Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

PURPOSE: Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. METHODS: We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. RESULTS: The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. CONCLUSION: Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Metastatic basal cell carcinoma to the bone: A case of bone metastasis in uncommon sites.

Basal cell carcinoma (BCC) is the most common malignant tumor of the skin. Despite the indolent nature, metastatic BCC can occur, albeit rarely. Metastasis to the bone is very rare. From its approval, mBCC patients are treated with vismodegib, a selective hedgehog pathway inhibitor. Unfortunately, in recent period, it was demonstrated an emergence of drug resistance, due to Smoothened (SMO) mutation. To date, several groups are studying the effectiveness of immunotherapy in BCC. Clinical trials with Immune Checkpoint Inhibitors are ongoing. We report the rare case of a man with multiple bony metastasis, with a resistance to vismodegib, and we evaluated all manuscripts in literature reporting bone metastasis. Moreover, we review all the manuscripts in literature reporting bone metastasis, and we summarize the main therapeutic strategies, and the further perspectives.

Cyclin-dependent kinase inhibitors plus aromatase inhibitor in first-line treatment hormone-receptor-positive/HER2-negative advanced breast cancer women with or without visceral disease: time to turn page?

Breast cancer is the most common female tumour type and accounts for the leading cancer mortality in women worldwide. Up to 75% of breast cancers express the oestrogen receptor or progesterone receptor (hormone-receptor-positive). Aromatase inhibitors were the preferred first-line treatment option. New and acquired resistance to hormonal blockade has led to the development of targeted treatments. Cyclin-dependent kinases (CDKs) are a large family of serine-threonine kinases that play an important role in regulating cell cycle progression: palbociclib, ribociclib, and abemaciclib. We conducted a study to evaluate the efficacy of CDK inhibitors (CDKi) plus aromatase inhibitor in hormone-receptor-positive/HER2-negative ABC patients with visceral disease, postponing the use of chemotherapeutic agents and strengthening the power of endocrine agents. We enrolled 22 patients treated with CDKi (palbocilib) plus aromatase inhibitor (group A) and 38 patients treated with chemotherapy (group B). Our small study confirms the effectiveness of treatment with CDKi plus aromatase inhibitor, even in patients with visceral metastases, when compared with chemotherapy.

Short Peptide Vaccine Induces CD4+ T Helper Cells in Patients with Different Solid Cancers.

Previous cancer vaccination trials often aimed to activate CD8(+) cytotoxic T-cell (CTL) responses with short (8-10mer) peptides and targeted CD4(+) helper T cells (TH) with HLA class II-binding longer peptides (12-16 mer) that were derived from tumor antigens. Accordingly, a study of immunomonitoring focused on the detection of CTL responses to the short, and TH responses to the long, peptides. The possible induction of concurrent TH responses to short peptides was widely neglected. In a recent phase I vaccination trial, 53 patients with different solid cancers were vaccinated with EMD640744, a cocktail of five survivin-derived short (9- or 10-mer) peptides in Montanide ISA 51VG. We monitored 49 patients and found strong CD8(+) T-cell responses in 63% of the patients. In addition, we unexpectedly found CD4(+) TH cell responses against at least two of the five short peptides in 61% (23/38) of the patients analyzed. The two peptides were recognized by HLA-DP4- and HLA-DR-restricted TH1 cells. Some short peptide-reactive (sp)CD4 T cells showed high functional avidity. Here, we show that a short peptide vaccine is able to activate a specific CD4(+) T-cell repertoire in many patients, facilitating a strong combined CD4(+)/CD8(+) T-cell response.

Pregnancy after breast cancer: Are young patients willing to participate in clinical studies?

Young patients with breast cancer (BC) are often concerned about treatment-induced infertility and express maternity desire. Conception after BC does not seem to affect outcome, but information in estrogen-receptor positive (ER+) disease is not definitive. From September 2012-March 2013, 212 evaluable patients with ER+ early BC, <37 years at diagnosis, from 5 regions (Europe/US/Canada/Middle-East/Australia) answered a survey about fertility concerns, maternity desire and interest in a study of endocrine therapy (ET) interruption to allow pregnancy. Overall, 37% of respondents were interested in the study; younger patients (≤30 years) reported higher interest (57%). Motivation in younger patients treated >30 months was higher (83%) than in older women (14%), interest was independent of age in patients treated for ≤30 months. A prospective study in this patient population seems relevant and feasible. The International-Breast-Cancer-Study-Group (IBCSG), within the Breast-International-Group (BIG) - North-American-Breast-Cancer-Groups (NABCG) collaboration, is launching a study (POSITIVE) addressing ET interruption to allow pregnancy.

Estramustine phosphate sodium in heavily pretreated patients with metastatic breast cancer: a retrospective consecutive case series.

BACKGROUND: Estramustine phosphate sodium (EMP) is an oral agent poorly developed--although active--in patients with metastatic breast cancer (MBC). To resume interest in EMP in MBC, we analyzed a retrospective series of consecutive patients with estrogen receptor-positive disease. METHODS: EMP was given orally at a dose of 140 mg daily. Treatment discontinuation rates due to progressive disease/toxicity and response rates were assessed. RESULTS: Twenty postmenopausal patients with mainly visceral disease were treated with EMP, in five cases in combination with other anticancer drugs. Median numbers of previous chemotherapies and hormonal treatments were six and four, respectively. From the entire cohort, one complete response and four partial responses were observed. The proportions of patients free of progression at 6 and 12 months were 39 and 8 %, respectively. Six patients discontinued EMP, three each for toxicity and adverse events. CONCLUSION: Good disease control was obtained in heavily pretreated MBC patients receiving EMP. Toxicity was manageable and reversible although treatment discontinuation has to be considered. A prospective study should be encouraged to identify the optimal use of the drug.

Dose-response relationship in phase i clinical trials: a European Drug Development Network (EDDN) Collaboration Study.

INTRODUCTION: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. EXPERIMENTAL DESIGN: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. RESULTS: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). CONCLUSION: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD).

Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors.

PURPOSE: Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. EXPERIMENTAL DESIGN: This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 µg. Secondary objectives included safety, tolerability, and clinical efficacy. RESULTS: In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. CONCLUSIONS: Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors.

The aim of this phase I study was to identify a feasible dose and schedule for the combination of cisplatin and trabectedin. The regimen evaluated consisted of cisplatin at a fixed dose of 75 mg/m(2) 1-hour intravenous (i.v.) infusion followed by escalating doses of trabectedin 3-hour i.v. infusion, both administered on day 1 every 3 weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7 days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75 mg/m(2)). The immediately lower dose (trabectedin 0.60 mg/m(2)) was evaluated in a total of 8 patients; no DLTs occurred and this was declared the recommended dose (RD). The safety profile of the combination at this dose and schedule was consistent with the known side effects of each agent alone: nausea, fatigue, transient transaminase elevations and neutropenia. No new or unexpected adverse reactions were observed. Two partial responses were reported at the RD in patients with pretreated ovarian cancer. Comparison with population pharmacokinetic data suggests a PK interaction between trabectedin and cisplatin leading to increased plasma exposure of trabectedin in the first 48 h, lower platinum clearance and longer half-life. In conclusion, although the trabectedin dose achieved with this combination was low (50 % of single-agent when given q3wks), this day 1 q3wks trabectedin plus cisplatin combination showed a feasible administration, a tolerable safety profile and some antitumor activity.

A phase I study of the oral platinum agent satraplatin in combination with oral vinorelbine in patients with advanced solid malignancies.

BACKGROUND: The broad spectrum of antitumor activity of the oral platinum satraplatin (S) and vinorelbine (V) were the rationale for performing a phase I trial to define the maximum tolerated (MTD) and the recommended (RD) dose in adult patients with advanced solid tumors. PATIENTS AND METHODS: 4 dose levels (DLs) of S (mg/m(2)/day, days 1-5) and V (mg/m(2)/day, days 1, 8, 15, and 22) every 28 days were explored: S60/V60 on days 1, 8 and 15 only; S60/V60; S70/V60; and S80/V60. Subsequently, 3 further DLs were evaluated with V omitted on day 22: S70/V60, S80/V60, and S80/V80. RESULTS: Treating 27 patients, the MTD was S80/V80 on days 1, 8, and 15, with 2 dose-limiting toxicities in 2 patients (nausea and vomiting grade (G) 3 with skipping of V on day 15, and neutropenia G4 with infection). The RD was S80/V60 on days 1, 8, and 15. The most frequent toxicities (any G) were nausea (70%), diarrhea (59%), anorexia (37%), vomiting (33%), asthenia (26%), constipation (26%), and paresthesia (18%). Partial responses were observed in 2 platinum-sensitive ovarian cancer patients and in 1 prostate cancer patient. CONCLUSION: The combination of S and V is tolerable at a DL of S80/V60 on days 1, 8, and 15; further evaluations in platinum- and V-sensitive tumor types would be of interest.

T-cell activation by treatment of cancer patients with EMD 521873 (Selectikine), an IL-2/anti-DNA fusion protein.

BACKGROUND: EMD 521873 (Selectikine or NHS-IL2LT) is a fusion protein consisting of modified human IL-2 which binds specifically to the high-affinity IL-2 receptor, and an antibody specific for both single- and double-stranded DNA, designed to facilitate the enrichment of IL-2 in tumor tissue. METHODS: An extensive analysis of pharmacodynamic (PD) markers associated with target modulation was assessed during a first-in-human phase I dose-escalation trial of Selectikine. RESULTS: Thirty-nine patients with metastatic or locally advanced tumors refractory to standard treatments were treated with increasing doses of Selectikine, and nine further patients received additional cyclophosphamide. PD analysis, assessed during the first two treatment cycles, revealed strong activation of both CD4+ and CD8+ T-cells and only weak NK cell activation. No dose response was observed. As expected, Treg cells responded actively to Selectikine but remained at lower frequency than effector CD4+ T-cells. Interestingly, patient survival correlated positively with both high lymphocyte counts and low levels of activated CD8+ T-cells at baseline, the latter of which was associated with enhanced T-cell responses to the treatment. CONCLUSIONS: The results confirm the selectivity of Selectikine with predominant T-cell and low NK cell activation, supporting follow-up studies assessing the clinical efficacy of Selectikine for cancer patients.

A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma.

BACKGROUND: The safety, pharmacokinetics (PK) and pharmacodynamics of CEP-18770, a new peptide boronic acid proteasome inhibitor, have been investigated after intravenous administration on days 1, 4, 8 and 11 of every 21d cycle in patients with solid tumours and multiple myeloma (MM). PATIENTS AND METHODS: Thirty-eight patients were treated with CEP-18770 at escalating doses from 0.1 to 1.8mg/m(2) where 2 out of 5 patients showed dose limiting toxicities. The maximum tolerated/recommended dose (MTD/RD) of 1.5mg/m(2) was tested in 12 additional patients. Skin rash was dose-limiting and occurred in 53% of patients; other frequent toxicities were asthenia (29%), stomatitis (21%) and pyrexia (16%). No significant peripheral neuropathy was observed. PK in plasma was linear with a half-life of the elimination phase of 62.0±43.5h. Proteasome inhibition in peripheral blood mononuclear cells was dose related in MM patients; it was of 45.4±11.5% at the RD. CONCLUSIONS: CEP-18770 showed a favourable safety profile with lack of neurotoxicity and linear plasma PK. The definition of the optimal biological dose and schedule of treatment is actively pursued because of the high incidence of skin toxicity of the twice a week schedule.

A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours.

BACKGROUND: EMD 521873 (Selectikine), an immunocytokine comprising a DNA-targeting antibody, aimed at tumour necrosis, fused with a genetically modified interleukin-2 (IL-2) moiety, was investigated in this first-in-human phase I study. METHODS: Patients had metastatic or locally advanced solid tumours failing previous standard therapy. Selectikine was administered as a 1-hour intravenous infusion on 3 consecutive days, every 3 weeks. A subgroup of patients also received 300 mg/m(2) cyclophosphamide on day 1 of each cycle. Escalating doses of Selectikine were investigated with the primary objective of determining the maximum tolerated dose (MTD). RESULTS: Thirty-nine patients were treated with Selectikine alone at dose levels from 0.075 to 0.9 mg/kg, and nine were treated at doses of 0.45 and 0.6 mg/kg in combination with cyclophosphamide. A dose-dependent linear increase of peak serum concentrations and area under curve was found. The dose-limiting toxicity was grade 3 skin rash at the 0.9 mg/kg dose-level; the MTD was 0.6 mg/kg. Rash and flu-like symptoms were the most frequent side-effects. No severe cardiovascular side-effects (hypotension or vascular leak) were observed. At all dose-levels, transient increases in total lymphocyte, eosinophil and monocyte counts were recorded. No objective tumour responses, but long periods of disease stabilisation were observed. Transient and non-neutralising Selectikine antibodies were detected in 69% of patients. CONCLUSIONS: The MTD of Selectikine with or without cyclophosphamide administered under this schedule was 0.6 mg/kg. The recommended phase II dose was 0.45-0.6 mg/kg. Selectikine had a favourable safety profile and induced biological effects typical for IL-2.

Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study.

PURPOSE: Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. PATIENTS AND METHODS: After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). RESULTS: The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors. CONCLUSION: Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

Patient selection for oncology phase I trials: a multi-institutional study of prognostic factors.

PURPOSE: The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials. PATIENTS AND METHODS: Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis. RESULTS: The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality. CONCLUSION: Patient selection using any of these prognostic scores will reduce non-drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.

Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: a multi-institutional retrospective analysis.

BACKGROUND: Patients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy. PATIENTS AND METHODS: We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. RESULTS: The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors. CONCLUSIONS: The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy.

A phase I study of the oral platinum agent satraplatin in sequential combination with capecitabine in the treatment of patients with advanced solid malignancies.

BACKGROUND: The broad spectrum of antitumor activity of both the oral platinum analogue satraplatin (S) and capecitabine (C), along with the advantage of their oral administration, prompted a clinical study aimed to define the maximum tolerated dose (MTD) of the combination. PATIENTS AND METHODS: Four dose levels of S (mg/m(2)/day) and C (mg/m(2)/day) were evaluated in adult patients with advanced solid tumors: 60/1650, 80/1650, 60/2000, 70/2000; a course consisted of 28 days with sequential administration of S (days 1-5) and C (days 8-21) followed by one week rest. RESULTS: Thirty-seven patients were treated, 24 in the dose escalation and 13 in the expansion phase; at the MTD, defined at S 70/C 2000, two patients presented dose limiting toxicities: lack of recovery of neutropenia by day 42 and nausea with dose skip of C. Most frequent toxicities were nausea (57%), diarrhea (51%), neutropenia (46%), anorexia, fatigue, vomiting (38% each). Two partial responses were observed in platinum sensitive ovarian cancer and one in prostate cancer. CONCLUSION: At S 70/C 2000 the combination of sequential S and C is tolerated with manageable toxicities; its evaluation in platinum and fluorouracil sensitive tumor types is worthwhile because of the easier administration and lack of nephro- and neurotoxicity as compared to parent compounds.

Thrombotic thrombocytopenic purpura associated with renal failure after autologous transplantation for multiple myeloma successfully treated with rituximab.

Thrombotic thrombocytopenic purpura (TTP) is a haematological syndrome characterised by a dramatic onset requiring an urgent treatment with plasma exchange (PE). However, the prognosis is still dismal for PE related complications, a rate of failure and remarkable frequencies of relapse. TTP post transplantation is largely described as an outstanding, unusual complication of allogenic transplantation, but it is rarely mentioned after autologous transplantation. We describe a 62-year-old Caucasian patient who presented with TTP, accompanied by renal failure, after an autologous transplantation for multiple myeloma. PE together with hemodialysis was rapidly initiated but without any benefit. Since empirical administration of Rituximab, anti CD20 monoclonal antibody,was reported to be effective, we administered four courses of Rituximab inducing a complete remission of TTP and subsequently of the renal failure. This response to Rituximab in TTP post transplantation is suggestive of a possible implication of B-lymphocytes in the pathogenesis of TTP and it paves the way for an investigational approach in this settings.