Jens Atzpodien

We compared the efficacy and tolerability of cisplatin, gemcitabine, and treosulfan (CGT) therapy in younger patients (age, <60 years) and in elderly patients (age, ≥60 years) with pretreated relapsed American Joint Committee on Cancer stage IV cutaneous malignant melanoma. A total of 91 patients at the age of 18 to 80 years, in relapse after first-, second-, or third-line therapy received 40 mg/m intravenous (i.v.) cisplatin, 1000 mg/m i.v. gemcitabine, and 2500 mg/m i.v. treosulfan on days 1 and 8. CGT-therapy was repeated every 5 weeks until progression of disease occurred. Younger (n = 49) and elderly (n = 42) patients showed a significant difference in disease stabilization in 25% versus 7% (P ≤ 0.05), as opposed to 69% versus 91% patients exhibiting disease progression. In contrast, the overall median survival probability was not significantly different (P = 0.8153). Neither treatment-related toxicity nor toxicity-associated dose reduction showed substantial differences. Our results demonstrated that CGT therapy could be safely administered to a patient up to age 80 years.

The aim of this study was to evaluate the prognostic impact of pretreatment neutrophils, previously rendered statistically independent, on the response and on long-term survival of metastatic renal carcinoma patients treated with outpatient subcutaneous (s.c.) interleukin-2 (IL-2) and s.c. interferon (IFN)-α. We assessed a total of 495 patients receiving s.c. IL-2/s.c. IFN-α-based therapy. While 417 patients with neutrophil counts =6500 cells/μL had 18% objective responses and a median survival of 9 months (p = 0.0000). In conclusion, pretreatment periphal blood neutrophils

Purpose The efficacy of cisplatin, gemcitabine, and treosulfan (CGT) was evaluated in patients with chemotherapy pretreated relapsed AJCC stage IV uveal malignant melanoma. Methods Patients received i.v./intrahepatic cisplatin, i.v. gemcitabine, and i.v. treosulfan (CGT) on day 1 and 8 as first-line (n = 1), second-line (n = 9), third-line (n = 1) or fourth-line (n = 1) therapy. Cisplatin, gemcitabine, and treosulfan (CGT)-therapy was repeated every 5 weeks until progression of disease occurred. A maximum of six CGT-cycles (mean, 2 cycles) was administered per patient. Results No objective response was observed, six patients (50%) had stable disease and six (50%) patients progressed upon first reevaluation. Overall survival of all the 12 patients was 6 months. Patients with stable disease reached a median overall survival of 12 months, while patients with disease progression upon first reevaluation had a median overall survival of 4 months, only. Grade III/IV related hematotological side effects were experienced in six (leukopenia) and four (thrombocytopenia) patients. Conclusions Treatment with CGT may lead to disease stabilization and prolonged survival in a substantial proportion of progressive stage IV uveal melanoma patients, even following heavy chemotherapy treatment.

Background: We analyzed the effect of histology and various clinical and laboratory predictors in a new continuous prognostic index for metastatic renal-cell carcinoma based on fractional polynomials. Patients and Methods: We evaluated 322 metastatic renal-cell carcinoma patients treated with subcutaneous recombinant cytokine-based home therapies in consecutive trials. We evaluated papillary histology, along with age, disease localizations, C-reactive protein, and neutrophil count in a new prognostic index, which was based on the multivariable fractional polynomial (MFP) algorithm. Results: The MFP model allowed us to divide patients into three risk groups, using seven selected significant prognostic factors: histology, neutrophils, C-reactive protein, bone metastases, liver metastases, lymph node metastases, and age. Using the multivariable fractional polynomial model, median overall survival for high-, intermediate-, and low-risk patients was 10 months (n = 80), 23 months (n = 162), and 41 months (n = 80) (scheme A; p ≤ 0.01), or 7.9 months (n = 16), 20 months (n = 226), and 41 months (n = 80) (scheme B; p ≤ 0.001), respectively. Conclusions: Histology, clinical, and laboratory predictors contribute to a MFP algorithm-based prognostic index, allowing for a highly effective long-term risk discrimination in metastatic renal-cell carcinoma patients receiving recombinant immunotherapy. The flexibility in creating patient groups by using a continuous prognostic index allows to meet clinical needs in terms of improved prediction and optimized treatment selection.

Twenty-four (24) pretreated patients with relapsed high-risk resected The American Joint Committee on Cancer (AJCC) stage IIA-IV melanoma received adjuvant peptide vaccinations derived from the melanosomal antigens MelanA/MART1, MAGE-1, gp100, and tyrosinase, according to patient tumor-associated human leukocyte antigen (HLA) restricted antigen expression, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Pretreatment was comprised of surgery (n=23 primary tumor; n=23 metastases), local radiotherapy (n=2), immunotherapy (n=23), chemotherapy (n=10), and chemoimmunotherapy (n=1), respectively. All patients received peptide vaccines in an adjuvant setting. Seven (7) patients were relapse free for 3+ up to 25+ months. Of the patients exhibiting progressive disease (n=17), 13 patients developed metastases during vaccination (9 local, 4 distant), and 4 patients developed metastases (2 local, 2 distant) after finishing vaccine therapy. Two (2)-year local and distant metastases-free survival, 2-year distant metastases-free survival, and 2-year overall survival were calculated as 8.6%, 68%, and 85%, respectively. Vaccine treatment was well tolerated, with no severe side-effects. Twenty (20) of 24 patients developed local delayed-type hypersensitivity (DTH) reactions to synthetic peptide vaccination. Transient fever (n=2) and pain in muscle/bone (n=2) occurred rarely. In conclusion, antigenic peptide vaccination, combined with GM-CSF, is safe and may yield clinical benefits in relapsed high-risk resected melanoma patients.

We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-α2a (sc-IFN-α2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate 70 mm h⁻¹ and neutrophil counts 6000 μl⁻¹ (group I) were randomised to arm A: sc-IL-2, sc-IFN-α2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-α2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines.

In this paper, we report on the long-term therapeutic efficacy of maintenance treatment in 12 advanced renal carcinoma patients. Following prior systemic treatment with 8-week cycles of subcutaneous interferon- alpha2a (s.c. IFN-alpha2a) and subcutaneous interleukin-2 (s.c. IL-2)-based immunotherapy (5-day standard Atzpodien regimen), patients received prolonged maintenance treatment consisting of intermittent s.c. IFN-alpha2a and s.c. IL-2, combined with long-term daily peroral 13-cis-retinoic acid (p.o. 13cRA). Patients received a mean of 10 months (range, 0-27 months) of maintenance treatment. Median progression-free survival was calculated at 6 months (range, 0-61 months), and median overall suvival was 22 months (range, 2-65 months) from the start of maintenance therapy. Of 12 patients, 5 were still alive (> or = 60 months) and 2 patients remained progression-free (61 months) at last follow-up. Maintenance treatment was well or moderately tolerated. Maintenance treatment with s.c. IL-2/s.c. INF-alpha2a/p.o. 13-cRA may support long-term efficacy of prior s.c. IL-2/s.c. INF-alpha2a-based therapy in advanced renal carcinoma patients.

We present a prognostic model for metastatic renal cell carcinoma based on fractional polynomials. We retrospectively analysed 425 metastatic renal cell carcinoma patients treated with subcutaneous recombinant cytokine-based home therapies in consecutive trials. In our approach, we categorised a continuous prognostic index produced by the multivariable fractional polynomial (MFP) algorithm, using a strategy in which continuous predictors are kept continuous. The MFP algorithm selected five prognostic factors as significant at the 5% level in a multivariable model: lymph node metastases, liver metastases, bone metastases, age, C-reactive protein and neutrophils. The MFP model allowed us to divide patients into four risk groups achieving median overall survivals of 38 months (low risk), 23 months (low intermediate risk), 15 months (high intermediate risk) and 5.6 months (high risk). Our approach, based on categorising a continuous prognostic index produced by the MFP algorithm, allowed more flexibility in the determination of risk groups than traditional approaches.