Renal toxicity and osteonecrosis of the jaw in cancer patients treated with bisphosphonates: a long-term retrospective analysis.

BACKGROUND: Bisphosphonates (BPs) are the mainstay of bone-directed therapy for bone metastases from multiple myelomas and a wide range of solid tumours, but some patients experience renal toxicity or osteonecrosis of the jaw (ONJ). PATIENTS AND METHODS: We reviewed data relating to 398 patients treated with intravenous BP for bone metastases, checking their serum creatinine levels throughout the treatment period in order to assess renal function, and seeking any signs and symptoms of ONJ recorded in their medical records. We also analysed other risk factors for renal toxicity and ONJ in patients who developed them. RESULTS: The median treatment period was 14 months (range 1-119); 108 patients received BP for more than 1 year, and 112 for more than 2 years. Sixteen patients (4%) developed renal toxicity after a median of 24 months of BP treatment, eight of them had been treated for more than 2 years. Ten patients (2.5%) were diagnosed as having ONJ after a median of 39 months on BP, only three of them had been treated for less than 2 years. Two patients experienced both ONJ and renal toxicity. CONCLUSIONS: The low incidence of ONJ and renal toxicity indicates the safety of BP. However, prevention and early detection are still the "first-line therapy" for decreasing their occurrence further.

Carboplatin, doxorubicin and etoposide in the treatment of tumours of unknown primary site.

The aim of this study was to assess the activity and toxicity of a platinum-based treatment on a group of patients with unknown primary tumours (UPTs). Patients with a diagnosis of UPT underwent a standard diagnostic procedure. Treatment was started within 2 weeks from diagnosis and consisted of carboplatin 400 mg m(-2) day 1, doxorubicin 50 mg m(-2) day 1, etoposide 100 mg m(-2) days 1-3, every 21 days. Response was evaluated after three courses and treatment continued in case of objective response (OR) or symptom control. A total of 102 patients were eligible. The median age was 59 years, sex male/female 54/48, histology was mainly adenocarcinoma or poorly differentiated carcinoma. Nodes, bone, liver and lung were the most frequently involved sites. In all, 79 patients received at least three courses of treatment; 26 patients received six courses or more. Six complete responses and 21 partial responses were observed, for a total of 27 of 102 ORs or 26.5% (95% confidence interval 18.2-36.1%). The median survival was 9 months and median progression-free survival was 4 months. Toxicity was moderate to severe, with 57.8% of patients experiencing grade III-IV haematological toxicity, mainly leucopenia. The regimen employed has shown activity in tumours of unknown primary site, but was associated with significant toxicity. Such toxicity may be considered unjustified, given the large proportion of patients with tumours not likely to respond. Efforts should therefore be addressed to identify predictors of response to chemotherapy, thus limiting aggressive treatment to those patients who could benefit from it.

Quality of life evaluation in a randomised trial of chemotherapy versus bio-chemotherapy in advanced melanoma patients.

This study analyses the health related quality of life (HRQOL) of advanced melanoma patients, in a randomised trial comparing bio-chemotherapy (bio-CT) versus chemotherapy (CT). The trial enrolled 178 patients and the median survival was not statistically different between the two arms. HRQOL was assessed at baseline and before each cycle of therapy, using the Rotterdam Symptom Checklist (RSCL) questionnaire completed with 140 patients. At baseline, overall quality of life and psychological distress scores were the most impaired, compared with the normal population. During treatment, the difference between the two arms in the changes from baseline was statistically significant (P=0.03) only in the overall quality of life score, with a decrease of 6.28 points in the bio-CT arm. The mean values decreased significantly in all domains in bio-CT arm, but only in activity level and physical symptom distress scores in the CT arm. Testing HRQOL variables and prognostic clinical factors in a Cox model, only the serum level of lactic dehydrogenase, baseline overall quality of life and the physical symptom distress scores remained significant independent prognostic factors for survival. A score of less than 75 points in the overall quality of life and in the physical symptom distress domains was associated with a Hazard Ratio (HR) of 2.31 (95% Confidence Interval (CI): 1.09-4.90) and 1.92 (95% CI: 1.10-3.36), respectively.

Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients.

This randomized phase II trial was performed to define the activity and toxicity of the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP) and tamoxifen (DBDT regimen) versus DTIC alone in patients with metastatic melanoma. Sixty patients with metastatic melanoma were randomly assigned to receive BCNU 150 mg/m2 intravenously (i.v.) on day 1, cisplatin 25 mg/m2 i.v. daily on days 1 to 3, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and tamoxifen 160 mg orally daily for 7 days prior to chemotherapy (DBDT arm; arm A). Treatment cycles were repeated every 28 days, while BCNU was given every two cycles. The DTIC arm (arm B) patients received DTIC alone 1200 mg/m2 i.v. on day 1, repeated every 21 days. Patients were evaluated every two cycles; responding patients continued the treatment for a maximum of 12 cycles. The overall response rate was 26% in the DBDT arm and 5% in the DTIC arm. Complete responses were 2.5% for DBDT and 0% for DTIC. The median progression-free survival and the median survival were 4 and 9 months, respectively for DBDT, and 2 and 7 months for DTIC. DBDT was associated with significant haematological toxicity: 33% of the patients experienced a grade III or IV neutropenia and 28% a grade III or IV thrombocytopenia. In conclusion, the overall response rate obtained with DBDT was greater than that obtained with DTIC alone; however, this combination increases toxicity with limited impact on overall survival.

Comparative study of clinical, pathological and biological characteristics of symptomatic versus asymptomatic breast cancers.

BACKGROUND: It is well known that mammographic screening reduces breast cancer mortality. One possible explanation for this effect is that screening makes it possible to detect smaller breast cancers with fewer involved nodes, but another hypothesis is that some screening-detected tumors are in a pathologically and biologically different phase of evolution from those that are detected clinically. The aim of the present study was to compare the biological, pathological and clinical characteristics of symptomatic vs. asymptomatic breast cancers. PATIENTS AND METHODS: The study considers a series of 1916 consecutive patients who underwent surgery for stage I and II infiltrating breast cancer at Verona hospitals after having undergone ultrasound and mammography (at least one of which was positive). They were divided into two groups on the basis of why they decided to undergo the imaging examinations: group A refers to the 1247 patients with a palpable lump, and group B to the 616 who were asymptomatic. RESULTS: The patients in group A were older, and had larger tumors and a higher percentage of positive nodes than those in group B; they also had significantly higher grade tumors, higher Ki-67 levels, and a higher percentage of ER and PgR negative and c-erbB-2 positive tumors (all of the P-values were significant). A logistic regression analysis adjusted for tumor diameter and age showed a reduction in the significance of each of the considered variables, but all of them remained significantly associated with the modality of diagnosis except ER, PgR and c-erbB-2. CONCLUSIONS: Our results suggest that asymptomatic tumors are biologically different from their clinically presenting counterparts, thus confirming the hypothesis that progression towards greater malignancy may occur during the natural history of breast cancer.

Bone marrow micrometastases in breast cancer patients.

The presence of epithelial cells in bone marrow may be a prognostic factor in breast cancer, and so we evaluated their evolution in treated and untreated patients. A first bone marrow aspirate was obtained from 125 stage I/II breast cancer patients at diagnosis and repeated every 6-8 months; the samples were processed for leukocyte separation, used to prepare cytospin slides, stained with a pool of monoclonal antibodies (MoAb) recognising epithelial antigens, and immunocytochemically processed. The median follow-up was 48 months (range 15-82); 23 patients relapsed, and 14 died. MoAb positive cells were observed in 31.2% of first, 24.3% of second, and 27.8% of third aspirates. In 68/100 pairs of successive aspirates, bone marrow status remained unchanged; in 20 it became negative, and in 12 positive (not statistically significant even after adjusting for adjuvant therapy). An analysis based on Mantel and Byar's approach to time-dependent covariates using all 225 aspirates found no statistically significant prognostic difference between the patients with negative and positive bone marrow. Bone marrow status changed over time in about 1/3 of the patients; adjuvant therapy did not affect the probability of its becoming negative or positive. No significant association was found between bone marrow evolution and relapse or death, but the relatively high probability of a change in status over time cannot exclude the possibility that a positive aspirate during the course of breast cancer may be a negative prognostic factor.

A double blind randomized study of oral clodronate in the treatment of bone metastases from tumors poorly responsive to chemotherapy.

Bisphosphonates are used in oncology as a means of decreasing complications due to bone metastases, in association with anticancer treatment, especially in patients with breast cancer, prostate cancer and myeloma. Little is known about the effects of bisphosphonates on bone metastases from other tumors and in particular from tumors for which no effective treatment is available. We conducted a randomized, double-blind placebo-controlled trial of oral clodronate in patients with bone metastases from tumors poorly responsive to chemotherapy, with the aims of evaluating the effects of this drug on symptoms control and bone metastases evolution. Sixty-six patients with poorly responsive tumors such as non-small cell lung cancer (NSCLC), bladder cancer, gastrointestinal cancers, kidney cancer, melanoma and metastatic carcinoma of unknown origin entered the study. Patients were randomized to receive either clodronate 1,600 mg/day for one year or identical placebo-containing tablets. Various parameters such as Karnofsky performance status, pain score (measured by a visual-analogue scale) and analgesic requirement were recorded at monthly intervals. Of the 66 patients enrolled, 9 were observed for one month or less; 7 were followed for two months; only 50 patients were followed for more than 2 months and could be adequately evaluated. At 3 months both clodronate and placebo-treated patients had a decrease in Karnofsky performance status, with the decrease being more evident in the placebo group. Mean pain scores showed an increase of pain in patients receiving placebo and a decrease of pain in patients receiving clodronate, although the difference failed to be statistically significant. Analgesics requirement increased in both groups, but significantly more in patients receiving placebo (p = 0.042), in whom increase in opioid requirements was particularly evident. Toxicity was low, with occasional gastroenteric discomfort in both groups. The main problem of this study was the difficulty in recruiting an adequate number of patients and following them for a sufficient period of time: general conditions rapidly deteriorated in many patients, and approximately 25% of the 66 enrolled were not considered evaluable; few patients survived for the length of the study, one year. This might partly account for the lack of significance of some of the parameters under study. With these limits, oral clodronate demonstrated some efficacy in symptom control and in reducing the need for analgesics.

Prognostic significance of estrogen receptors in 405 primary breast cancers: a comparison of immunohistochemical and biochemical methods.

Over the last few years, estrogen receptor determination by means of immunohistochemistry has been extensively used. The aim of this study was to compare this technique with estrogen receptor determination by means of dextran-coated charcoal, and to evaluate whether one of the two methods is more predictive of prognosis. Estrogen receptors were determined by means of both the dextran-coated charcoal method and immunohistochemistry in 405 patients with primary breast cancer; age, pathological tumor size, nodal status, and progesteron receptors by dextran-coated charcoal method were also recorded. The disease-free and overall survival probabilities were estimated using the product-limit method; Cox's proportional hazard model was used to evaluate the prognostic role of estrogen receptors as determined by the two methods. There appears to be a close association between estrogen receptor determination by the two methods (81.5% of concordant results) and their prognostic role was similar, even when the patients were divided into different groups (on the basis of their estrogen receptor status) and adjustments for the effect of other prognostic variables were taken into account. Our study shows that the two methods can be used indifferently to evaluate estrogen receptor status as a prognostic factor in breast cancer patients.

Ki-67 immunostaining in 322 primary breast cancers: associations with clinical and pathological variables and prognosis.

Cell-proliferation markers are very important in the clinical management of cancer patients, and the identification of Ki-67 (a monoclonal antibody that recognizes proliferating cells) can make it easier to define the level of proliferative activity. This study investigated the associations between the Ki-67 levels measured by means of immunohistochemistry, and other clinical and pathological variables and prognosis in 322 breast-cancer patients. A significant association was found (p < 0.001) between Ki-67 values and tumor size, nodal status, estrogen and progesterone receptor status; multivariate analysis showed that Ki-67 levels were associated with disease-free and overall survival, thus confirming that it is an independent prognostic variable. Various statistical approaches were used in an attempt to establish the best cut-off point for dividing patients into groups at high or low risk of relapse but, in this series, we could find no evidence leading to a single "best" cut-off point. We conclude that the quantitative level of Ki-67 could be used as a prognostic factor in breast-cancer patients.

Bone marrow micrometastases in 109 breast cancer patients: correlations with clinical and pathological features and prognosis.

BACKGROUND: The presence in bone marrow of cells which react with monoclonal antibodies against tumor-associated antigens has been proposed over the last few years as a new prognostic factor in breast cancer patients. PATIENTS AND METHODS: Bone marrow aspirates were obtained from 109 stage I and II breast cancer patients during or 2-4 weeks after primary surgery. The samples were processed for leukocyte separation on a Ficoll-Hypaque gradient and then used to prepare cytospin slides for immunocytochemical analysis. The slides were stained with a pool of monoclonal antibodies (MoAbs) which recognize tumor associated antigens, using the alkaline phosphatase anti-alkaline phosphatase method. The median follow-up was 36 months (range 15-62): 22 patients relapsed and 7 died. RESULTS: Thirty-four of the 109 patients (31.1%) had MoAb positive bone marrow cells. The bone marrow was positive in 28/74 (37.9%) patients who had the aspirate taken during surgery and in 6/35 (17.1%) who had it taken after surgery (p = 0.055). No association was found between bone marrow positivity and tumour size, nodal status, menopausal status, estrogen receptor positivity or the proliferative index. No association was found between bone marrow and prognosis: the log-rank test was 0.291 (p > 0.5) for OS and 0.023 for DFS; the hazard ratio (positive vs negative) was 1.51 for OS (95% CI: 0.33-6.86) and 0.93 for DFS (95% CI: 0.35-2.45). CONCLUSIONS: In our series, bone marrow positivity did not correlate with prognostic parameters or prognosis. Of interest is the relative excess of positivity when the bone marrow was obtained during surgery.

Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma.

The relationship between tumor proliferative activity and response to first-line chemotherapy and survival was investigated in 76 advanced breast cancer patients. Proliferative activity was determined by means of Ki-67 immunohistologic staining on primary tumors (55 patients) or at the relapse site (21 patients), and was classified as low ( < or = 25% of stained cells) or high ( > 25% of stained cells). The usual WHO response criteria were used. The median duration of follow-up was 18 months (range 3-58). Forty-seven patients (62%) had tumors with low, and 29 (38%) had tumors with a high rate of proliferative activity. The two groups were well balanced in terms of important variables such as disease-free survival, performance status, age, menopausal status, and the type of first-line chemotherapy (anthracycline-based regimens versus cyclophosphamide-methotrexate-5-fluorouracil). The estrogen receptor (ER) content, measured by means of immunohistochemical assay, was markedly different in the two groups, with 27/47 tumors with low proliferative activity (57%) and 6/29 with high-proliferative activity (21%) being ER positive ( > or = 45% of stained cells) (p = 0.003). Moreover, a significant difference in the metastatic pattern was also evident, with a higher incidence of bone and a lower incidence of soft tissue metastases in the group of patients with tumors with low proliferative activity (p = 0.004). Overall, 10/47 responses (21%: PR = 7, and CR = 3) were observed in the group with a low rate of proliferative activity, versus 14/29 (48%: PR = 9, and CR = 5) in the group with highly proliferative tumors, the difference being statistically significant (p = 0.03). When a multivariate analysis was performed, the only factor that retained independent prognostic significance was the predominant site of disease, particularly soft tissues (p = 0.003). Despite the difference in response rate, when survival analysis was performed according to the Kaplan-Meier method, no significant difference was observed in the two groups, but when the analysis was limited to responsive patients, the median survival observed in those with a low and those with a high rate of proliferation was 35 and 19 months respectively (p = 0.02). The same results were obtained when multivariate survival analysis was carried out using Cox's regression model. These data suggest that there is a link between tumor proliferative activity and response to chemotherapy in advanced breast cancer, and may indicate the need to use more intensive treatments in selected patients with highly proliferative tumors.

Estrogen receptors in 699 primary breast cancers: a comparison of immunohistochemical and biochemical methods.

BACKGROUND: Over the last few years, estrogen receptor (ER) determination by immunohistochemistry (ER-ICA) has been extensively used, but it still remains to be established whether this method can replace the standard biochemical technique using dextran-coated charcoal (ERDCC). PATIENTS AND METHODS: ER were determined by both the dextran-coated charcoal (DCC) method and immunohistochemistry (ICA) in 699 patients with primary breast cancer; other parameters (age, pathological T-pT- and nodal status -pN-, progesterone receptors by DCC, proliferative index by ICA) were also recorded. The 'best' cut-off for ERICA was evaluated by means of Receiver Operating Characteristics (R.O.C.) analysis; logistic regression analysis was used to find adequate 'weights' for stain intensity. RESULTS AND CONCLUSIONS: A significant correlation was found between the two methods (p < 0.001). R.O.C. analysis revealed that the 'best' cut-off for the ERICA score was 45% (sensitivity 0.810, specificity 0.804). Logistic regression analysis showed that an ERICA score which also considers staining intensity does not add any useful information concerning ER content in breast cancers.

Estrogen and progesterone receptors in breast cancer: correlation with clinical and pathological features and with prognosis.

Estrogen and progesterone receptor status was reviewed in 405 patients from prior adjuvant breast cancer trials at the University of Verona. Only 233 patients were actually examined with respect to hormone status and outcome. No relationship between hormone receptor status and most of the commonly followed prognostic signs, i.e. tumor size, nodal status, and age, was found. Overall survival was correlated with hormone receptor positivity for patients with more than 4 positive axillary nodes. Disease-free survival was correlated only with PgR positivity, in premenopausal and in T1 groups.

[Persistent generalized lymphadenopathy: pre-AIDS. First description of a case observed in Italy]. / Linfadenopatia persistente generalizzata: pre-AIDS. Prima descrizione di un caso osservato in Italia.

Persistent Generalized Lymphadenopathy (PGL) is considered a possible early stage of AIDS (pre-AIDS), caused by the same virus and characterized by the same immunologic abnormalities. So far, no case of PGL has been reported in Italy: therefore we describe a typical clinical history, immunologic studies and lymph-node histology of a young italian patient affected by PGL. We treated him with thymocyte protein extract (TP-1). We think PGL is not rare in Italy and probably a percentage of cases, especially in heroin addicts and homosexual males, is not recognized.