Poul F. Geertsen

Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model

We aimed to create a prognostic model in metastatic melanoma based on independent prognostic factors in 321 patients receiving interleukin-2 (IL-2)-based immunotherapy with a median follow-up time for patients currently alive of 52 months (range 15–189 months). The patients were treated as part of several phase II protocols and the majority received treatment with intermediate dose subcutaneous IL-2 and interferon-α. Neutrophil and monocyte counts, lactate dehydrogenase (LDH), number of metastatic sites, location of metastases and performance status were all statistically significant prognostic factors in univariate analyses. Subsequently, a multivariate Coxs regression analysis identified elevated LDH (P<0.001, hazard ratio 2.8), elevated neutrophil counts (P=0.02, hazard ratio 1.4) and a performance status of 2 (P=0.008, hazard ratio 1.6) as independent prognostic factors for poor survival. An elevated monocyte count could replace an elevated neutrophil count. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the three independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 12.6 months (95% confidence interval (CI), 11.4–13.8), 6.0 months (95% CI, 4.8–7.2) and 3.4 months (95% CI, 1.2–5.6), respectively. The low-risk group encompassed the majority of long-term survivors, whereas the patients in the high-risk group with a very poor prognosis should probably not be offered IL-2-based immunotherapy.

Efficient palliation of haemorrhaging malignant melanoma skin metastases by electrochemotherapy.

Electric pulses can cause transient permeabilization of cell membranes (electroporation) and this can be utilized to increase the uptake of chemotherapy (electrochemotherapy). Preclinical studies have shown that in vivo electroporation causes transient shut down of blood flow both in normal and, in particular, malignant tissues. We report the successful palliation of a malignant melanoma patient with bleeding skin metastases using electrochemotherapy. In an on-going study of combined electrochemotherapy and low dose interleukin-2, one patient with bleeding skin metastases was included. Nine skin metastases, of which seven were ulcerated, were treated. After intratumoral bleomycin injection, needle electrodes with two arrays 4 mm apart were inserted into the tumours. Eight square wave electric pulses each 99 μs in duration and with an applied voltage to electrode distance ratio of 1.2 kV/cm were administered. In all the treated lesions, bleeding immediately stopped on administration of the electric pulses and did not recur. The treated metastases developed crusts and the lesions healed in a matter of weeks. Treatments were given under local anaesthesia, lasted a few minutes, and patient discomfort was brief and modest. In conclusion, we propose that electrochemotherapy should be considered for the palliation of haemorrhaging metastases as it is an efficient, tolerable, brief, outpatient, once-only treatment.

Effect of chemotherapy on carcinoma in situ of the testis

Summary Background Approximately 5% of patients with testicular cancer harbour carcinoma in situ (CIS) in the contralateral testis. CIS will progress into invasive tumour in about 50% of cases within five years. The present study evaluated the effect of platinum containing chemotherapy on CIS. Patients and methods Thirty-three patients with disseminated germ-cell cancer and biopsy proven CIS of the testis were evaluated. Results CIS had disappeared in the first follow-up biopsy in 30 patients. Six patients had a relapse of CIS with or without invasive cancer after 30, 31,47, 51, 76 and 95 months from start of chemotherapy. Two relapses were among six patients who initially received cisplatin, vinblastine and bleomycine and four among 27 patients who initially received cisplatin, etoposide and bleomycine. The estimated cumulative risk of CIS five and 10 years after chemotherapy was 21% and 42%, respectively. The estimated cumulative incidence of spermatogenesis was 64% and 81% at five and 10 years of follow-up, respectively. Conclusion Platinum containing chemotherapy may eradicate CIS. However, patients with CIS may develop invasive cancer in spite of chemotherapy. In the light of the present data, we recommend radiotherapy to the affected testicle in patients with CIS in the contralateral testis and in patients with bilateral testicular CIS. In patients with extragonadal disease and CIS in one testicle, orchiectomy of the affected testicle is recommended. In patients for whom future fertility is an important issue, follow-up including repeated biopsies can be offered for a period of at least 10 years.

Elevated serum level of YKL-40 is an independent prognostic factor for poor survival in patients with metastatic melanoma.

YKL‐40 is a growth factor for connective tissue cells and stimulates migration of endothelial cells. Cancer cells, macrophages, and neutrophils secrete YKL‐40. Its function in cancer is unknown. High serum YKL‐40 levels have been associated with a poor prognosis in patients with several solid tumors. The prognostic impact of serum YKL‐40 in metastatic melanoma was evaluated.

Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial.

Therapeutic dendritic cell (DC) vaccination against cancer is a strategy aimed at activating the immune system to recognize and destroy tumor cells. In this nonrandomized phase 1/2 trial, we investigated the safety, feasibility, induction of T-cell response, and clinical response after treatment with a DC-based vaccine in patients with metastatic renal cell carcinoma. Twenty-seven patients with progressive cytokine-refractory metastatic renal cell carcinoma were vaccinated with DCs loaded with either a cocktail of survivin and telomerase peptides or tumor lysate depending on their HLA-A2 haplotype, and low-dose IL-2 was administered concomitantly. Tumor response, immune response, and serum IL-6 and YKL-40 were measured during treatment. Vaccine generation was successful in all patients and no serious adverse events were observed. None of the patients had an objective response but 13/27 patients obtained disease stabilization (SD) for more than 8 weeks. An antigen-specific immune response was demonstrated in 6/6 patients tested. Furthermore, significant alterations in serum YKL-40 and IL-6 were found during treatment. In conclusion, DC vaccination in our setting is feasible and without severe toxicity. Almost half of the patients obtained SD, and in more than 1/3 of the patients, SD persisted for more than 6 months. However, the evaluation of SD is difficult to interpret in the absence of a randomized trial and, therefore, these results should be interpreted with caution. Antigen-specific immune responses were observed in a subset of the treated patients.

Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial

BACKGROUND AND AIM Dendritic cells are regarded as the most effective antigen presenting cells and coordinators of the immune response and therefore suitable as vaccine basis. Here we present results from a clinical study in which patients with malignant melanoma (MM) with verified progressive disease received vaccination with autologous monocyte-derived mature dendritic cells (DC) pulsed with p53, survivin and telomerase-derived peptides (HLA-A2+ patients) or with autologous/allogeneic tumor lysate (HLA-A2(−) patients) in combination with low-dose interleukin (IL)-2 and interferon (IFN)-alpha2b. RESULTS Of 46 patients who initiated treatment, 10 stopped treatment within 1-4 weeks because of rapid disease progression and deterioration. After 8 weeks, 36 patients were evaluable: no patient had an objective response, 11 patients had stable disease (SD); six had continued SD after 4 months, and three patients had prolonged SD for more than 6 months. The mean overall survival time was 9 months, with a significantly longer survival (18.4 months) of patients who attained SD compared with patients with progressive disease (PD) (5 months). Induction of antigen-specific T-cell responses was analyzed by multidimensional encoding of T cells using HLA-A2 major histocompatibility complex (MHC) multimers. Immune responses against five high-affinity vaccine peptides were detectable in the peripheral blood of six out of 10 analyzed HLA-A2+ patients. There was no observed correlation between the induction of immune responses and disease stabilization. A significant lower blood level of regulatory T cells (CD25(high) CD4 T cells) was demonstrable after six vaccinations in patients with SD compared with PD. CONCLUSIONS Vaccination was feasible and safe. Treatment-associated SD was observed in 24% of the patients. SD correlated with prolonged survival suggesting a clinical benefit. Differences in the level of regulatory T cells among SD and PD patients could indicate a significant role of these immune suppressive cells.

Human Papillomavirus Genotyping and p16 Expression As Prognostic Factors for Patients With American Joint Committee on Cancer Stages I to III Carcinoma of the Anal Canal

PURPOSE Carcinomas of the anal canal are strongly associated with the human papillomavirus (HPV). Expression of p16 is used as a surrogate marker of HPV infection. In a retrospective study, we evaluated HPV genotyping and p16 expression as prognostic markers of overall survival (OS) and disease-specific survival (DSS) in patients diagnosed with American Joint Committee on Cancer (AJCC) stages I to III carcinoma of the anal canal. PATIENTS AND METHODS HPV genotyping polymerase chain reaction (high-risk subtypes 16, 18, 31, 33, 45, 52, and 58) and immunohistochemical expression of p16 were analyzed by using paraffin-embedded tumor biopsies from 143 anal carcinomas. The patients were treated with combined chemoradiotherapy or radiotherapy alone. RESULTS HPV16 was detected in 81.0% of the tumors, followed by HPV33 (5.1%), HPV18 (2.2%), and HPV58 (0.7%). p16 positivity was found in 92.9% of the tumors. In univariable survival analysis, HPV positivity was significantly correlated with improved OS (74% v 52%; P=.036) and DSS (84% v 52%; P=.002), and p16 positivity was significantly correlated with improved OS (76% v 30%; P<.001) and DSS (85% v 30%; P<.001). In multivariable COX analysis that included HPV status, p16 status, sex, T stage, N stage, and treatment, p16 positivity remained an independent prognostic factor for OS (hazard ratio [HR], 0.07; 95% CI, 0.01 to 0.61; P=.016) and DSS (HR, 0.07; 95% CI, 0.01 to 0.53; P=.011). CONCLUSION p16 positivity is an independent prognostic factor for OS and DSS in patients with AJCC stages I to III carcinoma of the anal canal.

Recombinant interleukin-2 in metastatic renal cell carcinoma—A European multicentre phase II study

This multinational, multicentre study represents the introduction of recombinant interleukin-2 (rIL-2) in Europe. From December 1987 to June 1989, 57 eligible patients with metastatic renal cell cancer were treated with rIL-2 administered as continuous intravenous infusion. 8 out of 51 evaluable patients responded (16%), 2 complete remission (CR) and 6 partial remission (PR). 10 patients had no change (20%). The response duration for CR was 209 and 394+ days. The median response duration for PR was 371 (range 140-506+) days. Dose-limiting grade 3-4 toxicities were hypotension in 52% of the patients, arrhythmia (4%), dyspnoea (8%), creatinine rise (4%), peripheral neurotoxicity (10%) and central neurotoxicity (10%). Toxicities most often recovered solely on interrupted therapy. 2 patients died due to catheter-related septicaemia and one patient died of rIL-2 induced renal failure. The study confirmed the antitumour efficacy of rIL-2 in renal cell cancer. Toxicities were numerous, but manageable by close observation in a normal oncology ward without routine use of an intensive care unit.

Predictive factors of response to cisplatin-based chemotherapy and the relation of response to survival in patients with metastatic urothelial cancer.

Purpose: To identify pretreatment variables predicting overall and complete response to cisplatin-based chemotherapy for metastatic urothelial cancer, and to study the relation between response and the duration of survival. Patients and methods: A total of 119 evaluable patients with recurrent locally advanced or metastatic urothelial cancer received cisplatin-based combination chemotherapy in four consecutive phase II studies from 1987 to 1997. The relationship of pretreatment variables and response was evaluated with logistic regression, and prognostic factors for survival were analyzed with Coxs multivariate model. Results: Response was achieved in 49% of the patients with a complete response rate of 15%. Good performance status and absence of bone metastases were independently predictive of overall response. Good performance status and normal hemoglobin were independently predictive of complete response. Median survival was 8.9 months. Performance status, alkaline phosphatase, s-creatinine, liver and bone metastases were independent prognostic factors for survival. Median survival was 12.4 months in responding patients and 6.3 in non-responding patients. Response to chemotherapy was included in the multivariate model and was the strongest prognostic factor for survival. Conclusion: The presence of bone metastases, low hemoglobin or poor performance status predicts decreased chance of response to chemotherapy. Response to chemotherapy is an independent prognostic factor for prolonged survival in patients with metastatic urothelial cancer.

Treatment of metastatic renal cell carcinoma by continuous intravenous infusion of recombinant interleukin-2: a single-center phase II study.

PURPOSE A single-center phase II study was performed to evaluate the efficacy of recombinant interleukin-2 (rIL-2) administered by continuous infusion to patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Thirty-one patients with RCC were entered onto the study. rIL-2 (Proleukin; Eurocetus Corp, Amsterdam, The Netherlands) was administered intravenously in a dose of 18 x 10(6) IU/m2 per 24 hours. A maximum of two induction cycles and four maintenance cycles were given. Each induction cycle consisted of two rIL-2 infusion periods of 120 hours and 108 hours duration, respectively; these were separated by a 6-day rest period. Each maintenance cycle consisted of a 120 hours rIL-2 infusion period. RESULTS Six of 30 assessable patients (20%) responded; two (7%) with a complete response (CR) and four (13%) with a partial response (PR). The response duration for patients with CR was 209 and 715+ days, and for those with PR 161, 197, 245, and 353 days. Seven patients had stable disease (SD) with a median duration of 261 days (range, 127 to 381 days). The overall median survival was 261 days (range, 13 to 905+ days). The most frequent toxicities requiring dose reductions of rIL-2 were: hypotension in 87% of patients, dyspnea in 32%, CNS toxicity in 55%, and an increase in serum creatinine levels in 48%. Septicemia occurred in 16% of patients. Toxicities usually reversed on interruption of rIL-2 infusion. One patient (3%) died as a result of the treatment from initial CNS toxicity followed by multiorgan failure. CONCLUSIONS The study confirmed the antitumor efficacy of rIL-2 administered by continuous infusion in patients with metastatic RCC. The response rate was similar to that obtained by high-dose bolus injections of rIL-2. Toxicity was substantial but manageable in a specialized oncology ward without routine use of an intensive care unit.