Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer.

The purpose of this study was to compare long-term survival in first-line chemotherapy with and without platinum in advanced-stage ovarian cancer. From July 1987 to November 1992, 161 untreated patients with FIGO stage III-IV epithelial ovarian cancer were randomized: 81 patients received no platinum and 80 received platinum combination. Residual disease after surgery was <2 cm in 61 patients without platinum, 59 with platinum. Median age was 58 years in nonplatinum arm and 55 years in platinum arm (range: 15-73). Complete and partial responses were 51% and 10% for nonplatinum arm and 51% and 8% for platinum arm, respectively (P= 0.7960). Stable disease was observed in 18% of patients in nonplatinum arm and 15% of patients in platinum arm and progression in 20% of nonplatinum- and 21% of platinum-treated cases. Ten-year disease-free survival was 37% for therapy without platinum and 31% for platinum combination (P= 0.5679); 10-year overall survival was 23% without platinum and 31% with platinum combination (P= 0.2545). Fifteen-year overall survival showed a trend of short duration in favor of platinum (P= 0.0678). Relapses occurred after 60 months in ten patients (seven with and three without platinum). The overall and disease-free survivals at 5, 10, and 15 years show no statistically significant long-term advantage from the addition of cisplatin; however, there is a slight trend in its favor.

A Randomized Study of Epithelial Ovarian Cancer: Is Chemotherapy Useful after Complete Remission?

Objective. The aim of this study is to verify whether consolidation chemotherapy with Cisplatin improves disease-free survival and/or overall survival in patients affected by epithelial ovarian cancer.Methods. A multicenter study examined 122 randomized patients in complete remission as judged by laparoscopy or laparotomy following first-line chemotherapy consisting of ACy (Adriamycin + Cyclophosphamide), PCy (Cisplatin + Cyclophosphamide), or Mitoxantrone + Carboplatin. Sixty-one of these patients were treated with 3 cycles of 5-Fluorouracil (FU) 500 mg/m2 for 5 days followed by Cisplatin at 100 mg/m2 on the 6th or 7th day every 28 days; the other 61 received no further treatment (nihil group).Results. Sixty patients in the Cisplatin arm were evaluable. There were 36 relapses in the FU+Cisplatin arm and 30 in the nihil arm. Peritoneal relapses were 25% for Cisplatin treatment vs. 16.4 % for nihil. There were 29 deaths in the Cisplatin arm vs. 27 for nihil. Median overall survival time (95 months with Cisplatin vs. 96 months in the nihil group) and median disease-free survival (66 months with Cisplatin vs. 73 in the nihil group) were similar in both arms (p=0.66 and p=0.41, respectively). There were no significant differences in tumor stage and grade between the two arms. Seven patients presented a second neoplasm during follow-up: six in the nihil arm, but only one patient in the Cisplatin arm. Death in these patients was due to the second neoplasm and not to progression of ovarian cancer.Conclusion. Three courses of additional platinum+FU treatment after five cycles of first-line chemotherapy without FU produced no increase in overall survival or disease-free survival.

Modulating effect of lonidamine on response to doxorubicin in metastatic breast cancer patients: results from a multicenter prospective randomized trial.

Previous results from our preclinical studies have shown that lonidamine (LND) can positively modulate the antiproliferative activity of doxorubicin (DOX) on breast cancer cell lines. To evaluate the effect of LND in a clinical setting, a multicenter randomized trial was carried out on patients with advanced breast cancer. From September 1991 to July 1993, 181 patients were enrolled in the trial and received an initial treatment of DOX at 75 mg/m2 for 3 cycles. The 137 patients who reached complete remission, partial remission, or stable disease were randomized to receive either DOX alone (75 mg/m2 day 1) (arm A) or DOX plus LND (600 mg orally/day) (arm B). The patients enrolled in the two arms were fairly homogeneous in terms of major clinical characteristics. Toxicity was similar in both arms except for myalgia: WHO grade > or=2 was observed in 57% of arm B patients. Overall response rate to DOX + LND was 50% and to DOX alone 38% in evaluable patients, and 48% vs 37% in all registered patients, as determined by an intention-to-treat analysis. The differences did not reach statistical significance. Conversely, in agreement with previous findings, we observed a significant difference in response rate in the subgroup of patients with liver metastases, regardless of the extent of hepatic involvement (DOX + LND 68% vs DOX 33%, p=0.03). This observation makes LND an important tool in association with anthracyclines in the treatment of this subgroup of patients.

Surgical second look in ovarian cancer: a randomized study in patients with laparoscopic complete remission--a Northeastern Oncology Cooperative Group-Ovarian Cancer Cooperative Group Study.

PURPOSE: The usefulness of extensive and repetitive surgery for patients with ovarian cancer still remains unproven (at least for some conditions). We planned an accurate prospective test of the hypothesis that patients with advanced-stage disease, after they had reached a clinical complete remission (CR), may benefit from surgical second look (SSL). PATIENTS AND METHODS: One hundred two patients in CR (as assessed by clinical findings, markers, and visualization by computed tomographic [CT] scan and laparoscopy), after initial debulking and first-line chemotherapy, were randomized to two arms, which were well balanced for predictive criteria such as age, stage at presentation, histology, grading, date of randomization, and residua after first surgery. Forty-eight patients were randomly assigned to receive follow-up evaluation only, while 54 were assigned to receive second surgery (eight of them refused). Of 46 surgical patients, 35 had negative and 11 positive surgical findings (24% clinically false-negative). RESULTS: Despite the microscopic residua found at open surgery, and the fact that the patients were then treated with second-line chemotherapy, SSL did not increase the probability of survival in this setting. In an analysis of the results according to the intention-to-treat criteria, after a 60-month follow-up period, the overall survival rates in the two groups of patients (SSL v no SSL) were 65% and 78%, respectively (P = .14). Multivariate analysis according to predictive criteria confirmed there was no significant difference between the two groups (P = .39). CONCLUSION: Our study shows the following: (1) our second-line treatment is scarcely effective; (2) SSL accurately defines complete responders to first-line chemotherapy; (3) SSL per se does not prolong survival; and (4) if confirmed, a less invasive procedure could replace SSL as a valuable method in new first-line regimens in ovarian cancer patients with clinical CR confirmed by laparoscopy.

ErbB2 assay in breast cancer: possibly improved clinical information using a quantitative method.

ErbB2/neu protein (p185) expression was evaluated by ELISA in 115 breast cancer specimens. Distribution was subdivided in quartiles and showed a distinct behaviour in comparison with both clinico-biological parameters and clinical outcome. In particular, intermediate concentration groups showed a significantly better disease-free survival than the low and high concentration groups (p = 0.02). We classified the patients as "low risk" (64 samples with p185 concentrations between 2150 and 30000 U/mg of proteins) and "high risk" on the basis of the results of the multivariate analysis. The p185 grouped as described showed a significant relationship with the disease free survival in multivariate analysis. Although the data must be considered as preliminary, they suggest the possibility of identifying more appropriately the high risk patients through the biochemical determination of p185.

Quantitative chemiluminescent immunoassay of p53: prognostic significance in 220 node-negative breast cancer tissue.

The prognostic and predictive role of p53 overexpression in breast cancer samples is usually investigated by using molecular biology or immunohistochemical methods. However, the results are to date controversial, and this is in part due to the methodological pitfalls of both the methods. To study the possibility of overcoming, at least in part, these problems we evaluated a commercially available chemiluminescent immunoassay with which the p53 concentrations of 220 specimens from node negative breast cancer were determined. The assay showed good analytical performance and found detectable levels in 84.7% of cases (median 0.22 ng/mg of proteins, range 0-50 ng/mg of proteins). p53 has been found inversely correlated with estrogen receptors and directly correlated with cathepsin D. The prognostic role of p53 was evaluated in two different ways: a) two previous studies (Borg et al 1995, DeWitte et al. 1996) using the same method found almost 30% of samples had significantly shorter DFS and OS. We subdivided our cases in order to identify the same positivity rate and to verify if the previous cathegorizations were effective also in our patient series. We confirmed the independent association with DFS (p = 0.006) and OS (p = 0.0005); b) considering that any categorization of quantitative parameters could cause a loss of clinical information, we also evaluated p53 as a continuous variable. Multivariate analysis showed a significant quantitative relationship between p53 and both disease free (p = 0.026) and overall survival (p = 0.02).

Biochemical parameters for prognostic evaluation in patients with breast cancer.

We evaluated the prognostic value of tissue polypeptide antigen (TPA), cathepsin D and pS2 in 267 patients operated for primary breast cancer. Cathepsin D, pS2 and cytosol TPA were independent of each other and of N, T, estrogen (ER) and progesterone (PgR) receptors. Cathepsin D was the best prognostic indicator for disease-free survival and pS2 for overall survival. The simultaneous evaluation of the three parameters was an effective discriminator between high and low risk patients in both N- and N+. Considering that cathepsin D, pS2 and cytosol TPA can be easily measured with reliable methods in small amounts of tissue, we conclude that they are a promising panel of biochemical parameters suitable for the assessment of the risk of relapse in patients with breast cancer.

Cisplatin and etoposide versus cyclophosphamide, epirubicin and vincristine in small cell lung cancer: a randomised study.

From September 1986 until December 1991, 139 patients with histologically-proven small cell lung cancer, age < 75 years, performance status > 40, absence of brain metastases and no previous treatment, were randomised to receive either CEV cyclophosphamide 1000 mg/m2 intravenous (i.v.), epirubicin 70 mg/m2 i.v., vincristine 1.2 mg/m2 i.v., every 3 weeks or PE (cisplatin 20 mg/m2 i.v. and etoposide 75 mg/m2 i.v. for 5 consecutive days, every 3 weeks) for six cycles. After three cycles, responding patients received radiotherapy to the chest (45 Gy/15 sessions) and to the brain (30 Gy/10 sessions--only in patients with limited disease achieving complete remission). 3 patients were ineligible. Patient characteristics included (CEV/PE) total number 66/70, median age 60/61 years, median performance status 80/80, extended disease 33/48 cases (P = 0.04). In evaluable patients, 42/62 (67.7%) responded to CEV while 42/58 (72.4%) responded to PE (P = non-significant); respective complete response rates were 16.1 and 29.3% (P = non-significant) and respective complete response rates in patients with extended disease were 9.4 and 28.9% (P = 0.03). Median survival was 10.5 months, without significant differences in the two treatment arms, even after adjustment for stage. PE was less well tolerated than CEV. Although PE is more active than CEV in certain subsets of patients, its apparent inability to improve survival in this and in other studies questions its routine use in small cell lung cancer.

PS2 in breast cancer--alternative or complementary tool to steroid receptor status? Evaluation of 446 cases.

The oestrogen induced pS2 protein was measured in the cytosol of 446 breast cancer samples by an immunoradiometric assay. The relationships between pS2 and several clinical and biological parameters were evaluated. pS2 was not correlated to age, pT and nodal status, while it was higher in pre- than in peri- and post-menopausal women. A statistically significant positive association was found between pS2 and ER, PgR and cathepsin D. However, the frequency of pS2 negative values in ER+ (25.6%), PgR+ (21.7%) and cathepsin D-(19.0%) cases suggests that pS2 provides information independent of the above parameters in a fairly high percentage of patients. The prognostic role of pS2 was evaluated in 267 cases (follow up time 24-102 months). pS2+ showed longer RFS (P = 0.016) and OS (P = 0.004) than pS2-. pS2+ cases were significantly associated with a better prognosis in N+ but not in N- cases. Multivariate analysis showed that pS2 is an independent prognostic factor being the second most effective indicator for OS after nodal status and the third for RFS after nodal status and cathepsin D. From the present findings, we conclude that pS2 probably provides additional biological information to steroid receptor status and cathepsin D in patients with primary breast cancer.

Phase I-II intraperitoneal mitoxantrone in advanced pretreated ovarian cancer.

36 previously treated patients (25 with anthracyclines) with advanced epithelial ovarian cancer have been treated with intraperitoneal (i.p.) mitoxantrone (M) at increasing doses. The response was evaluated through repeated laparoscopy with multiple biopsies and serial measurement of Ovarian Cancer Antigen 125 (CA 125); 11/36 patients had a complete (6 patients) or partial (5 patients) response. Toxicity (both local and general) was observed starting from 25 mg/m2 of M per cycle. The amount of drug reaching systemic circulation was monitored by measuring M plasma value after i.p. treatment. This study showed wide variations in serum levels obtained after i.p. doses ranging from 23 to 36 mg/m2. The area under the curve (AUC) of mitoxantrone plasma samples, did not correlate with the i.p. administered dose. Conversely, a correlation seems to exist between the plasma AUC and the responder status. Patients who showed clinical responses to i.p. treatment with mitoxantrone had AUCs and plasma peak levels of the drug that were significantly higher than those in non-responders (P = 0.03, Fisher's exact test).

Tissue polypeptide antigen in breast cancer cytosol: a new effective prognostic indicator.

Since 1982 we have been evaluating oestrogen and progesterone receptors (PgR), cathepsin D and the cytosolic levels of the tumour marker, tissue polypeptide antigen (TPA), in 257 patients radically resected for breast cancer (follow-up 24-81 months). TPA was measured by an immunoradiometric assay previously validated for cytosol. No significant associations were found between cytosolic TPA and age, tumour size, lymph-node status, receptor status and cathepsin D. TPA+ cases showed a significantly longer disease-free survival (DFS) and overall survival (OS) than TPA-patients (log-rank P < 0.0001). The prognostic value of cytosolic TPA was also demonstrated after stratification by nodal status, PgR and cathepsin D. The prognostic value of TPA was independent of the other prognostic indicators, being the most powerful among the evaluated indices (Cox multivariate analysis: chi 2 15.5 for DFS, 11.4 for OS). We conclude that cytosolic TPA is a powerful additional prognostic factor in primary breast cancer. Its prognostic role should therefore be extensively evaluated.

Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer.

Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m2) (arm B). An overall response rate of 58.9% was observed in arm A and 50.6% in arm B, respectively. No differences in the pattern of relapse were noted between the two treatment groups. Median time to progression was 10.6 months for arm A and 14.2 months for arm B. Median survivals were 10.3 months and 9.97 months, respectively. Toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant advantage of the combined treatment over radiation therapy only was found. The encouraging results achieved in some trials together with the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological basis of the combined treatment.

The tumour associated antigen CA15.3 in primary breast cancer. Evaluation of 667 cases.

CA15.3 preoperatory serum levels have been determined in 667 patients with primary untreated breast cancer and in 193 controls. The relationships between CA15.3 and several clinical and pathological parameters were evaluated. CA15.3 levels showed a highly significant direct relationship with stage, T, pT, N and the number of positive lymph nodes. The close relationship between CA15.3 and the number of positive lymph nodes was also demonstrated in a subgroup of 406 patients in which more than ten lymph nodes had been examined. CA15.3 levels were correlated with tumour size in patients without axillary metastasis as well as with the number of positive lymph nodes in pT1 tumours. CA15.3 was significantly higher in medullary than in ductal carcinoma. No relationships were found between serum CA15.3 and receptor status. We conclude from the present findings that CA15.3 in primary untreated breast cancer is a marker of tumour burden as well as of the tendency of local invasiveness (relationship between CA15.3 and nodal status in pT1 tumours).

Treatment patterns in elderly patients (greater than or equal to 70 years) with breast carcinoma. A retrospective study of the Gruppo Oncologico Clinico Cooperativo del nord-Est (GOCCNE).

The pattern of treatment used in elderly women affected by breast carcinoma was evaluated in a retrospective study by the North-East Clinical Cooperative Group in Italy (GOCCNE). Six divisions were involved in the study. The medical records of 115 elderly women were reviewed; the women's median age was 75 years (range, 70-93). Surgery was used in 70/72 operable patients (97%), although limited surgery plus radiotherapy was used in only 7.5%. Most stage II patients were treated with adjuvant tamoxifen, as were younger postmenopausal patients, according to the guidelines of the Bethesda Consensus Meeting. Comorbid conditions are of particular concern in therapy planning, considering that more stage III patients died of competing causes than for disease progression. The role of chemotherapy was very marginal.

[Changes in lymphocyte subsets after radiotherapy]. / Variazione dei subset linfocitari dopo radioterapia.

Radiation therapy seems to induce depletion of lymphocytes, which are very important cells for immunity response. The lymphocyte phenotype was studied in 41 non-pretreated patients with normal immunological parameters who received postoperative radiation therapy for breast, mediastinal or pelvic cancer with at least 50 Gy/25 fractions. The functional immunological assessment was analyzed by Multiskin test (Merieux) too. The lymphocyte phenotype was determined on whole-blood lysate employing an Ortho double-fluorescence cytofluorimeter. All patients, after radiation treatment, exhibited decrement in absolute and percent lymphocyte subpopulations; the Multiskin test demonstrated simultaneous change in skin-test response. The results are highly significant (p 2-tailed area less than 0.0001) for absolute cells count and skin-delayed response test, but percent variations are not significant when verified by t-test.

Tissue polypeptide antigen in tumor cytosol: a new prognostic indicator in primary breast cancer.

The assessment of the risk of relapse is a critical need in the management strategy of breast cancer patients. To date, the most reliable prognostic factor is axillary nodal status. Several other pathological and biological parameters are currently under evaluation. Since 1982 we have been studying the prognostic role of several tumor markers in breast cancer cytosol. Elevated cytosol concentrations of tissue polypeptide antigen (TPA) have been found to have a highly significant direct correlation with both prolonged relapse-free interval (RFI) and higher survival rate. The information provided by cytosol TPA was independent of both axillary nodal status and steroid receptor content. In patients with a low risk of relapse (no axillary metastases, estrogen and progesterone receptor positive), cytosol TPA was still a significant prognostic indicator.

Is tissue polypeptide antigen still a useful tumor marker in breast carcinoma? Comparison with CA15.3 and MCA.

Serum levels of tissue polypeptide antigen (TPA) are related to the proliferative activity and to the mass of the malignancy, differently from any other available tumor marker. We therefore evaluated TPA in comparison with CA15.3 and MCA (mucinous-like carcinoma-associated antigen) in patients with primary breast cancer. TPA was measured in tumor cytosol and in serum. Cytosol and serum TPA levels were not significantly correlated. Serum TPA was higher in patients with locally more advanced disease and in receptor-negative cases. The relation between TPA and disease spread was not directly dependent on tumor bulk, whereas CA15.3 and MCA were highly correlated to the number of positive lymph nodes and tumor size. No correlations were found between TPA and CA15.3 or MCA, and the positivity concordance rate between TPA and CA15.3 or MCA was very low. Patients with higher TPA serum levels showed a worse prognosis in cases with and in those without axillary metastases. From our data we conclude that TPA provides information different from that obtained with breast-specific tumor markers and could therefore be useful in association with CA15.3 and/or MCA in the management of patients with breast cancer.

[Postoperative radiotherapy in the treatment of breast tumors. Evaluation of a 5-year case series]. / La radioterapia post-chirurgica nel trattamento dei tumori della mammella. Valutazione di una casistica di 5 anni.

Between January 1981 and December 1985, 364 female patients underwent surgical treatment for breast cancer in Mestre General Hospital. The pathological stage of the disease was stage I in 60 patients, stage II in 215 patients, stage III A in 30 patients, stage III B in 44 patients and stage IV in 15 patients. The patients with T1-T2 N0 lesions located in the outer quadrants received no additional treatment after surgery, while the others received adjuvant therapy. The patients with stage-IV disease (M+) were treated with chemo and/or hormonotherapy. All patients were followed for an average of 33 months up to December 1986 (range 1-71 months). Local-regional relapses developed in 17 patients, 15 on the chest wall and 2 in the drainage lymph nodes (only 7 within the previously-treated area). A 5-year actuarial survival rate was observed of about 78%, and 66% of relapse-free survival, in the whole group of patients (100% and 92% in stage I; 92.5% and 76% in stage II; 51% and 33% in stage III A; 32% and 19% in stage III B; 31% in stage IV, respectively). As far as our series of patients is concerned, the massive involvement of axillary lymph nodes seems to be the most adverse prognostic factor in survival rates. Even though the short follow-up does not allow definitive conclusions to be drawn, the authors believe such loco-regional treatments as surgery and radiation therapy to be extremely important in the local control of breast cancers, as well as in the patients' survival in the long run.