Joseph Kerger

Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1.

Thirty‐nine tumor‐bearing patients with metastatic melanoma were treated with 3 subcutaneous injections of the MAGE‐3.A1 peptide at monthly intervals. No significant toxicity was observed. Of the 25 patients who received the complete treatment, 7 displayed significant tumor regressions. All but one of these regressions involved cutaneous metastases. Three regressions were complete and 2 of these led to a disease‐free state, which persisted for more than 2 years after the beginning of treatment. No evidence for a cytolytic T lymphocyte (CTL) response was found in the blood of the 4 patients who were analyzed, including 2 who displayed complete tumor regression. Our results suggest that injection of the MAGE‐3.A1 peptide induced tumor regression in a significant number of the patients, even though no massive CTL response was produced. Int. J. Cancer 80:219–230, 1999.

Phase III Trial Comparing Two Dose Levels of Epirubicin Combined With Cyclophosphamide With Cyclophosphamide, Methotrexate, and Fluorouracil in Node-Positive Breast Cancer

PURPOSE To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks). RESULTS Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.

Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis.

PURPOSE This phase I study of Taxotere (RP 56976, NSC 628503; docetaxel, Rhône-Poulenc Rorer, Antony, France) was undertaken to determine the maximum-tolerated dose (MTD), toxic effects, and basic pharmacokinetics of a day-1 and -8 schedule of this novel semisynthetic product related to Taxol (paclitaxel; Bristol-Myers Squibb, Wallingford, CT). PATIENTS AND METHODS Thirty-two eligible patients with refractory solid malignancies have been treated with a 1-hour infusion of Taxotere on a day-1 and -8 schedule every 3 weeks as long as patients maintained a polymorphonucleotide count > or = 1,500/microL and a platelet count > or = 100,000/microL. Dose levels tested have ranged between 20 and 110 mg/m2 per course. RESULTS Considering 128 assessable courses, the main toxicities have been neutropenia (which was dose-limiting), asthenia, alopecia, hypersensitivity reactions, skin toxicity, and edema. No significant cardiac or platelet toxicity has been observed. Seven patients have had aggravation of preexisting paresthesias or new onset of sensory symptoms during Taxotere treatment. The MTD at this schedule appears to be 110 mg/m2 per course, with six of 10 patients at this level experiencing severe toxicity. Five partial remissions have been observed in four heavily pretreated patients with breast cancer and in one patient with adenocarcinoma of unknown origin. Two patients with ovarian cancer have had meaningful decreases in CA125 levels. CONCLUSION Like Taxol, this novel chemotherapeutic agent appears to possess promising activity in patients with refractory breast and ovarian neoplasms, with tolerable toxicities. Using this schedule, 100 mg/m2 per course is the recommended dose for future phase II trials.

Prospective Randomized Study Comparing Docetaxel, Estramustine, and Prednisone With Docetaxel and Prednisone in Metastatic Hormone-Refractory Prostate Cancer

PURPOSE To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer. PATIENTS AND METHODS One hundred fifty patients were randomly assigned to D alone (35 mg/m(2) on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA > or = 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%. RESULTS The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04). CONCLUSION The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

Comparison of proposed diagnostic criteria with FACT-F and VAS for cancer-related fatigue: Proposal for use as a screening tool

The objective was to validate the use of the proposed International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10) criteria for fatigue (P-ICD10) through comparison with the Functional Assessment of Cancer Therapy Fatigue (FACT-F) subscale and three visual analogue scale (VAS) qualities in cancer patients thought to be fatigued. Fatigue was assessed in 834 cancer patients at three clinical centres in Belgium, using P-ICD10, FACT-F, and VAS to assess: level of energy (VAS1), quality of life (VAS2), and ability to perform daily activities (VAS3). Of the 834 interviewed cancer patients, 54% were classified as fatigued by the P-ICD10 criteria. Internal consistency of P-ICD10 was very good (alpha coefficient 0.82). The principal component analysis corroborated good internal consistency with all variables included in the first component; a second component was used to identify psychological fatigue (concentration and short-term memory disabilities). An abridged set of screening tools based on the first three general symptoms of the P-ICD10 is proposed with 100% specificity and 86% specificity, respectively. There was a marked decrease in FACT-F and VAS1 scores in patients diagnosed as fatigued by the P-ICD10 (mean±SD, FACT-F 20±9 vs 39±8, VAS1 34±21 vs 61±21). A logistic regression model between P-ICD10 criteria diagnosis and FACT-F (VAS1) identified a score of 34 (61) on the FACT-F scale as a proposed cut-off point for the diagnosis of fatigue. The ICD-10 criteria can be recommended as a diagnostic tool, whereas the FACT-F scale and the level of energy 100-mm VAS assess the intensity of fatigue, and are more suitable for follow-up of cancer-related fatigue.

Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer

OBJECTIVE The aim of this review is to report our experience and the feasibility of neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer. METHODS Forty-five patients with primarily unresectable advanced-stage epithelial ovarian cancer were treated in our center between 1995 and 2002 by platinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Their files were reviewed retrospectively. RESULTS At the end of neoadjuvant chemotherapy, according to RECIST criteria, 1 patient (2.2%) had achieved a clinical complete response (CR), 33 (73.4%) a partial response (PR), and 8 (17.8%) had stable disease (SD). Only 3 (6.6%) patients showed disease progression (PD). Surgery was performed in patients with objective response or SD after a median number of 4 courses (range: 2-6) of induction chemotherapy. A complete macroscopic debulking was achieved in 24 (53.3%) out of 39 patients in whom cytoreductive surgery was performed. For the entire group, median overall survival was 29 months. Survival was significantly improved in patients with optimal debulking compared to patients with persistent tumor after surgery: 41 months versus 23 months (P = 0.0062). Median survival for patients responding to neoadjuvant chemotherapy (CR and PR) was 44 months compared to 27 months for patients with SD or PD after initial chemotherapy (P = 0.01). Neither treatment-related deaths nor significant toxicities were observed. CONCLUSION Neoadjuvant chemotherapy followed by optimal debulking may be a safe and valuable treatment alternative in patients with primarily unresectable advanced-stage bulky ovarian cancer. Patients with an objective response to chemotherapy or absence of macroscopic residual tumor after surgery have a better outcome. This approach is currently being tested in large, prospective randomized clinical trials.

Cancer and renal insufficiency results of the BIRMA study

Background:Half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed.Methods:Primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006.Results:A total of 1218 patients were included. The prevalence of elevated SCR (⩾1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR<90 ml min−1 per 1.73 m2. In all, 78.6% of treated patients (n=1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment.Conclusions:The RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing.

Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC early clinical trials group

The antitumour activity of docetaxel was investigated in patients with advanced malignant melanoma. Docetaxel, 100 mg/m2, intravenous, over 60 min, was administered every 3 weeks. Response evaluation was performed after two cycles. No prophylactic treatment with steroids or antihistamines was given. 38 patients were included, 36 were eligible and evaluable for toxicity and 30 patients were evaluable for response. The main haematological toxicity was neutropenia [17 patients with common toxicity criteria (CTC) grade 4 and 11 CTC grade 3] with nadir after 5-8 days and rapid recovery. The most frequent non-haematological toxicity was generalised alopecia (83% of the patients). Asthenia, malaise and fatigue were also seen in 58%. Skin toxicity was also frequent. Hypersensitivity reactions (erythematous rash, urticaria, blood pressure changes and tachycardia), seen in 42% of the patients, were mild to moderate. Oedema was registered in one fifth of the patients and developed after four or more treatment cycles. The overall response rate in the evaluable patients was 17% (five partial responders). We conclude that docetaxel has activity in advanced malignant melanoma.

Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel

BackgroundTo determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel.MethodsWe studied the incidence and duration of amenorrhea induced by two chemotherapy regimens: (i) 6 cycles of 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks (6FEC) and (ii) 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (3FEC/3D). Reversible amenorrhea was defined as recovery of regular menses and, where available (101 patients), premenopausal hormone values (luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol) in the year following the end of chemotherapy.ResultsOne hundred and fifty-four premenopausal patients were included: 84 treated with 6FEC and 70 with 3FEC/3D. The median age was 43.5 years (range: 28–58) in the 6FEC arm and 44 years (range: 29–53) in the 3FEC/3D arm. Seventy-eight percent of patients were treated in the context of the PACS 01 trial. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was similar in the two groups: 93 % in the 6FEC arm and 92.8 % in the 3FEC/3D arm. However, in the year following the end of chemotherapy, more patients recovered menses in the 3FEC/3D arm than in the 6FEC arm: 35.5 % versus 23.7 % (p = 0.019). Among the 101 patients for whom hormone values were available, 43 % in the 3FEC/3D arm and 29 % in the 6FEC arm showed premenopausal levels one year after the end of chemotherapy (p < 0.01). In the 3FEC/3D group, there was a statistically significant advantage in disease-free survival (DFS) for patients who were still amenorrheic after one year, compared to patients who had recovered regular menses (p = 0.0017).ConclusionOur study suggests that 3FEC/3D treatment induces more reversible amenorrhea than 6FEC. The clinical relevance of these findings needs to be investigated further.

Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study

BACKGROUND Cetuximab in combination with platinum and 5-fluorouracil is the standard of care in the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab and taxane combinations have shown promising activity. This study evaluated the efficacy and safety of four cycles of docetaxel associated with cisplatin and cetuximab (TPEx), followed by maintenance with cetuximab every 2 weeks. PATIENTS AND METHODS Patients with a histologically confirmed HNSCC with metastasis or recurrence unsuitable for locoregional curative treatment received docetaxel and cisplatin (75 mg/m(2) both) at day 1 and weekly cetuximab 250 mg/m(2) (loading dose of 400 mg/m(2)), repeated every 21 days for four cycles, followed by maintenance cetuximab 500 mg/m(2) every 2 weeks until progression or unacceptable toxicity. Prophylactic administration of granulocyte colony-stimulating factor was done systematically after each chemotherapy cycle. Patients had a good general status (performance status ≤1) and were under 71 years. Prior total doses of cisplatin exceeding 300 mg/m(2) were not allowed. The primary end point was objective response rate (ORR) after four cycles. RESULTS Fifty-four patients were enrolled. The primary end point was met with an ORR of 44.4% (95% CI 30.9-58.6). Median overall and progression-free survivals were, respectively, 14 months (95% CI 11.3-17.3) and 6.2 months (95% CI 5.4-7.2). The most common grade 3/4 adverse events were skin rash (16.6%) and non-febrile neutropenia (20.4%). There were one pulmonary embolism and two infectious events leading to death. CONCLUSIONS The TPEx regimen showed promising activity as first-line treatment in fit patients with recurrent/metastatic HNSCC. Further studies are needed to compare the TPEx versus EXTREME regimen in this population. CLINICALTRIALGOV NCT01289522.