Non-haematological Side Effects Research Articles

Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study

Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard front-line treatment for follicular lymphoma. The combination of lenalidomide and rituximab has shown high efficacy in relapsed or refractory and untreated follicular lymphoma. We aimed to evaluate the safety and activity of the combination of lenalidomide and R-CHOP (R2-CHOP) in previously untreated patients with high burden follicular lymphoma. This single-arm, open-label, multicentre, phase 2 trial was done in 16 hospitals in France, all of which were Lymphoma Study Association (LYSA) sites. Eligible patients were aged 18-70 years and had previously untreated CD20-positive follicular lymphoma of grade 1, 2, or 3a; at least one high tumour burden criterion according to Groupe d'Etude des Lymphomes Folliculaires criteria; an Eastern Cooperative Oncology Group performance status score of 2 or less; and a minimum life expectancy of more than 3 months. Patients received induction therapy with six cycles of R2-CHOP every 3 weeks (one cycle involved standard R-CHOP on days 1-5, and 25 mg oral lenalidomide per day on days 1-14), followed by two rituximab infusions at 3-week intervals. The total treatment schedule was 24 weeks. Patients who achieved a complete or partial response to induction therapy received maintenance therapy consisting of one rituximab infusion every 8 weeks for 2 years. The primary outcome was the proportion of patients who achieved a complete response (complete response and complete response unconfirmed), according to International Workshop to Standardize Response Criteria, at the end of induction treatment. Safety was assessed in all patients who completed treatment. This trial is registered with ClinicalTrials.gov, number NCT01393756, and is closed to accrual. Between Dec 21, 2010, and Jan 25, 2012, 80 patients were enrolled, and 68 (85%) completed six cycles of R2-CHOP. At the end of the induction phase, 59 patients achieved a complete response (74%, 95% CI 63-83). 55 patients achieved a complete response at 30 months from enrolment (69%, 57-78). The most frequent adverse event was grade 4 neutropenia in 52 (65%) patients. The most frequent non-haematological side-effects included grade 1-2 sensory neuropathy in 28 (35%) patients and grade 1-2 transient rash in 27 (34%) patients. Four patients died during the study period; none of these deaths were judged to be related to treatment. Lenalidomide in combination with R-CHOP had an acceptable safety profile and showed anti-cancer activity in patients with previously untreated high burden follicular lymphoma. A future comparative study showing evidence of a survival advantage would be necessary for this combination to be proposed as a treatment for follicular lymphoma. French Ministry of Health, Celgene Corporation, and Amgen France.

Artesunate to treat severe malaria in travellers: review of efficacy and safety and practical implications.

Artesunate (AS) is the WHO first-line treatment of severe malaria in endemic countries, in adults and children. However, despite solid evidence that AS is safe and more effective than quinine in endemic areas, its deployment in non-endemic areas has been slow, due in part to the absence of a full good manufacturing practice (GMP) qualification (although prequalification has been granted in 2010). Prospective comparative trials were not conducted in travellers, but several retrospective studies and case reports are providing insights into the efficacy and safety of AS in imported severe malaria. We performed a systematic review on AS use in non-endemic areas for the treatment of imported severe malaria, using the Prisma method for bibliographic reports. Post-AS delayed haemolysis (PADH) was defined by delayed haemolytic episodes occurring 7-30 days after treatment initiation. We summarized prescription guidelines and generated answers to frequently asked questions regarding the use of AS in travellers with severe malaria. We analysed 12 retrospectives and 1 prospective study as well as 7 case reports of AS treatment in 624 travellers. Of 574 patients with reported outcome, 23 died (4%). No death was attributed to AS toxicity. Non-haematological side effects were uncommon and mainly included mild hepatitis, neurological, renal, cutaneous and cardiac manifestations. PADH occurred in 15% of the treated patients. No death or sequelae were reported. Overall blood transfusion was administered in 50% of travellers with PADH. AS is highly efficacious in travellers with severe malaria. The frequency of PADH supports the need of weekly follow-up of haematological parameters during 1 month. Full GMP qualification for the drug and rapid approval by drug agencies is warranted, backed by clear recommendations for optimal use.

ドキソルビシン／シクロホスファミド併用療法施行乳がん患者における化学療法誘発性悪心・嘔吐に対するアプレピタントの効果の検討

Chemotherapy-induced nausea and vomiting (CINV) is one of the most unpleasant non-haematological side effects that affects a patient's quality of life and leads to poor adherence to further chemotherapy. The current antiemetic guidelines recommend a three-drug combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant for patients undergoing highly emetogenic chemotherapy. However, the efficacy of aprepitant has not been well investigated in breast cancer patients receiving doxorubicin and cyclophosphamide (AC). We investigated the incidence of nausea and vomiting before and after the introduction of aprepitant therapy in breast cancer patients. In addition, we also attempted to identify the risk factors predisposing these patients to CINV development.

C21 - First Italian Multicentre Experience in using Ra-223 in patients with metastatic castration resistant prostate cancer (mCRPC)

Aim: Radium-223 is a novel bone-targeted &agr;-emitter associated with a survival benefit. We present first Italian multicentre experience in using Ra-223 in mCRPC patients. Material and methods: Data from mCRPC pts submitted to Ra-223 treatment over 3 years (August 2013-February 2016) were retrospectively collected. Information included Gleason score, age, prior treatments, bone symptoms, analgesic requirements, imaging and blood results. Ra-223 (50 kBq/kg) was administered every 4 weeks, up to the recommended 6 therapy cycles. Endpoints assessed included Overall Survival, pain score using Visual Analog scale (VAS), side effects, skeletal related events (SREs), disease biomarkers (PSA & ALP levels) and haematological parameters. Results: 90 pts received Ra-223 in three Italian Oncology/Radiotherapy/Nuclear Medicine Departments. Up to April 2016 only Pisa Departments data are available. Median age was 69 yr (range 52-85 yr). Median follow-up was 8,6 months (range 1-18 months). Mean Gleason score was 7. All patients received 3 previous lines of treatment on average. All bone scans showed foci of abnormal uptake. CT scans was used to exclude visceral involvement and the presence of pathologic lymph nodes with a diameter = 3 cm. 16/32 pts completed the recommended 6 cycles, of whom: 5 had bone pain reduction, 3 had worsening, 8 had absence of bone pain, remaining stable and not requiring analgesia. 16 pts stopped treatment : 3 cases of delay due to lack in radiopharmaceutical supplies, 9 developed extra skeletal disease/skeletal progression, 3 deteriorated clinically, 1 experienced SRE during treatment. About non-haematological toxicity we observed 3 cases of G3 anorexia, 3 cases of G1 diarrhoea, 2 cases of G2 asthenia. No patients developed SREs during follow-up. Concerning haematological toxicity, bone marrow failure resulted in 8 cases of G2 anaemia, 6 cases of G3 anaemia, 2 cases of G2 leucopoenia, 1 case of G2 thrombocytopenia. Regarding biomarkers, median ALP decline was 50%, median LDH decline was -5%, 32% of pts showed a reduction in PSA level. OS mean is at the present date about 8 months, and median OS has not been achieved yet. Conclusion: Ra-223 has a major impact on serum ALP levels, with negligible effect on PSA levels. Therefore, ALP appears to be a useful biomarker of therapy response. Haematological and non-haematological side effects were acceptable. Stability in pain or palliative effects occurred in the majority of patients.

264PD - Gain2: Adjuvant Phase III Trial Comparing an Intensified Dose-Dense Adjuvant Therapy with Enpc Compared with a Dose-Dense, Dose-Adapted Therapy with Dtec Dtdocetaxel in Patients with Primary Breast Cancer and a High Risk of Recurrence

ABSTRACT Aim: Combined chemotherapy requires compromises in terms of dosage and treatment interval due to toxicities. The sequential administration of monotherapies allows high doses of single substances and dose-dense intervals. So far, such regimens have proved to be very effective in early breast cancer with high risk of recurrence. Nab-paclitaxel (nP) leads to a more favorable toxicity profile and greater efficacy compared with solvent-based taxanes. Methods: The GAIN2 study compares toxicity and efficacy of a pre-defined dose-dense high-dose regimen (EnPC) with a dose-dense regimen, where single doses are adjusted depending on individual haematological and non-haematological toxicities (dtEC-dtD). Primary endpoint is the invasive disease-free survival in patients with primary node-positive or high-risk node-negative breast cancer. Two safety interim analyses after 200 and 900 patients who have completed chemotherapy are planned. The results of the first safety analysis will be presented. In addition to the standard analyses for haematological and non-haematological toxicities, any affections of the cranial nerves as well as the rate of macular degeneration and anaphylactic reactions are of special interest. Results: In terms of hematological adverse events, the rate of febrile neutropenia grade 3-4 (14% vs. 5%) and thrombocytopenia grade 3-4 (14% vs. 5%) was significantly increased in the EnPC arm. As for the non-haematological side effects, there were significantly more patients developing anorexia (grade 1-4) in the EnPC arm. There were no differences between the treatment arms for the toxicities of special interest. In the EnPC arm, 28% required dose-reductions due to hematological toxicities compared with only 11% in the dtEC dtD arm (p = 0.002). The dose could be escalated to the maximum in half of the patients receiving dtEC dtD. In 7% of women a reduction was required in the 4th cycle of docetaxel. Conclusions: Due to similar toxicity profiles, the study will be continued without changes. Disclosure: A. Schneeweiss: Honoraria, Research Funding and Advisory Role: Celgene and Roche; G. von Minckwitz: Honoraria and Research Funding: Amgen, Celgene and Roche; V. Mobus: Honoraria and Research Funding: Amgen, GSK, Sanofi-Aventis, Pfizer, Roche. All other authors have declared no conflicts of interest.

Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: A randomised phase II study

IntroductionMistletoe preparations, such as iscador, are common complementary medications. This randomised phase II study of iscador combined with carboplatin-containing regimens was conducted in chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC) patients to assess its influence on chemotherapy-related side-effects and QoL. MethodsPatients with advanced NSCLC were randomised to receive chemotherapy alone or chemotherapy plus iscador thrice weekly until tumour progression. Chemotherapy consisted of 21-day cycles of carboplatin combined with gemcitabine or pemetrexed. ResultsSeventy-two patients (control: 39; iscador: 33) were enrolled in the study. Most (65%) were in stage IV, and 62% had squamous histology. Median overall survival in both groups was 11months. Median TTP was 4.8months for the controls and 6months in the iscador arm (p=NS). Differences in grade 3–4 haematological toxicity were not significant but more control patients had chemotherapy dose reductions (44% versus 13%, p=0.005), grade 3–4 non-haematological toxicities (41% versus 16%, p=0.043) and hospitalisations (54% versus 24%, p=0.016). ConclusionNo effect of iscador could be found on quality of life or total adverse events. Nevertheless, chemotherapy dose reductions, severe non-haematological side-effects and hospitalisations were less frequent in patients treated with iscador, warranting further investigation of iscador as a modifier of chemotherapy-related toxicity.

Elacytarabine — A New Agent in the Treatment of Relapsed/Refractory Acute Myeloid Leukaemia

The prognosis for patients with relapsed acute myeloid leukaemia (AML) is poor, and effective treatments for this patient group remain a substantially unmet clinical need. Elacytarabine is a promising new cytotoxic nucleoside agent made by an esterification reaction between cytarabine and elaidic acid, currently in development for use in the treatment of relapsed/refractory AML. Unlike cytarabine, cellular uptake of elacytarabine is independent of human equilibrative nucleoside transporter-1 (hENT-1) and results in prolonged intracellular retention of the active nucleoside. In addition, elacytarabine inhibits DNA synthesis for twice the duration seen with cytarabine and exhibits a different intracellular distribution. A Phase I trial in patients with AML identified a recommended dose of 2,000 mg/m²/day for five days and showed limited non-haematological side effects, liver toxicity being dose-limiting. Elacytarabine can be safely combined with idarubicin. A recent Phase II trial demonstrated an improved complete remission rate and overall survival with elacytarabine as a single agent in patients with advanced AML, as compared with a historical control group treated with second salvage therapy. Following these encouraging results, the results of an ongoing Phase III clinical trial comparing elacytarabine with the investigator’s choice of standard of care are awaited with interest.

Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics

Development of advanced and high-throughput methods to study variability in human genes means we can now use pharmacogenomic analysis not only to predict response to treatment but also to assess the toxic action of drugs on normal cells (so-called toxicogenomics). This technological progress could enable us to identify individuals at high and low risk for a given side-effect. Pharmacogenomics could be very useful for stratification of cancer patients at risk of developing chemotherapy-induced peripheral neurotoxicity, one of the most severe and potentially permanent non-haematological side-effects of modern chemotherapeutic agents. However, study data reported so far are inconsistent, which suggests that methodological improvement is needed in clinical trials to obtain reliable results in this clinically relevant area.

Bortezomib-induced peripheral neuropathy: facts and genes – Authors' reply

Cavaletti states that a major bias was introduced in our report 1 Broyl A Corthals SL Jongen JL et al. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010; 11: 1057-1065 Summary Full Text Full Text PDF PubMed Scopus (183) Google Scholar because of the method we used to assess chemotherapy-induced peripheral neuropathy. Neuropathy was assessed with the National Cancer Institute's Common Toxicity Criteria (NCI-CTC) version 3.0, which requires limited neurological assessment to measure weakness, sensory alteration, and loss of deep tendon reflexes. At the start of the HOVON-65/GMMG-HD4 trial in 2005, data on neuropathy after bortezomib treatment was beginning to emerge; peripheral neuropathy was induced by bortezomib in a higher proportion of patients and with a higher proportion at grade 3–4 than by conventional treatment with vincristine. These findings formed the basis for dose-adaptation guidelines that were based on neuropathy assessment with the widely accepted NCI-CTC criteria. At that time, electrophysiological testing was not routinely done, because although these patients have small-fibre damage they are clinically asymptomatic. Bortezomib-induced peripheral neuropathy: facts and genesThe paper by Broyl and colleagues1 in the November, 2010, issue of The Lancet Oncology reports an extensive assessment of the gene-expression profile of patients with myeloma who are receiving bortezomib or vincristine treatment. The authors claim that specific genetic profiles might be associated with the risk of developing chemotherapy-induced peripheral neuropathy as well as with its course and severity. These results seem to be very important, because chemotherapy-induced peripheral neuropathy is one of the most severe, unpredictable, and potentially permanent non-haematological side-effects of the treatment of multiple myeloma. Full-Text PDF

BACOPP-D - An Etoposide-Free Dose-Escalated Polychemotherapy Regimen In Advanced Hodgkin's Lymphoma

AbstractAbstract 1754 Introduction:The development of the escalated BEACOPP regimen let to an improved outcome in patients with advanced Hodgkin's lymphoma (HD9 study of the GHSG). However, the application of high dose etoposide (cumulative 4,8 g/m2 per 8 cycles) seems to be associated with an increased incidence of secondary MDS and AML, respectively. Therefore, the aim of our multicenter pilot study was to evaluate the efficacy and toxicity of the etoposide-free as well as dose-intensified BACOPP-D protocol. Methods:From May 2000 until August 2008 a total of 139 untreated patients with Hodgkin's lymphoma (HL) stage IIB, III, and IV were treated with BACOPP-D which included cyclophosphamide 1250 mg/m2 (d1), adriamycin 25 mg/m2 (d1+2), dacarbazine 250 mg/m2 (d1-3), procarbazine 100 mg/m2 (d1-7), prednisolone 40 mg/m2 (d1-14), bleomycin 10 mg/m2 (d8) and vincristine 1,4 mg/m2 (maximum 2 mg, d8) at three-weekly intervals with granulocyte colony-stimulating factor (G-CSF). A consolidating involved field radiation (30 Gy) was performed only in patients who achieved less than CR following chemotherapy. Post-treatment follow-up included PET imaging. Results:All patients (median age 34 years, range 16–65; 86 male, 53 female) are assessable for toxicity and treatment outcome. We analyzed the acute toxicity for 1060 cycles of BACOPP-D. CTC grade III/IV haematological toxicities per patient were observed as follows: leukopenia 92%, anemia 40%, and thrombocytopenia 35%. CTC grade III/IV non-haematological side effects included documented infection (8%) and lung toxicity (one patient). Consolidation radiotherapy was given in 73 patients (52,5%). A total of 125 patients (89,9%) achieved complete remission, 9 patients (6,5%) achieved partial remission, five patients (3,6%) had progressive disease. At a median observation time of 46 months (5-109 months), 9 patients (6,5%) have relapsed, and 11 deaths were documented (4 HL-specific and 4 treatment related deaths, 1 death due to ruptured Meckel diverticulum with peritonitis, one 65 year-old woman died in CR following myocardial infarction and 1 death due to secondary malignancy). Only two patients developed a second neoplasia (hypopharyngeal carcinoma in an alcoholic; melanoma). The overall survival and progression free survival rates at 46 months were 89,7% and 85,9%, respectively. Discussion: BACOPP-D regimen appears as a feasible and effective treatment which induced a complete morphologic remission in a high proportion of patients with advanced HL. The treatment was associated with moderate acute toxicity. No secondary AML or MDS occurred so far. Disclosures:No relevant conflicts of interest to declare.

Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem‐cell transplantation or conventional chemotherapy: results of a Phase I clinical trial

Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose-limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low-dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high-dose therapy with stem-cell support. BPT comprised fixed doses of bendamustine (60 mg/m(2)) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty-four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression-free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non-haematological side effects were observed and no patient developed dose-limiting haematotoxicity. Transient grade 3-4 neutropenia was reported in 12 patients, and grade 3-4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study.

Fludarabine, Amsacrine, High-Dose Cytarabine and Total Body Irridation Followed by Allogeneic Stem Cell Transplantation for the Treatment of High Risk or Relapsed Acute Lymphoblastic Leukemia.

In this prospective study we examined the use of an intensified conditioning regimen followed by allogeneic blood-stem-cell transplantation (BSCT) for the treatment of young adults in physically good condition with relapsed or high risk acute lymphoblastic leukaemia (ALL). Eleven patients with ALL received FLAMSA chemotherapy (fludarabine 30mg/m2 - cytarabine 2000mg/m2 -amsacrine 100 mg/m2 on day −10, − 9, − 8and −7), Anti-Thymocyte-Globulin (ATG 20 mg/kg BW on day −6, −5 and −4) and fractionated TBI (2 x 2 Gy on day −3, − 2 and −1) followed by matched unrelated donor (n=10) or matched sibling donor (n=1) SCT. The principle reasons for high risk stratification were refractory disease during first-line induction therapy (6, 55%), relapse (2, 18%), extramedullary disease manifestation (1, 9%), ALL subtype (6, 55%), unfavorable cytogenetics (5, 45%) and white blood count >30000 μL at time of diagnosis (3, 27%). After a median follow-up time of 604 days (range 202 – 1042 days) 8 patients (73%) are alive and 3 patients (27%) died. The median overall survival was not reached. Two patients died after relapse on days +121 and +449, another patient died from treatment related complications (HUS-TTP) on day +87. One patient relapsed on day +200 and is currently alive, the remaining 7 patients are alive and free of desease. Treatment related toxicities were acceptable. With 6 out of 11 patients developing grade III/IV infections during neutropenia, infectious complications remained of major importance. Other non-haematological side effects seen within this group of patients were less frequent and almost exclusively limited to gastrointestinal toxicities. Five patients (45%) had grade III/IV mucositis and 5 patients (45%) had grade III/IV nausea, while 4 patients (36%) showed grade III/IV diarrhoea. There was no case of acute toxicity related to the cardiavascular or central nervous system. The incidence of acute GvHD (aGvHD) was 36% (n = 4) and limited to grades II-III. Eight patients were evaluable for chronic GvHD (cGvHD). Out of those 4 patients (36%) developed cGvHD (3 limited disease, 1 extensive disease). We conclude that allogeneic transplatation after the FLAMSA-ATG-TBI regimen is feasible and provides effective therapy for this group of high-risk patients.

BACOPP-D - An Etoposide-Free Dose-Escalated Polychemotherapy Regimen in Advanced Hodgkin Lymphoma.

Introduction: The development of the escalated BEACOPP regimen let to an improved outcome in patients with advanced Hodgkin Lymphoma (HD9 study of the GHSG). However, the application of high dose etoposide (cumulative 4,8 g/m2 per 8 cycles) seems to be associated with an increased incidence of secondary MDS and AML, respectively. Therefore, the aim of our multicenter pilot study was to evaluate the efficacy and toxicity of the etoposide free as well as dose intensified BACOPP-D protocol.Methods: Since May 2000 a total of 115 patients with Hodgkin Lymphoma (HL) stage IIB, III, and IV were treated with BACOPP-D which included cyclophosphamide 1250 mg/m2 (d1), adriamycin 25 mg/m2 (d1+2), dacarbazine 250 mg/m2 (d1-3), procarbazine 100 mg/m2 (d1-7), prednisolone 40 mg/m2 (d1-14), bleomycin 10 mg/m2 (d8) and vincristine 1,4 mg/m2 (maximum 2 mg, d8) at three-weekly intervals with granulocyte colony-stimulating factor (G-CSF). A consolidating involved field radiation (30 Gy) was performed only in patients who achieved less than CR following chemotherapy. Post-treatment follow-up included PET imaging.Results: Until now 97 patients (median age 35 years, range 17-65; 61 male, 36 female) are assessable for toxicity and treatment outcome. We analyzed the acute toxicity for 728 cycles of BACOPP-D. CTC/WHO grade III/IV haematological toxicities per patient were observed as follows: leukopenia 93%, anemia 39%, and thrombocytopenia 33%. CTC grade III/IV non-haematological side effects included documented infection (4%) and lung toxicity (one patient). A total of 85 patients (88%) achieved complete remission, 9 patients (9%) achieved partial remission, three patients (3%) had progressive disease. At a median observation time of 39 months (0,9-77 months), five patients have relapsed, and nine deaths were documented (4 HL-specific and 3 treatment related deaths, 1 death due to ruptured Meckel diverticulum with peritonitis, one 65 year-old woman died in CR following myocardial infarction). One patient developed a second neoplasia (hypopharyngeal carcinoma in an alcoholic). The overall survival and freedom from treatment failure rates at 39 months were 91% and 85%, respectively. FDG-PET scans after BACOPP-D chemotherapy were performed in 68 of 97 patients. PET scans revealed no increased FDG uptake in 48/68 patients (71%), in 20 patients (29%) increased FDG uptake was detected. In the group of patients with increased FDG uptake, one patient developed progressive disease and four patients relapsed. In the group with PET-negative findings no patient relapsed.Diskussion: BACOPP-D regimen appears as a feasible and effective treatment which induced a complete morphologic and metabolic remission in a high proportion of patients with advanced HL. The treatment was associated with moderate acute toxicity. No secondary AML or MDS occurred until now.

Phase II trial of pegylated liposomal doxorubicin (Caelyx™) plus Gemcitabine in chemotherapeutically pretreated patients with advanced breast cancer

A phase II trial was performed to investigate the efficacy and tolerance of combined gemcitabine and liposomal doxorubicin±recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapeutically pretreated metastatic breast cancer. Thirty-four patients were entered in this trial. Chemotherapy consisted of gemcitabine and liposomal doxorubicin±G-CSF. Twenty seven patients received this regimen as 2nd line therapy, five patients as 3rd line and two patients as 4th line therapy after having failed taxane- and/or anthracycline-based chemotherapy or other drug combinations. After a median of six courses, an overall response rate of 26% (9 PR in 34 enrolled patients) was observed; 14 patients had disease stabilization (41%), and eight (24%) progressed. Three patients were not evaluable for response due to anaphylaxis after the first course and protracted thrombocytopenia. The median TTP was 7.5 months, and median overall survival was 15 months. Myelosuppression was the most frequently observed toxicity. Non-haematological side effects were generally mild to moderate. Our data suggest that gemcitabine and liposomal doxorubicin±G-CSF is an effective and fairly well tolerated regimen for chemotherapeutically pretreated patients with advanced breast cancer.

Randomised phase II study evaluating weekly docetaxel in combination with cisplatin and 5FU or capecitabine in metastatic oesophago-gastric cancer

4067 Background: Docetaxel (T), cisplatin (C) and 5FU (F) are active agents in oesophago-gastric cancer. A recent phase III study using TCF achieved a survival advantage but was associated with high rates of haematological toxicity (30% incidence of febrile neutropenia/neutropenic infection) as well as non-haematological side effects (Moiseyenko et al, 2005 Pr ASCO abstr 4002). Weekly docetaxel is associated with a lower incidence of haematological toxicity. This randomised phase II study aimed to test weekly docetaxel based combination chemotherapy regimens with the aim of maintaining the activity of docetaxel based combination regimens but reducing toxicity. Methods: Eligibility included; histologically confirmed, metastatic oesophageal or gastric (OG) carcinoma, measurable disease, PS0–2, adequate organ function, no prior treatment, informed consent. Pts were randomised to receive weekly (w) T 30 mg/m2 d1, 8 C 60 mg/m2 d1 F 200 mg/m2/d continuously q 3w or wT 30 mg/m2 d1, d8 and capecitabine (×)1600 mg/m2/d d1–14 q3w. The primary endpoint is confirmed response rate (RR), with each arm analysed independently. Simon’s 2 stage design was used, with 5/21 responses required in the first stage to allow continuation to 48 pts per arm. Results: 79 pts enrolled to date. Protocol specified interim analysis of efficacy after 21 pts per arm and of toxicity after 25 pts per arm ( Table ). In the first 21 pts per arm; 12 responses (11 confirmed) in wTCF arm, 6 responses (5 confirmed) in wTX arm. Trial continues accrual to target of 48 pts per arm. Complete accrual expected by April 2006. Updated data will be presented at the meeting. Conclusions: wTCF and wTX have encouraging activity and and a more favourable toxicity profile than TCF administered 3-weekly. [Table: see text] [Table: see text]

Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I–II study

The aim of this study was to evaluate feasibility and toxicity of escalating doses of epirubicin and paclitaxel plus fixed dose of etoposide and to define the activity of the triplet in extensive disease small-cell lung cancer. Thirteen patients entered the phase I study: the maximum tolerated doses were epirubicin (EpiDX) 90 mg m−2 and paclitaxel (P) 175 mg m−2 with febrile neutropenia as dose-limiting toxicity. The recommended schedule for this regimen for the phase II study was EpiDX 75 mg m−2, P 175 mg m−2, etoposide (E) 100 mg m−2 intravenous (fixed dose) days 1–3 with courses repeated every 21 days. The prophylactic use of colony-stimulating factors (CSFs) was not allowed. Twenty patients entered the phase II trial: median age was 61 years (range 50–70), median Eastern Cooperative Oncology Group performance status 0 (0–2); nine patients had visceral disease and 17 had more than two metastatic sites. A total of 100 courses were administered with a median of 5 (range 1–6) per patients. Main toxicity (NCI-CTC) was myelosuppression: neutropenia grades 3 and 4 in 16 and 35% of the courses, respectively. Seven episodes of febrile neutropenia were documented and one patient required hospital admission. Nonhaematological toxicity was moderate. Seven out of 19 evaluable patients achieved a complete response (37%), nine patients (47.3%) a partial response with an overall response rate of 84.2% ((95% confidence interval=60.4–96.6)). In this poor prognostic population of patients the triplet epirubicin/paclitaxel/etoposide showed high antitumour activity with mild nonhaematological side effects. The use of CSFs should be able to improve the haematological profile.

Early and tardive skin adverse events in chronic myeloid leukaemia patients treated with imatinib

Imatinib related non-haematological side-effects are reported in <10% of chronic myeloid leukaemia patients and include oedema, weight gain, nausea, vomiting and muscle cramps. Cutaneous reactions are well-recognized events occurring mostly in patients treated at doses of 600 mg/d and higher, either in stable or progressive disease. We report on our experience relating to dermatological toxicities in imatinib treated CML patients showing a spectrum of skin reactions ranging from rashes to cutaneous carcinoma.

Weekly paclitaxel (T) and pegylated liposomal doxorubicin (PLD) as first line treatment in metastatic breast cancer (MBC) patient

704 Background: Paclitaxel-Doxorubicin combination chemotherapy is highly active in metastatic breast cancer patients (pts) but may be cardiotoxic in a small percentage of cases. PLD is a new formulation of Doxorubicin with significant reduced cardiac toxicity and for this reason PLD can be given safe in elderly patients with cardiac risk factors or in younger patients with prior exposure to anthracycline-containing regimens. The main side effect of PLD is Hand-Foot syndrome but when given in intervals not below 4 weeks and with a dose intensity not exceeding 10 mg/sqm per week, this side effects is clearly reduced. Methods: : We carried out a phase 2 study to verify the activity of P 70 mg/sm weekly day 1–8-15 and PLD 30 mg/mq every four weeks. Inclusion Criteria were: age <75, Performance Status (PS)<=2, normal kidney and liver function, absence of brain symptomatic metastases, adjuvant chemotherapy with anthracyclines (relapse free survival>12months) or patients with LVEF beetween 40–50%, informed consent. Results: Out of the 11 patients so far included, 9 were evaluable for toxicity and response. Five patients (55.5%) showed a response including 4 PR and 1 CR, 1 patients (11.1 %) obtained SD and 2 pts (33.3%) progressed. Median time to progression and median survival have to be reached. Haematological side effects were: Neutropenia G1–2 in 4 pts (44.4%), thrombocytopenia G1–2 in 3 pts (33.3%). The non-haematological side effects were mild with the total absence of grade 3–4 toxicities. Only 3 patients (33.3%) experienced grade 2 nausea and stomatitis. G1–2 peripheral sensory neuropathy was seen in 1 pt (11.1%). Hand-Foot syndrome G1–2 occurred in 2 pts (22.2%). Conclusions: The treatment with weekly Paclitaxel and PLD with this schedule appears to be a well tolerated therapy with an interesting activity in this subset of patients. No significant financial relationships to disclose.

Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial

Surgery is the main treatment for localised renal cell carcinoma, but use of radical nephrectomy for metastatic disease is highly controversial. We aimed to establish whether radical nephrectomy done before interferon-alfa-based immunotherapy improved time to progression and overall survival (primary endpoints) compared with interferon alfa alone. We included 85 patients from June, 1995, to July, 1998: two (one per group) were ineligible. 42 of the 83 participants were randomly assigned combined treatment (study group) and 43 immunotherapy alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at entry. In study patients, surgery was done within 4 weeks of randomisation, and immunotherapy (5x10(6) IU/m(2) subcutaneously three times per week) started 2-4 weeks later. In controls, immunotherapy was started within 1 working day of randomisation. Follow-up visits were monthly. All analyses were by intention to treat. 40 (53%) of 75 patients received at least 16 weeks of interferon-alfa treatment, which was also the median duration of treatment. Time to progression (5 vs 3 months, hazard ratio 0.60, 95% CI 0.36-0.97) and median duration of survival were significantly better in study patients than in controls (17 vs 7 months, 0.54, 0.31-0.94). Five patients responded completely to combined treatment, and one to interferon alfa alone. Dose modification was necessary in 32% of patients, most commonly because of non-haematological side-effects. Radical nephrectomy before interferon-based immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma who present with good performance status.

Phase I Dose Escalation Study of Gemcitabine and Paclitaxel Plus Colony-Stimulating Factors in Previously Treated Patients with Advanced Breast and Ovarian Cancer

Gemcitabine and paclitaxel (PTX) are among the most active new drugs in advanced breast and ovarian cancer. In this Phase I study, we used fixed doses of gemcitabine administered on days 1 and 8 and escalating doses of paclitaxel on day 1 of a 21-day cycle in patients with pretreated metastatic breast or ovarian cancer. The dose of gemcitabine was fixed at 1000mg/m2; PTX was commenced in the first small patient group at a dose of 90mg/m2, which was then escalated in subsequent groups by 30mg/m2 per step. From the third dose level onwards, all patients received granulocyte colony-stimulating factor 300μg by subcutaneous injection on days 5 and 6, and granulocyte macrophage colony-stimulating factor on days 15–18. Cohorts of at least 3 patients were treated at each dose level. Dose escalation was stopped if at least a third of the patients in a given cohort had dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia, or grade 3–4 non-haematological toxicity. The maximum tolerated dose (MTD) was defined as the dose level immediately below that causing DLT in one-third of the patients or more. Evaluation of the tumour response was performed every three cycles.Forty-five patients (31 with breast cancer, 14 with ovarian cancer) were treated at seven different dose levels. Only at the seventh PTX dose level was DLT observed after the first course of therapy: three grade 4 neutropenia, one grade 4 thrombocytopenia, and one grade 4 anaemia. DLT occurred in 5/6 patients at at PTX dose of 270mg/m2; therefore dose escalation was stopped at that level and the dose immediately before it (PTX 240mg/m2) was considered as the MTD and recommended for further studies.No toxic deaths occurred. Grade 3–4 uncomplicated neutropenia was observed in four patients. Three had uncomplicated grade 3–4 thrombocytopenia. One patient had grade 3 and one grade 4 anaemia. Nonhaematological side effects were generally mild. Among 30 evaluable patients with metastatic breast cancer, four complete responses (CR) (13%) and 12 partial responses (PR) (40%) were observed, for an overall response rate of 53% (95% confidence interval (CI) 34–72). The median duration of response was 31 weeks. Among 13 evaluable patients with advanced ovarian cancer, one CR (8%) and five PRs (38%) were observed, for an overall response rate of 46% (95% CI 19–78). The median duration of response was 32 weeks.Our study shows that gemcitabine and PTX can be administered in combination in patients with breast and ovarian cancer without unexpected toxicities and with encouraging therapeutic results.