Ovarian cancer in elderly patients: carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in late relapse: a Gynecologic Cancer Intergroup (GCIG) CALYPSO sub-study.

BACKGROUND: CALYPSO (CAeLYx in Platinum Sensitive Ovarian) patients compared carboplatin-pegylated liposomal doxorubicin (C-PLD) with carboplatin-paclitaxel (C-P) in patients with late-relapsing recurrent ovarian cancer (ROC). We analyzed outcomes in patients ≥70 years. PATIENTS AND METHODS: Nine hundred and seventy-six patients with taxane-pretreated ROC relapsing >6 months after first- or second-line platinum-based therapy were randomly assigned to 4-weekly C area under the curve (AUC) 5 plus PLD 30 mg/m(2) or 3-weekly C AUC 5 plus P 175 mg/m(2) for six or more cycles. RESULTS: One hundred and fifty-seven (16%) patients ≥70 years (median: 74 years, C-PLD; 73 years, C-P; range 70-82 years) were included (n = 71, C-PLD; n = 86, C-P). In comparing elderly and younger, elderly patients experienced fewer grade ≥2 allergic reactions (P = 0.005) but more grade ≥2 sensory neuropathy (P = 0.007). Myelosuppression did not differ with age. Elderly patients completed planned treatment as frequently as younger (79%, C-PLD; 82%, C-P). In comparing arms within elderly patients, C-P was associated with more grade ≥2 alopecia, sensory neuropathy, arthralgia/myalgia (P < 0.001 for all), severe leukopenia plus febrile neutropenia; C-PLD was associated with more grade ≥2 hand-foot syndrome (P = 0.005). Median progression-free survival was 11.6 months (C-PLD) and 10.3 months (C-P; P = 0.44). CONCLUSIONS: Patients ≥70 years experienced more neuropathy, with a higher incidence in the C-P arm. Similar to all study patients, C-PLD provided a better therapeutic index with less toxicity than C-P in elderly women with platinum-sensitive ROC.

Carboplatin and pegylated liposomal doxorubicin for advanced ovarian cancer: preliminary activity results of the MITO-2 phase III trial.

BACKGROUND: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. PATIENTS AND METHODS: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m(2) or PLD 30 mg/m(2) every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). CONCLUSIONS: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.

Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study.

This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) were > or =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs > or =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.

Role of pegylated liposomal doxorubicin (PLD) in epithelial ovarian cancer.

Pegylated liposomal doxorubicin (PLD, Caelyx) is an emerging option for patients with recurrent ovarian carcinoma. Several phase II studies showed promising activity of PLD in recurrent ovarian cancer patients with response rate ranging from 16 to 25%. A phase III randomized trial compared PLD 50 mg/m2 day 1 every 4 weeks with Topotecan 1.5 mg/m2 daily for 5 days q 21 in recurrent ovarian cancer patients. No differences in progression free survival and overall survival were documented between treatment arms in the general population but a survival advantage was reported for platinum-sensitive subset. Our experience with PLD in the treatment of ovarian cancer is reported in this review article. Pegylated liposomal doxorubicin is effective as a second line treatment in ovarian cancer patients; comparative data are needed to establish its role in first line therapy.

Evaluation of circulating immune complexes (C.I.C.) in endometrial cancer.

We evaluated the presence of CIC in 32 patients with histological proven cancer of endometrium: 23 stage IA or IB (i.e. localized disease), 9 in stage II or III (i.e. advanced disease). The determination of CIC was done at the time of the diagnosis before the patients underwent any surgical or medical therapy. The presence of CIC was demonstrated in 17% (4/23) of the patients with localized disease and in 56% (9/9) of the patients with more advanced disease. Our findings indicate that the presence of CIC is higher in patients with advanced endometrial carcinoma (stage II, III), than in those suffering of a more limited disease (stage IA, IB) and this seems could be consistent with a possible role in modulating the immune response against tumour itself.

EUS-guided fine needle tissue acquisition for the diagnosis of pleural metastases from endometrial cancer.

Transesophageal EUS-FNA have become a useful tool in the evaluation of the mediastinum, especially during the staging work-up examination of patients with non-small-cell lung cancer (NSCLC) or other malignancies. We report a challenging case of a 53 years-old woman with an endometrial adenocarcinoma who subsequently presented with right pleural effusion, diffuse pleural thickening with few pleural lesions. The patient referred a long history of exposure to amiantum, this posing a differential diagnosis between primary pleural tumour (mesothelioma) and neoplastic pleural localization of the endometrial cancer. The cytological examination of the pleural effusion (sampled via thoracenthesis) was not adequate to reach a diagnosis. Although a right-video-assisted thoracoscopy was considered the gold standard in this clinical setting to achieve a tissue acquisition of the pleura, an EUS (as the least invasive procedure) was attempted to reach a definitive diagnosis. EUS-FNTA of the pleura was done using a 19-Gauge needle and the pathological and immunophenotypic features were diagnostic for a pleural metastasis of high-grade endometrial serous carcinoma. The patient received adjuvant chemotherapy with a complete regression of the pleural lesions. We take the opportunity of this challenging case to discuss the efficacy and safety of EUS-FNAT to sample the pleural lesions with the use of a large calibre needle if the lesion lies just under the EUS cursor. We may assume that, in selected patients, this technique could be presented as a viable option to the more invasive surgical procedure, which has been previously the gold standard for the pleural tissue acquisition.

Successful multimodal treatment of a breast cancer patient with a recurrence invading the chest wall.

We describe successful operative management of a solitary breast cancer metastasis in the chest wall after complete response with concomitant non-pegylated liposomal doxorubicin (NPLD) and docetaxel followed by sternal rib resection with prosthetic reconstruction. We report a case of a 41-year-old woman who had a breast cancer recurrence infiltrating neighboring osteo-cartilage of the left sternal body, the cartilaginous portion of the third and fourth ipsilateral ribs and was inseparable from the rear side pectoral reaching deep into contiguity with the pericardium. After 6 cycles of chemotherapy with NPLD plus docetaxel, sternal rib resection with prosthetic reconstruction was performed. Histological examination did not show any evidence of residual tumor. At 9 months of follow-up, the patient appears free of disease. Our case demonstrates that a multimodal approach in patients with chest wall recurrence of breast cancer without distant metastasis, may be safe and effective for maintaining a good quality of life.

Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia ('hand-foot' syndrome).

Palmar-plantar erythrodysesthesia (PPE), also called hand-foot syndrome or hand-to-foot syndrome, is a distinctive and relatively frequent dermatologic toxic reaction associated with certain chemotherapeutic agents. Pegylated liposomal doxorubicin (PLD), a long-circulating formulation of doxorubicin in which doxorubicin hydrochloride is encapsulated within pegylated liposomes, is approved to treat patients with metastatic breast cancer, advanced ovarian cancer, and acquired immunodeficiency syndrome-related Kaposi's sarcoma. The incidence of PPE is increased in patients receiving PLD compared with conventional doxorubicin. In studies that utilized the currently approved dose of PLD (50 mg/m(2) every 4 weeks), approximately 50% of all patients receiving PLD experienced PPE, and approximately 20% experienced grade 3 PPE. The pathophysiology of PPE, as it occurs with any drug with which it is associated, is not well understood. Studies evaluating the development of PPE specifically associated with PLD have not fully elucidated the mechanism; however, data support the roles of drug excretion in sweat and local pressure as contributors. When PPE develops, clinical interventions with respect to altering PLD administration include dose reduction, less frequent dosing, and ultimately, drug withdrawal with several consequences on treatment efficacy. This article will review the available data regarding the etiology and potential management strategies of PPE associated with PLD.

A multicentre phase II study of carboplatin plus pegylated liposomal doxorubicin as first-line chemotherapy for patients with advanced or recurrent endometrial carcinoma: the END-1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) group.

Anthracyclines and platinum derivates are active drugs for advanced endometrial carcinoma (AEC), but new schedules with higher efficacy and better tolerability are needed. A phase II study was conducted to describe activity and tolerability of carboplatin (C)+pegylated liposomal doxorubicin (PLD) in patients with AEC. Patients with chemonaive AEC, PS < or = 2, aged < 75 years, with at least one measurable lesion were eligible. Treatment was C (area under curve 5)+PLD (40 mg m(-2)) on day 1 every 4 weeks, up to six cycles. Forty-two patients were needed in a single-stage design, with at least 13 objective responses to define the treatment active. Forty-two patients were enrolled. Median age was 64 years (31-74). A total of 64% of patients were recurrent while 36% were advanced. Three complete (7%) and 22 partial responses (52%) were observed, for an overall response rate of 59.5% (95% exact CI: 43.3-74.3). One death potentially related to treatment was recorded (death at home for unknown reasons after 6th cycle). Other relevant toxicities (% of patients) were grade 3/4 neutropaenia 33%/14%, febrile neutropaenia 5%, grade 3/4 thrombocytopaenia 17%/5%, grade 3/4 anaemia 31%/2%. Skin toxicity was mild: grade 1 14%, grade 2 10%, grade 3 5%. Hair loss: complete 5%, partial 12%. The combination of carboplatin and PLD shows good activity and favourable toxicity as first-line chemotherapy of patients with AEC, deserving further studies in this setting.

Preclinical in vivo activity of a combination gemcitabine/liposomal doxorubicin against cisplatin-resistant human ovarian cancer (A2780/CDDP).

Both gemcitabine and liposomal doxorubicin are antineoplastic drugs with clinical activity in platinum-refractory ovarian cancer. The purpose of this study was to evaluate the antitumor activity of a combination gemcitabine/liposomal doxorubicin administered to athymic mice bearing cisplatin-resistant human ovarian cancer (A2780/CDDP) xenografts. Emphasis was on the use of very low doses of each drug and of different dosing schedules. Data obtained showed that combined treatment with 80 mg/kg gemcitabine and 15 mg/kg liposomal doxorubicin produced a significant enhancement of antitumor activity compared with monotherapy at the same doses of these agents. Noteworthy is the fact that the majority of xenograft-bearing animals receiving the combination therapy demonstrated a complete tumor regression at the end of the study. A similar trend was observed when doses of both drugs were reduced to 20 mg/kg gemcitabine and to 6 mg/kg liposomal doxorubicin. Again, three out of ten mice receiving the combination were tumor free at the end of the study. No significant differences were observed in antitumor activity when comparing the simultaneous vs the consecutive dosing schedule. Remarkably, no additive toxicity was observed in any experimental trials. These data encourage clinical trials to prove the advantages of this combination treatment with respect to the single-agent chemotherapy in platinum-refractory ovarian cancer patients.

Phase II study of pegylated liposomal doxorubicin in heavily pretreated epithelial ovarian cancer patients. May a new treatment schedule improve toxicity profile?

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) has shown promising activity in the treatment of recurrent ovarian cancer but skin toxicity remains the dose-limiting toxicity of the drug. The aim of this study was to investigate whether a different treatment schedule may improve the toxicity profile, especially in terms of dermatological and mucosal toxicity. METHODS: It is an open-label phase II study in a population of heavily pretreated ovarian cancer patients. PLD was administered at the dose of 35 mg/m2 q21 until disease progression or unacceptable toxicity. RESULTS: Thirty-seven heavily pretreated (median number of previous chemotherapy regimens 2, range 1-6) ovarian cancer patients were enrolled. All patients received at least two courses of chemotherapy and all were evaluated for response. No one showed complete response, while five partial responses (13.5%), 16 stabilizations of disease (48.6%) and 14 progressions of disease (37.8%) were observed. The median time to response was 12 weeks (range 8-16). The median duration of response was 22.8 weeks (range 4-68), the median duration of stabilization of disease was 17.6 weeks (range 4-28). Palmar plantar erythrodysesthesia (PPE) occurred in 8 patients (21.6%) and was of grade 3 in one patient (2.8%). Grade 1 stomatitis occurred in 3 patients (8.1%). Grade 3-4 neutropenia occurred in only 4 patients (10.8%). CONCLUSIONS: PLD at the dose of 35 mg/m2 q21 seems to translate into an acceptable skin toxicity profile with a response rate comparable to others obtained with a standard schedule.

Transfected human dendritic cells to induce antitumor immunity.

Dendritic cells are professional antigen-presenting cells able to prime naive T lymphocytes and regulate steadily the delicate balance between tolerance and activation during the immune response. In past years several reports have shown that genetically engineered dendritic cells (DCs) can be a powerful tool for inducing an antigen-specific immune response. The use of such modified antigen-presenting cells is a real working hypothesis in preclinical studies and in clinical vaccination approaches for cancer treatment. The definition of optimal transfection conditions for preserving DC survival and functionality is necessary to design a correct immunotherapeutic protocol. Different lipid-based transfection compounds were studied for their effects on DC survival, phenotype and functional properties. All the transfection procedures were able to select DCs with a higher expression of activation and costimulatory molecules (ie MHCII-DR, CD83, CD86, CD25) than the untreated DCs. However, only two compounds (LipofectAMINE PLUS and FuGENE 6), preserved or even increased the immunopotency of DCs as antigen-presenting cells. These protocols were applied to modify DCs in order to express an epithelial tumor-associated antigen, MUC1, and such cells were able to induce in vitro a specific immune response in healthy donors.

Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer.

In total, 70 patients were enrolled into this phase II study, to evaluate the activity of the pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) combination in recurrent ovarian cancer patients. PLD, 30 mg m(-2), was administered on day 1 by 60' i.v. infusion, followed by GEM, 1000 mg m(-2), given by 30' i.v. on days 1 and 8; cycles were repeated every 21 days. In all, 67 patients are so far evaluable for response. Seven complete responses (10.4%, 95% CI: 3.1-17.7), 16 partial responses (23.9%, 95% CI: 13.7-34.1), 26 disease stabilisations (38.8%, 95% CI: 27.1-50.5) and 18 progressions (26.9%, 95% CI: 16.3-37.5) have been registered. Within the resistant population (n=36), the response rate was 25% (95% CI: 10.9-39.1). Within the group of platinum-sensitive patients (n=31), the response rate was 45.2% (95% CI: 27.7-62.7). A total of 443 courses are evaluable for toxicity. Grade 3-4 hematological toxicity was registered in 30 patients (42.8%), mainly represented by neutropenia (35.6%); palmar-plantar erythrodysesthesia affected 24 patients (34.2%), but it was of grade 3 in only seven of them (10%).