Long-term endometrial effects in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES)--a randomised controlled trial of exemestane versus continued tamoxifen after 2-3 years tamoxifen.

BACKGROUND: The antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen. PATIENTS AND METHODS: Sonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2-3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (> or =5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation. RESULTS: The analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67). CONCLUSION: Switching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.

A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients.

PURPOSE: A randomized phase II trial of oral vs. intravenous (i.v.) vinorelbine was designed to determine the efficacy and safety of oral vinorelbine with an intrapatient dose escalation in previously untreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between December 1997 and April 1999, 115 patients with stage IIIB or IV NSCLC were randomized (2 to 1) to receive either oral vinorelbine at a dose of 60 mg/m2/week for the first three administrations and then increased to 80 mg/m2/week in the absence of severe neutropenia, or i.v. vinorelbine at 30 mg/m2/week. RESULTS: One hundred and fourteen patients (76 in the oral arm and 38 in the i.v. arm) were treated. Ninety-eight patients (86%) were eligible and assessable. The two treatment arms were well-balanced for demographic and prognostic features. After external panel review, the response rates in evaluable patients were 14%, in the oral arm and 12% in the i.v. arm. The median progression-free survival with oral and i.v. vinorelbine was 3.2 months and 2.1 months, respectively, and the median survival 9.3 and 7.9 months, respectively. The most common hematological toxicity was neutropenia, which was severe (grade 3-4) in 46% of patients and for 7% of administrations in the oral arm, and in 62% of patients and for 25% of administrations in the i.v. arm. Non-hematological toxicities including nausea, vomiting, anorexia, weight loss, diarrhea .and constipation were generally mild to moderate. CONCLUSION: The activity of oral and i.v. vinorelbine in advanced NSCLC appears to be comparable. The safety profiles of both formulations look qualitatively similar. Oral vinorelbine can therefore be considered a good alternative to i.v. administration.

Does chemotherapy-induced leukopenia predict a response in small-cell lung cancer?

The correlation between chemotherapy-induced toxicity and treatment outcome in cancer patients has not been studied thoroughly. Our aim was to evaluate whether there is any relationship between chemotherapy-induced leukopenia and response to treatment in small-cell lung cancer (SCLC). Data derived from records of 228 patients treated within two prospective multicentre phase II studies were analysed. In the first study (101 patients) chemotherapy included vincristine, epirubicin and cyclophosphamide and, in the second (127 patients), cyclophosphamide, etoposide and epirubicin; both regimens were given every 3 weeks. In the present analysis, the correlation between treatment outcome (response rate and survival) and highest scores of leukopenia within the first two and up to the fourth chemotherapy cycle, respectively, was evaluated. The objective response rate for the entire group was 66%; 53% in patients whose white blood cells remained normal and 85% in those who developed leukopenia within the first two cycles (P = 0.000). In multifactorial analysis, also including other treatment- and patient-related factors, independent correlation with response to chemotherapy was found for leukopenia (P = 0.001), chemotherapy regimen (P = 0.002) and the combined relative dose intensity (P = 0.018), but not for patient sex, age, performance status, pre-study weight loss, extent of disease and initial white blood cell count. Leukopenia within the first two cycles of chemotherapy was not correlated with survival, whereas such correlation for leukopenia occurring up to the fourth cycle was at the borderline level (P = 0.06). These findings suggest a relationship between chemotherapy-induced leukopenia and tumour response in SCLC.

Autopsy findings in small cell lung cancer.

The objective of this study was to assess the pattern of autopsy findings in 174 small cell lung cancer patients treated between 1971 and 1991 at seven Polish medical centres. Eighty nine autopsied patients were previously treated with different chemotherapy regimens including 32 patients who also received chest irradiation, 74 received only supportive care and for 11 patients the data on treatment were not available. The age range at diagnosis was 28-81 years (median 57); there were 39 females (22%) and 135 males (78%). Seventy two patients had limited disease at the time of diagnosis, 86-extensive disease and in 16 the disease extent was not determined. The primary tumor and/or metastases in regional lymph nodes were present in 157 autopsies (90%). There was a significant difference in the rate of locoregional disease found at autopsy in patients given chemotherapy and in those who received only supportive care (85% and 100%, respectively; p = 0.01). Chest radiation therapy given in limited disease as an adjunct to chemotherapy did not decrease the rate of persistent locoregional disease (primary tumor in the chest was found in 92% of irradiated and in 96% of nonirradiated patients). Locoregional tumor deposit only was found in 28 (16%). Distant metastases were distributed in 143 patients (82%) and were found in 25 different locations, most frequently in liver (49%), suprarenal glands (25%), peripheral lymph nodes (21%), kidneys (18%), brain (17%) and pancreas (12%). In 3 patients no tumor foci were found. The number of organs involved varied between 0 and 10 (median 3). The number of involved organs was not dependent on the disease extent at the time of diagnosis and on the type of treatment.

Combination chemotherapy with cyclophosphamide, epirubicin and etoposide in small cell lung cancer.

From March 1987 to February 1991, 136 patients with untreated small cell lung cancer (64 patients with limited disease and 72 with extensive disease), were treated as part of a prospective multi-center study, with a combination of cyclophosphamide 1000 mg/m2 i.v. on day 1, epirubicin 70 mg/m2 i.v. on day 1 and etoposide 100 mg/m2 i.v. on days 1, 3 and 5. Courses were repeated every 3 weeks. One-hundred thirty-four patients were evaluable. There were 42 (31%) complete responses and 66 (49%) partial responses for an overall response rate of 80% (95% confidence interval 71-87%). A complete response was seen in 24 patients (38%) with limited disease and in 18 patients (26%) with extensive disease, while a partial response was observed for 31 (48%) and in 35 (50%) patients, respectively. The median duration of response for all patients was 8.9 months (range, 1-60+ months). The median duration of survival for the entire group was 11.4 months (12.5 months for limited disease and 9.8 months for extensive disease). The 2-year survival rate for the whole group was 13%. The main side-effects were myelosuppression, alopecia, nausea and vomiting. Grade 4 toxicity was seen in 8.5% of patients. In conclusion, the studied regimen was found to be active and well tolerated and may be considered as an alternative to standard chemotherapy combinations in SCLC.

Neurological and cognitive impairment in long-term survivors of small cell lung cancer.

Despite its effectiveness in reducing the rate of brain metastases, the role of prophylactic cranial irradiation (PCI) in the management of small cell lung cancer (SCLC) remains controversial because of concern about radiation-induced neurological morbidity. In order to evaluate morbidity and its impact on quality of life 64 patients surviving > or = 2 years in remission were recalled for assessment. 52 had received PCI. Most of the patients were well: 95% had performance status < or = 1 and nine out of 37 neurological examinations were abnormal. On neuropsychometric testing, only 19% of patients performed at the level expected for their age and intellectual ability on all four tests used. Fifty-four per cent of patients were impaired on two or more of the tests, suggesting a significant degree of measurable cognitive dysfunction. The number of patients who had not received PCI was insufficient for comparative analysis with the number who had, but among those treated with PCI, patients receiving 8 Gy in 1 fraction appeared less impaired than those receiving higher radiation doses in multiple fractions. The study showed that neuropsychometric testing is acceptable to patients, can be administered by non-psychologists in the clinic and is sensitive to otherwise undetected deficits of cognitive function in this patient population. Prospective evaluation of PCI should include neuropsychometric testing.

[Analysis of prognostic factors for long term survival in patients with small cell lung cancer]. / Analiza czynników rokowniczych warunkujacych dlugotrwale przezycia chorych na drobnokomórkowego raka pluca.

Prognostic factors for long term survival were analyzed in a group of 719 patients with small cell lung carcinoma treated within 4 consecutive prospective multicenter trials between 1981 and 1990. 74 patients (10.3%) survived more than 2 years; 30 of them (4.2%) with no evidence of disease. The most significant determinator of prolonged survival was extent of disease: 13.9% (59/424) of patients with limited disease vs. 5.1% (15/295) with extensive disease survived more than 2 years (p < 0.001). Of 138 female patients 24 (17.4%) were long term survivors, compared to 8.6% (50/581) of males (p < 0.01). Initial good performance status and no weight loss were also found to be correlated with long term survival. Of the group of 2-year survivors 51 patients subsequently died (median survival duration 31 months), 10 are alive with cancer or are lost to follow up and 13 are in complete remission with median follow up of 64 months. 20 patients (3.8%) survived more than 5 years. This study confirms the possibility of cure in SCLC, especially in patients with favorable prognostic factors.

Phase II study of vinorelbine (Navelbine) in previously treated small cell lung cancer patients. EORTC Lung Cancer Cooperative Group.

26 previously treated patients with progressive recurrent small cell lung cancer (SCLC) were given vinorelbine (Navelbine), 30 mg/m2 weekly. All patients had responded to first-line chemotherapy and were off therapy for at least 3 months. Partial response was observed in 4 out of 25 eligible patients (16%; 95% confidence interval 4-36%), stable disease in 7 patients and progression in 12 patients. The limiting toxicity was a non-cumulative leucopenia (80%, 32% WHO grade 3-4). Reaction at the site of injection was observed in 5 patients, causing treatment discontinuation in 2 cases. Other non-haematological toxicities were moderate. These results suggest acceptable toxicity and some antitumour activity of vinorelbine in pretreated SCLC patients.

Combination chemotherapy with vincristine, epirubicin and cyclophosphamide in small cell lung carcinoma. Polish Lung Cancer Cooperative Group.

The aim of this prospective study was to assess the activity of a combination of vincristine, epirubicin and cyclosphosphamide (VEC) in previously untreated patients with limited small cell lung carcinoma (SCLC) and to delineate the feasibility of dose escalation for epirubicin in this regimen. The chemotherapy schedule included cyclophosphamide, 1000 mg/m2, vincristine, 1 mg/m2 and escalating doses of epirubicin: 50 mg/m2, 70 mg/m2 and 90 mg/m2; respectively in three consecutive groups of patients. Drug cycles were repeated every 3 weeks. 118 patients from eight institutions were enrolled in this study between February 1986 and March 1989. Objective tumour response was observed in 81 of 116 evaluable patients (70%) including 25 patients (22%) who achieved a complete remission. Responding patients received thoracic radiation after the fourth cycle of chemotherapy. The median duration of response was 30 weeks and the median duration of survival was 52 weeks. There were no significant differences in treatment results between the consecutive groups of patients. The regimen was well tolerated for all doses of epirubicin. The main toxicities included alopecia (96%), nausea and vomiting (81%) and leukopenia (44%). Grade 4 haematological toxicity was observed in 3 patients (2.6%). No significant epirubicin dose-dependent side effects, except for mucositis were observed.

The importance of surgery as the first step in multimodality treatment of small cell bronchial carcinoma. The ISC Lung Cancer Study Group.

For patients with small cell lung cancer (SCLC) in their early stages (TNM I, II), surgery for cure was used to eliminate the primary tumour and its regional lymph-nodes followed by intermittent chemotherapy and radiotherapy within the first six postoperative months. After the pathohistological examination of the operation-specimen a two-arm-randomization was performed: standard chemotherapy (1000 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine) compared with sequential chemotherapy using three different drug-combinations (A: 1500 mg/m2 cyclophosphamide, 100 mg/m2 lomustine, 15 mg/m2 methotrexate; B: 1000 mg/m2 cyclophosphamide, 40 mg/m2 doxorubicin, 1 mg/m2 vincristine; C: 5 x 1.6 g/m2 ifosfamide plus mesna, 5 x 120 mg/m2 etopside). Thereafter disease-free patients only received prophylactic cranial irradiation (PCI: administering 3600 TD Gy/18 fractions) according to the protocols of the International Society of Chemotherapy Studies I and II. Preliminary evaluations in March 1990 of 170 patients from 24 cooperating departments for thoracic surgery showed that the projected life-table four-year-survival rate of 63 patients with SCLC at pTNM-stage I was 61%, of 54 patients at pTNM-stage II was 35%, of 13 patients at stage pT3, 4 NO, 1 MO was 59% and of 40 patients at stage pT N2 MO was 35%. The indication for surgery is emphasized for pTNM-stages I + II. For N2-lesions surgery would not be recommended in general, but the survival rate seems to indicate that this treatment was not detrimental, being rather more favourable compared with chemotherapy or radiotherapy alone. The continuation and enlargement of these studies seem not only justified, but emphatically indicated.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term survival of patients with small cell lung cancer]. / Dlugotrwale przezycia chorych na drobnokomórkowego raka pluca.

The analysis of clinical determinants of long-term survival in small cell lung cancer was investigated in consecutive series of 469 patients included in prospective multicenter clinical trials from 1981 to 1985. Forty eight patients (19.2%) were alive after 2 years from initiation of therapy and among them 27 (5.8%) were disease free. The most important clinical determinants of long-term survival were: extent of disease, performance status and sex. 38 out of 243 patients with limited disease (15.6%) survived for 2 years or more as well as 10 out of 226 patients with extensive disease (4.4%, p less than 0.001), 33 out of 237 patients with WHO performance status 0 and 1 (13.9%), and 15 out of 232 patients with performance status from 2 to 4 (6.4%, p less than 0.01), 29 out of 229 (12.2%) with absence of weight loss before therapy and 19 out of 240 (7.9%) with weight loss (N.S.), 32 out of 392 males (8.2%) and 16 out of 77 females (20.7%, p less than 0.01). Out of 27 disease-free survivors 21 are alive with no sign of malignancy after 3.5 to 7 years from initiation of therapy. Ten patients out of 229 followed up for a minimum 5 years after inclusion to the studies survived this period with no signs of disease. This study confirms the possible curability of small cell lung cancer, especially in patients with favorable prognostic characteristic.

[Evaluation of the second line of treatment of patients with small cell carcinoma of the lung]. / Ocena skutecznosci drugiego rzutu leczenia chorych na drobnokomórkowego raka pluca.

Efficacy of second line therapy which included vepesid and adriamycin or vepesid, adriamycin and cis-platin, in small cell lung cancer was studied. Objective remission was seen in 35% of the once more treated patients. Analysis of survival time showed significant prolongation of it in cases treated once more in comparison with a group of patients with progression of the neoplastic process during primary therapy or patients not treated due to relapses of the process. The observed difference was bigger in patients that reacted with a remission to the second line therapy.

The role of ifosfamide and cyclophosphamide in the multi-modality treatment after surgery for cure for small-cell bronchial carcinomas (SCLC).

For the optimisation of the therapy for small cell bronchial carcinomas (SCLC), surgery is used to eliminate the primary tumor and its regional lymph nodes and chemo- and radiotherapy for the general treatment of micrometastasis. After patho-histological examination of the operation specimen, randomization for two arms is performed for a standard chemotherapy (CAV) or a sequential chemotherapy using three different drug combinations. Thereafter all disease-free patients receive prophylactic cranial irradiation (PCI). Preliminary evaluations in December 1987, of 112 patients from 19 cooperating departments show that the survival rate projected for 2 yr of 43 patients at stage pT1-3 N0 M0 is 76%, of 43 patients at stage pT1-3 N1 M0 it is 63% and of 26 patients at stage pT1-3 N2 M0 it is 38%.

Surgery for cure followed by combined modality treatment for small cell bronchial carcinoma. ISC Lung Cancer Study Group.

For patients with small cell lung cancer (SCLC) at early stages (TNM I, II) surgery for cure is used to eliminate the primary tumour and its regional lymph-nodes followed by intermittent chemotherapy and radiotherapy within the first six postoperative months. After the pathohistological examination of the operation-specimen a two-arm-randomization is performed: standard chemotherapy compared with sequential chemotherapy using three different drug-combinations. Thereafter tumour-free patients only receive prophylactic cranial irradiation. In preliminary evaluations of March 1988, of 121 patients from 20 cooperating departments it was found that the projected life-table survival rate, three years postoperatively, of 47 patients with SCLC at stages pT1-3 N0 M0 was 65%, of 46 patients at stages pT1-3 N1 M0, 56% and of 28 patients at stages pT1-3 N2 M0, 34%. The indication for surgery were emphasized for pTNM-stages I+II. For N2-lesions surgery would not be recommended in general, but the survival rate seemed to indicate that this treatment was not detrimental, but rather more favourable compared with chemotherapy or radiotherapy only. The continuation and enlargement of these studies seem not only justified but emphatically indicated. Multicentre cooperation has to be organized to collect within a reasonable period of time a sufficient number of patients to enable subdivisions to be made according to various prognostic factors.

[Cobalt radioisotope teletherapy of patients with metastases to the brain]. / Telekobaltoterapia chorych z przerzutami do mozgu.

The results are presented of palliative telecobaltotherapy in patients with metastases to the brain. The patients received a dose of 30 Gy in 10 fractions during 2 weeks. Clinical improvement was achieved in 28 out of 33 treated patients (85%). The survival time after the completion of radiotherapy was from 1 to 15 months, mean 5 months.