonsillar NHL (60%) in contrast to tonsillar NHL where stage II was more prominent (51.8%). Median survival was 86 months for the tonsillar while it has not been reached yet for the non-tonsillar patients. Patients in stage I and stage II of the non-tonsillar group had better survival compared to stages I and II of the tonsillar patients. Finally GI tract was a common site of relapse in the tonsillar group while a considerable number in CNS relapses were observed in the non-tonsillar group. We concluded that HN-NHL constitutes a heterogeneous group of patients. Tonsillar lymphomas represent a distinct group with some special clinicopathological findings.

Multiple myeloma in elderly patients: prognostic factors and outcome

Abstract:  Objectives: Purpose of this study was to compare prognostic factors and outcome of patients with multiple myeloma (MM) aged >70 yr at diagnosis with those of younger patients. We also applied the recently proposed International Staging System (ISS) for MM in these patients. Patients and methods: Among 1,162 newly diagnosed, symptomatic MM patients included in our database, 357 (31%) were >70 yr of age. Clinical and laboratory variables were evaluated in patients >70 yr and in younger patients and were assessed for possible correlation with survival in patients >70 yr of age. Results: Most clinical and laboratory features were similar in the two groups of patients but older patients presented more frequently with advanced ISS (P = 0.02). Despite similar response rates to primary treatment, younger patients survived longer than patients >70 yr of age (40 vs. 28 months, P = 0.001). There was a longer survival of younger patients than that of older patients diagnosed with ISS stage 1 (median 71 vs. 54 months, P = 0.007) and ISS stage‐2 patients (median: 38 vs. 26 months, P = 0.0008) but for patients with ISS stage 3 median survival was similarly poor in the younger and older age group (21 and 20 months, P = 0.283). Other variables associated with impaired prognosis were severe anemia, extensive bone marrow plasmacytosis and elevated serum LDH. Conclusions: Older patients with MM present more often with advanced ISS and have significantly shorter survival than younger patients. The ISS retained its prognostic significance within the group of elderly patients.

Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. A Hellenic Cooperative Oncology Group (HeCOG) Study

BACKGROUND The ubiquitin-proteasome system (UPS) plays a pivotal role in tumorigenesis. Components of the UPS have recently been implicated in breast cancer progression. In the present study, we sought to explore the prognostic and/or predictive significance of UBE2C messenger RNA (mRNA) expression on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. METHODS Five hundred and ninety-five high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative, dose-dense sequential chemotherapy with epirubicin followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without paclitaxel (Taxol). RNA was extracted from 313 formalin-fixed primary tumor tissue samples followed by one-step quantitative RT-PCR for assessment of mRNA expression of UBE2C. RESULTS High UBE2C mRNA expression was associated with poor DFS (Walds P = 0.003) and OS (Walds P = 0.005). High tumor grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of UBE2C. Results of the Cox multivariate regression analysis revealed that high UBE2C mRNA expression remained an independent adverse prognostic factor for relapse (P = 0.037) and death (P = 0.05). CONCLUSIONS High UBE2C mRNA expression was found to be of adverse prognostic significance in high-risk breast cancer patients. These findings need to be validated in larger cohorts.

Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH)

The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.

Primary fallopian tube carcinoma: results of a retrospective analysis of 64 patients.

OBJECTIVE The objective of this retrospective study was to determine the clinical outcomes of patients with primary fallopian tube carcinoma (PFTC) treated with paclitaxel and platinum analogue-based combination chemotherapy following primary cytoreductive surgery. METHODS Sixty-four patients with the diagnosis of PFTC were identified through the gynecology service database and the tumor registry of 4 different institutions. The majority of patients (48/64, 75%) were treated with carboplatin AUC (area under curve) 6 and paclitaxel 175 mg/m(2) as a 3 h infusion. RESULTS Among 28 patients with measurable disease, we observed 19 (68%) complete clinical and 7 (25%) partial responses for an overall response rate of 93%. After a median follow-up of 40 months (3+-134+ months), the 5-year survival rate of the entire population was 70% (median overall survival [mOS] not reached) and the median time to tumor progression (mTTP) was 81 months (95% CI: 53-109). Stage and residual disease were of prognostic significance. The mTTP was not reached in patients with stage I/II and was 38 months for patients with stage III/IV (p=0.004). The mOS for patients with stage I/II was not reached, whereas it was 62 months for those with stage III/IV (p=0.057). The mTTP was 86 and 23 months for patients with residual disease <2 cm and >2 cm, respectively (p<0.001). The mOS was not reached for patients with residual disease <2 cm, while it was 36 months for residual disease >2 cm (p<0.001). CONCLUSION Optimally cytoreduced patients with PFTC treated with platinum and paclitaxel-based chemotherapy regimen have an excellent possibility of survival.

Anthracycline-Based Chemotherapy of Primary Non-Hodgkin’s Lymphoma of the Testis: The Hellenic Cooperative Oncology Group Experience

Testicular non-Hodgkin’s lymphoma is an uncommon disease and its outcome following chemotherapy and/or radiotherapy has been variable. A retrospective analysis was performed on 26 patients with primary testicular lymphoma treated predominantly with anthracycline-based chemotherapy between 1984 and 1999. The patients’ median age was 60 years (range 19–82 years) with 17 (65.4%) patients being older than 60 years. Four (15.4%) patients had constitutional B symptoms. There were 11 (42.3%) patients with high grade lymphoma, 12 (46.2%) with intermediate grade, 1 (3.8%) with low grade and 2 (7.7%) were not classified. According to the Ann-Anbor staging system, 18 patients (69.2%) had early (stage I/II) and 8 (30.8%) advanced (stage III/IV) disease. Chemotherapy was administered to 24 patients including 22 patients who received anthracycline-based chemotherapy. Two stage IEA patients were treated with orchidectomy and adjuvant radiotherapy to the regional lymph nodes without systemic chemotherapy. Chemotherapy alone resulted in a complete remission (CR) in 14 (58.3%) of 24 patients and partial remission in 1 (4.2%), amounting to an overall response rate (RR) of 62.5%. Of the 5 stage I patients who had chemotherapy on an adjuvant basis, 4 (80%) had CR/no evidence of disease. Of the 11 stage II patients, 8 (72.7%) achieved CR and 1 (9.1%) PR (overall RR of 81.8%). CR was obtained in 2 (25%) of 8 stage III/IV patients. Both patients remain disease free for 26 and 65 months. Excluding the 5 stage I patients, chemotherapy resulted in a CR in 10/19 (52.6%) patients and a PR in 1/19 (5.2%), inducing an overall RR of 57.8%. The mean duration of response was 75 months (range 8–145.5+ months). After a median follow-up of 87 months (range 0.13–145.5+ months) the median survival time was 31 months (range 0.13–145.5+ months) and the median time to progression (TTP) 17 months (range 0.13–145.5+ months). The median TTP was significantly higher in early disease compared to that of advanced disease (52 vs. 3 months, p = 0.02). Of the 3 patients who relapsed following disease-free status, CNS involvement occurred in 2 stage II patients and contralateral testis involvement in 1 stage IEA, respectively. The latter remained disease free for 2 years following orchidectomy alone. The other 2 patients who relapsed did not respond to salvage chemotherapy and died. There was no significant relationship between the values of LDH and β2-microglobulin with the outcome except for ESR which was significantly related with the CR (p = 0.005) or RR (p = 0.005). In conclusion, patients with primary testicular lymphoma have a poor outcome, despite the treatment with anthracycline-containing regimens. Treatment with anthracycline-based chemotherapy is recommended in patients at early stages. In advanced disease, more intensive or investigational regimens should be considered. Because the relapse rate in the CNS and contralateral testis is quite high in most studies, prophylactic CNS treatment and radiotherapy to the other testis should be included in the management of testicular lymphoma.