Ulrich R. Kleeberg

Fulvestrant, Formerly ICI 182,780, Is as Effective as Anastrozole in Postmenopausal Women With Advanced Breast Cancer Progressing After Prior Endocrine Treatment

PURPOSE To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) and anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. PATIENTS AND METHODS Patients (n = 451) with advanced breast cancer were randomized to receive fulvestrant 250 mg as a once-monthly (one x 5 mL) intramuscular injection or an oral dose of anastrozole 1 mg in this open, parallel-group, multicenter trial. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rates, defined as complete response (CR) or partial response (PR), duration of response (DOR), and tolerability. RESULTS Patients were followed for a median period of 14.4 months. In terms of TTP, fulvestrant was as effective as anastrozole (hazard ratio, 0.98; confidence interval [CI], 0.80 to 1.21; P =.84). Median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole. OR rates showed a numerical advantage for fulvestrant (20.7%) over anastrozole (15.7%) (odds ratio, 1.38; CI, 0.84 to 2.29; P =.20). Clinical benefit rates (CR + PR + stable disease > or = 24 weeks) were 44.6% for fulvestrant and 45.0% for anastrozole. Median DOR was 14.3 months for fulvestrant and 14.0 months for anastrozole. Both treatments were well tolerated, with 3.2% and 1.3% of fulvestrant- and anastrozole-treated patients, respectively, withdrawn from treatment because of an adverse event. CONCLUSION Fulvestrant was as effective as anastrozole. These data confirm that fulvestrant is an additional, effective, and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy.

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: A prospective combined analysis of two multicenter trials

Fulvestrant (ICI 182,780) is a new type of estrogen receptor (ER) antagonist that down‐regulates the ER and has no known agonist effects. The authors report the prospectively planned combined analysis of data from 2 Phase III trials comparing fulvestrant 250 mg monthly (n = 428) and anastrozole 1 mg daily (n = 423) in postmenopausal women with advanced breast carcinoma (ABC) who previously had progressed after receiving endocrine treatment.

Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer

Background: Titanocene dichloride (MKT4) is a recently developed cytostatic agent that shows preclinical activity against human breast cancer xenograft models in nude mice. A phase II trial was conducted to evaluate the clinical activity of this inorganic early-transition metal complex in patients with metastatic breast cancer. Patients and Methods: Fifteen patients were enrolled into this multicenter phase II trial. Twelve patients with a median age of 58 years were eligible for toxicity and response. All 12 patients had prior surgery and metastatic disease at study entry. Seven patients had prior radiotherapy, 9 patients had prior hormone therapy, and 8 patients had prior adjuvant chemotherapy. No previous chemotherapy for metastatic disease was allowed. Titanocene dichloride was intravenously administered at a dose of 270 mg/m2 every 3 weeks. Results: Among the 12 eligible patients evaluable for response, no objective remission was observed. Two patients (17%) showed a ‘minor remission’, and 5 patients (42%) experienced a ‘no change’ situation of their disease. Moderate to severe drug-related toxicities (CTC grade II–III) affecting the gastrointestinal, neurological, hepatic and renal system occurred in the majority of patients. Therefore, in 5 patients the dose had to be reduced to 240 mg/m2. Conclusion: MKT4, given at a dose of 240–270 mg/m2 in this schedule, was not effective in patients with metastatic breast cancer. The tolerability of the 3-weekly dosing regimen was acceptable when the MKT4 dose was reduced to 240 mg/m2.

Malignant Melanoma S3-Guideline "Diagnosis, Therapy and Follow-up of Melanoma"

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

Dacarbazine, Cisplatin, and Interferon-Alfa-2b With or Without Interleukin-2 in Metastatic Melanoma: A Randomized Phase III Trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group

BACKGROUND Based on phase II trial results, chemoimmunotherapy combinations have become the preferred treatment for patients with metastatic melanoma in many institutions. This study was performed to determine whether interleukin-2 (IL-2) as a component of chemoimmunotherapy influences survival of patients with metastatic melanoma. PATIENTS AND METHODS Patients with advanced metastatic melanoma were randomly assigned to receive dacarbazine 250 mg/m2 and cisplatin 30 mg/m2 on days 1 to 3 combined with interferon-alfa-2b 10 x 10(6) U/m2 subcutaneously on days 1 through 5 without (arm A) or with (arm B) a high-dose intravenous decrescendo regimen of IL-2 on days 5 through 10 (18 x 10(6) U/m2/6 hours, 18 x 10(6) U/m2/12 hours, 18 x 10(6) U/m2/24 hours, and 4.5 x 10(6) U/m2 for 3 x 24 hours). Treatment cycles were repeated in the absence of disease progression every 28 days to a maximum of four cycles. RESULTS Three hundred sixty-three patients with advanced metastatic melanoma were accrued. The median survival was 9 months in both arms, with a 2-year survival rate of 12.9% and 17.6% in arms A and B, respectively (P = .32; hazard ratio, 0.90; 95% CI, 0.72 to 1.11). There was also no statistically significant difference regarding progression-free survival (median, 3.0 v 3.9 months) and response rate (22.8% v 20.8%). CONCLUSION Despite its activity in melanoma as a single agent or in combination with interferon-alfa-2b, the chosen schedule of IL-2 added to the chemoimmunotherapy combination had no clinically relevant activity.

Patient satisfaction and quality of life in cancer outpatients: results of the PASQOC* study

BackgroundSatisfaction with care and quality of life (QoL) are indicative of the quality of care of cancer patients. The purpose of this study was to lay a cornerstone for patient-centred quality management by assessing the current status of satisfaction with care and QoL among oncological outpatients in Germany, and by identifying the key factors that determine a patient’s willingness to recommend a medical facility.Patients and methodsA self-constructed and validated patient satisfaction questionnaire plus the SF-36 were distributed to a random sample of 3384 cancer patients who presented at 24 investigators’ offices nationwide within a defined recruiting period and who met the inclusion criteria. The return rate was 81.9% (n=2772). A total of 2659 (78.6%) questionnaires were evaluable. The most common cancer types were breast (22.9%) and intestine (19.8%).ResultsOverall satisfaction was high, but specific reporting questions revealed many areas for improvement such as shared decision making, doctor-patient communication and organization of care. QoL was significantly impaired in many domains. Patient-provider relationship, facility setting and information on diagnosis and treatment options are major determinants of a patient’s willingness to recommend a facility to a friend or relative if needed.ConclusionsThis multicentre study focusing on patient perspectives highlights that, although the overall degree of satisfaction was quite high, there are numerous areas for improvement.

Superior Outcome of Women With Stage I/II Cutaneous Melanoma: Pooled Analysis of Four European Organisation for Research and Treatment of Cancer Phase III Trials

PURPOSE Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. PATIENTS AND METHODS Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. RESULTS A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. CONCLUSION Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference.

The clinical benefit of pegylated liposomal doxorubicin in patients with metastatic breast cancer previously treated with conventional anthracyclines: a multicentre phase II trial

This study evaluates the clinical benefit of pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC), previously treated with conventional anthracyclines. Seventy-nine women with MBC previously treated with anthracyclines received PLD 50 mg m−2 every 4 weeks. All patients were previously treated with chemotherapy and 30% of patients had ⩾3 prior chemotherapies for metastatic disease. Patients were considered anthracycline resistant when they had disease progression on anthracycline therapy for MBC or within 6 months of adjuvant therapy. The overall clinical benefit rate (objective response+stable disease ⩾24 weeks) was 24% (16.1% in patients with documented anthracycline resistance vs 29% in patients classified as having non-anthracycline-resistant disease). There was no difference with respect to the clinical benefit between patients who received PLD >12 months and those who received PLD ⩽12 months since last anthracycline treatment for metastatic disease (clinical benefit 25 vs 24.1%, respectively). Median time to progression and overall survival were 3.6 and 12.3 months, respectively. The median duration of response was 12 months, and the median time to progression in patients with stable disease (any) was 9.5 months. Fourteen patients (17.7%) had a prolonged clinical benefit lasting ⩾12 months. In conclusion, PLD was associated with an evident clinical benefit in anthracycline-pretreated patients with MBC.

Infections and melanoma risk: results of a multicentre Eortc case-control study

Immune function plays a prominent role in the defence against cutaneous malignant melanoma and the increased risk of melanoma development during immunosuppression. Since the immune system is challenged beyond its routine activity by an infection, the effect of previous infectious diseases on the risk of melanoma may also be crucial. In a European Organization for Research and Treatment of Cancer (EORTC) case-control study performed in six European countries and Israel, we compared the history of severe infections in 603 melanoma patients with that in 627 population controls. We calculated adjusted odds ratios (ORs) to estimate the effect of infectious diseases on melanoma risk. The ORs for melanoma risk were below 1 for nearly all types of infections (except two) if body temperature was not taken into consideration, and for all infections with a body temperature above 38.5 degrees C. In the latter category significantly lowered ORs were found for pulmonary tuberculosis (0.16; 95% confidence interval [CI] 0.01-0.98), Staphylococcus aureus infections (0.54; 95% CI 0.31-0.94), sepsis (0.23; 95% CI 0.06-0.70), influenza and related infections (0.65; 95% CI 0.48-0.86) and pneumonia (0.45; 95% CI 0.27-0.73). Analysis of the cumulative influence revealed a consistent pattern of results pointing to a reduction in melanoma risk with increasing numbers of recorded infections and fever height. This apparent dose-response relationship suggests a causal association. Speculations on the underlying mechanism include a Shwartzman-like phenomenon when melanoma formation precedes the infection and/or an infection-related Th1-cell activation preventing the establishment of the tumour.

Reduced Incidence of Severe Palmar-Plantar Erythrodysesthesia and Mucositis in a Prospective Multicenter Phase II Trial with Pegylated Liposomal Doxorubicin at 40 mg/m2 Every 4 Weeks in Previously Treated Patients with Metastatic Breast Cancer

Purpose: The aim of this study was to assess whether the reduction in the total dose of pegylated liposomal doxorubicin (PLD) per cycle from 50 mg/m2 every 4 weeks to 40 mg/m2 every 4 weeks can effectively lower the incidence of treatment-related palmar-plantar erythrodysesthesia (PPE) and mucositis. Methods: Patients received PLD 40 mg/m2 every 4 weeks, and were evaluated for toxicity prior to each treatment and for response every 8 weeks. Results: All patients were previously treated with at least one chemotherapy regimen for metastatic disease, and 72% of the patients had a prior exposure to an anthracycline. Forty-six evaluable patients received a median of four PLD cycles, with a median dose intensity of 10 mg/m2/week and a median cumulative dose of 160 mg/m2. No National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 PPE was observed in these patients. NCI-CTC grade 3 or 4 mucositis occurred in 4.3% of patients, only. Response rates and survival results observed here were comparable to those observed with PLD 50 mg/m2 every 4 weeks in a matched patient population. However, patients treated with PLD 40 mg/m2 every 4 weeks experienced less PPE and mucositis and required clearly less dose reductions and treatment delays. Conclusion: The favorable safety profile observed in this study leads us to recommend the use of PLD 40 mg/m2 every 4 weeks for patients with advanced breast cancer.