Anja Lorch

Prognostic Factors in Patients With Metastatic Germ Cell Tumors Who Experienced Treatment Failure With Cisplatin-Based First-Line Chemotherapy

PURPOSE To develop a prognostic model in patients with germ cell tumors (GCT) who experience treatment failure with cisplatin-based first-line chemotherapy. PATIENTS AND METHODS Data from 1,984 patients with GCT who progressed after at least three cisplatin-based cycles and were treated with cisplatin-based conventional-dose or carboplatin-based high-dose salvage chemotherapy was retrospectively collected from 38 centers/groups worldwide. One thousand five hundred ninety-four (80%) of 1,984 eligible patients were randomly divided into a training set of 1,067 patients (67%) and a validation set of 527 patients (33%). Seminomas were set aside for posthoc analyses. Primary end point was the 2-year progression-free survival after salvage treatment. RESULTS Overall, 990 patients (62%) relapsed and 604 patients (38%) remained relapse free. Histology, primary tumor location, response, and progression-free interval after first-line treatment, as well as levels of alpha fetoprotein, human chorionic gonadotrophin, and the presence of liver, bone, or brain metastases at salvage were identified as independent prognostic variables and used to build a prognostic model in the training set. Survival rates in the training and validation set were very similar. The estimated 2-year progression-free survival rates in patients not included in the training set was 75% in very low risk, 51% in low risk, 40% in intermediate risk, 26% in high risk, and only 6% in very high-risk patients. Due to missing values in individual variables, 69 patients could not reliably be classified into one of these categories. CONCLUSION Prognostic variables are important in patients with GCT who experienced treatment failure with cisplatin-based first-line chemotherapy and can be used to construct a prognostic model to guide salvage strategies.

Conventional-Dose Versus High-Dose Chemotherapy As First Salvage Treatment in Male Patients With Metastatic Germ Cell Tumors: Evidence From a Large International Database

PURPOSE Conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) may both be successfully used as salvage treatment for patients with metastatic germ cell tumors (GCTs) who experience progression with first-line treatment. PATIENTS AND METHODS Data on 1,984 patients with GCTs who experienced progression after at least three cisplatin-based cycles and were treated with either cisplatin-based CDCT or carboplatin-based HDCT chemotherapy were collected from 38 centers or groups worldwide. Of 1,984 patients, 1,594 (80%) were eligible, and among the eligible patients, 1,435 (90%) could reliably be classified into one of the following five prognostic categories based on prior prognostic classification: very low (n = 76), low (n = 257), intermediate (n = 646), high (n = 351), and very high risk (n = 105). Within each of the five categories, the progression-free survival (PFS) and overall survival (OS) after CDCT and HDCT were compared using the Cox model adjusted for significant distributional differences between important variables. RESULTS Overall, 773 patients received CDCT, and 821 patients received HDCT. Both treatment modalities were used with similar frequencies within each prognostic category. The hazard ratio for PFS was 0.44 (95% CI, 0.39 to 0.51) stratified on prognostic category, and the hazard ratio for OS was 0.65 (95% CI, 0.56 to 0.75), favoring HDCT. These results were consistent within each prognostic category except among low-risk patients, for whom similar OS was observed between the two treatment groups. CONCLUSION This retrospective analysis suggests a benefit from HDCT given as intensification of first salvage treatment in male patients with GCTs and emphasizes the need for another prospective randomized trial comparing CDCT to HDCT in this patient population.

Single Versus Sequential High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: A Prospective Randomized Multicenter Trial of the German Testicular Cancer Study Group

PURPOSE To compare single versus sequential high-dose chemotherapy (HDCT) as first or subsequent salvage treatment in patients with relapsed or refractory germ cell tumors (GCTs). PATIENTS AND METHODS Between November 1999 and November 2004, 230 patients were planned to be recruited in a prospective, randomized, multicenter trial comparing one cycle of cisplatin 100 mg/m2, etoposide 375 mg/m2, and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (CE; arm A) versus three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2, and cyclophosphamide 6,400 mg/m2 (CEC; arm B). RESULTS The study was stopped prematurely after recruitment of 216 patients as a result of excess treatment-related mortality in arm B. One hundred eleven (51%) of 216 patients were randomly assigned to sequential HDCT, and 105 (47%) of 216 patients were randomly assigned to single HDCT. Five (2%) of 216 patients had to be excluded because of non-GCT histologies at review. With a median follow-up time of 36 months, 109 (52%) of 211 patients were alive, and 91 (43%) of 211 patients were progression free. At 1 year, event-free, progression-free, and overall survival rates were 40%, 53%, and 80%, respectively, in arm A compared with 37%, 49%, and 61%, respectively, in arm B (P > .05 for all comparisons). Treatment-related deaths, mainly as a result of sepsis and cardiac toxicity, were less frequent in arm A (four of 108 patients, 4%) compared with arm B (16 of 103 patients, 16%; P < .01). CONCLUSION We found no difference in survival probabilities between single HDCT using CE and sequential HDCT using CEC. Sequential HDCT was better tolerated and resulted in fewer treatment-related deaths.

Sequential Versus Single High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: Long-Term Results of a Prospective Randomized Trial

PURPOSE To evaluate the long-term survival rates in patients with relapsed or refractory germ cell tumors (GCTs) after single or sequential high-dose chemotherapy (HDCT). PATIENTS AND METHODS Between November 1999 and November 2004, 211 patients with relapsed or refractory GCT were randomly assigned to treatment with either one cycle of cisplatin 100 mg/m(2), etoposide 375 mg/m(2), and ifosfamide 6 g/m(2) (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m(2) and etoposide 1,500 mg/m(2) (CE, arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m(2), etoposide 1,800 mg/m(2), and cyclophosphamide 6,400 mg/m(2) (CEC, arm B) followed by autologous stem-cell reinfusion. Long-term progression-free survival (PFS) and overall survival (OS) 6 years after random assignment of the last patient were compared by using the log-rank test. RESULTS Overall, 108 and 103 patients were randomly assigned to arms A and B, respectivelyl. The study was stopped prematurely because of excess treatment-related mortality in arm B (14%) compared with that in arm A (4%; P = .01). As of December 2010, nine (5%) of 211 patients were lost to follow-up; 94 (45%) of 211 are alive and 88 (94%) of 94 patients are progression free. Five-year PFS is 47% (95% CI, 37% to 56%) in arm A and 45% (95% CI, 35% to 55%) in arm B (hazard ratio [HR], 1.16; 95% CI, 0.79 to 1.70; P = .454). Five-year OS is 49% (95% CI, 40% to 59%) in arm A and 39% (95% CI, 30% to 49%) in arm B (HR, 1.42; 95% CI, 0.99 to 2.05; P = .057). CONCLUSION Patients with relapsed or refractory GCT achieve durable long-term survival after single as well as sequential HDCT. Fewer early deaths related to toxicity translated into superior long-term OS after sequential HDCT.

High dose chemotherapy as salvage treatment for unresectable late relapse germ cell tumors.

PURPOSE We assessed the activity of high dose chemotherapy in patients with unresectable late relapse germ cell tumors. MATERIALS AND METHODS A total of 35 patients with late relapse were included in a group of 216 treated with high dose chemotherapy as first or subsequent salvage treatment in a prospective, randomized, multicenter phase III trial comparing single vs sequential high dose chemotherapy. Late relapse was defined as unequivocal evidence of relapse more than 2 years after completion of cisplatin based chemotherapy. All patients were considered to have unresectable, progressive, late relapse germ cell tumors. Responders were scheduled for surgical resection of all residual lesions when technically feasible. RESULTS We identified 4 late relapse groups, including late relapse in 20 of 35 patients (57%) after first line treatment (group 1), in 4 (11%) after first salvage treatment (group 2), in 4 (11%) after initial and after first salvage treatment (group 3), and in 7 (20%) after first line treatment and salvage treatment with rapid progression thereafter who were randomized to a high dose chemotherapy trial (group 4). Median time to late relapse was 4.7 years (range 2.1 to 18.3) in all groups. Resection of all residual lesions could be done in 15 of 35 patients (43%). At a median followup of 5.6 years (range 1.9 to 8.5) 5 of 35 patients (14%) had no progression, resulting in 15% projected progression-free survival. CONCLUSIONS Management for unresectable late relapse germ cell tumors remains controversial. High dose chemotherapy followed by resection of all residual lesions can result in long-term remission in individuals.

The role of residual tumor resection in the management of nonseminomatous germ cell cancer of testicular origin.

OBJECTIVE To assess the outcome of patients with testicular nonseminomatous germ cell tumors (TNSGCT) undergoing intrathoracic residual tumor resection (RTR) after previous chemotherapy (CT) at a single institution. METHODS The office records of all patients who underwent intrathoracic RTR for TNSGCT after CT at a single institution from January 2000 through December 2006 were reviewed. RESULTS There were 124 consecutive patients (age 33.1 ± 8.4 years) with residual masses who underwent 189 surgical procedures. Morbidity and mortality rates were 12.7 and 0.5%, respectively. Complete resections could be achieved in 121 patients (97.6%). In the resected lung masses, necrosis was the predominant histology, (44.4 vs. 29% in mediastinal masses p = 0.018). Mature teratoma was the leading histology in the mediastinum (62.1 vs. 39.5% in lung masses, p = 0.0006). Fifty-nine out of 124 patients (47.6%) required interventions at both lungs and had discordant histological results in 20.3% (12/59) of the cases. Mean survival was 86.6 ± 2.6 months. The overall 5-year-survival and 10-year survival rates were 87 and 85%, respectively. Viable cancer, incomplete resections, age ≥ 34 years, and major pulmonary resections were associated with inferior survival in a univariate Cox proportional hazards model. In a multivariable Cox proportional hazards model, viable cancer, incomplete resections, and major pulmonary resections remained significant prognostic factors. CONCLUSIONS In selected TNSGCT patients with residual masses, RTR can be performed safely after CT. RTR should be attempted at all sites because of possible discordant histological differentiation. Complete and parenchyma-sparing resections are associated with excellent long-term survival, which can be influenced by the surgeon.

Interdisciplinary Evidence-Based Recommendations for the Follow-Up of Testicular Germ Cell Cancer Patients

Over the last years, clear treatment recommendations for patients with testicular cancer have been published. This has led to significant improvements in outcome and survival. Moreover, active surveillance has become a cornerstone in the management of clinical stage I seminomatous and non-seminomatous germ cell tumors. On the other hand, the existing recommendations for the follow-up of testis cancer patients are unclear and differ widely. Follow-up recommendations in this young patient population have to be as evidence based as possible, feasible in order to ensure adherence, and must not be harmful. Therefore, attention has to be paid to the negative impact of unnecessary radiation exposure. Recently, new evidence became available regarding the relapse pattern of different disease stages of testicular cancer, the use of imaging at follow-up, and the risks of excessive radiation due to imaging, and in particular that of computed tomography (CT) scans. This article summarizes the recommendations for follow-up of testicular cancer patients of an interdisciplinary multinational working group consisting of urologists, medical oncologists, and radiation oncologists.

Outcome of men with relapse after adjuvant carboplatin for clinical stage i seminoma

Purpose Adjuvant carboplatin is one of three management strategies that may follow inguinal orchiectomy in clinical stage I seminoma. However, little is known about the outcome of patients who experience a relapse after such treatment. Patients and Methods Data from 185 patients who relapsed after adjuvant carboplatin between January 1987 and August 2013 at 31 centers/groups from 20 countries were collected and retrospectively analyzed. Primary outcomes were disease-free survival and overall survival. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results With a median follow-up of 53 months (95% CI, 48 to 60 months) the 5-year disease-free survival was 82% (95% CI, 77% to 89%), and the 5-year overall survival was 98% (95% CI, 95% to 100%). The median time from orchiectomy to relapse was 19 months (95% CI, 17 to 23 months); 15% (95% CI, 10% to 21%) of relapses occurred > 3 years after treatment. The majority of relapses were detected by computed tomography scan during routine follow-up, 98% in the International Germ Cell Cancer Collaborative Group good prognosis group. Chemotherapy was administered to 92% of patients, mostly as standard first-line treatment corresponding to stage; 8% of patients had additional local treatments. Only 28 patients experienced a second relapse. At last follow-up, 174 (94%) of 185 patients were alive without disease, and four patients with disease. Seven patients died, three of whom due to progressive disease. Conclusion Within the limitations of a retrospective analysis, the results suggest that the majority of patients who experience a relapse after adjuvant carboplatin for clinical stage I seminoma can be successfully treated with a cisplatin-based chemotherapy regimen adequate for stage. Because 15% of the relapses occurred > 3 years after adjuvant treatment, a minimum of 5 years follow-up is recommended.

Efficacy and safety of gemcitabine, oxaliplatin, and paclitaxel in cisplatin-refractory germ cell cancer in routine care—Registry data from an outcomes research project of the German Testicular Cancer Study Group

BACKGROUND Chemotherapy (CTX) with gemcitabine, oxaliplatin, and paclitaxel (GOP) has demonstrated efficacy with an overall response rate (ORR) of approximately 50% in patients with multiply relapsed or cisplatin-refractory germ cell cancer (GCC) or both within a phase II study. We analyzed the efficacy and safety of GOP in routine clinical practice within a registry of the German Testicular Cancer Study Group. METHODS Overall, 63 patients with refractory GCC, who received GOP because of progression under cisplatin-based treatment or relapse after high-dose CTX, were included in this database. Patient characteristics, response rate, toxicity, progression-free and overall survival (OS) were analyzed. For further risk stratification, univariate and multivariate analyses were performed. RESULTS GOP was applied as second to eighth treatment line (median fourth) after cisplatin-based CTX. The ORR was 44% with complete remissions achieved in 8 patients (4 patients with CTX plus additional residual tumor resections and 4 patients with CTX alone) and partial remissions achieved in 19 of all for best response evaluable patients. The median progression-free survival and OS were 4.0 months (95% CI: 3.08-4.94) and 13.3 months (95% CI: 9.50-17.06), respectively. Long-term OS of>2 years was achieved in 13 (21%), and grade III and IV toxicities, mainly thrombocytopenia and leukopenia, occurred in 29 patients. CONCLUSION Our results were similar compared with the previous results from the phase II study with a distinct activity with an ORR of 44%, and a long-term OS in 21% of the patients. Our data support the recommendation to use GOP ± secondary surgery in patients with multiply refractory metastatic GCC.

Interdisciplinary Evidence-Based Recommendations for the Follow-Up of Early Stage Seminomatous Testicular Germ Cell Cancer Patients

Purpose:To provide guidance regarding follow-up procedures after initial treatment of early stage testicular seminoma (clinical stages (CS) I–II A/B) based on current published evidence complemented by expert opinion.Methods and Material:An interdisciplinary, multinational working group consisting of urologists, medical oncologists, and radiation oncologists analyzed the published evidence regarding follow-up procedures in various stages of seminomatous and nonseminomatous testicular cancers. Focusing on radiooncological aspects, the recommendations contained herein are restricted to early stage seminoma (with radiotherapy being a standard treatment option). In particular, extent, frequency, and duration of imaging at follow-up were analyzed concerning relapse patterns, risk factors, and mode of relapse detection.Results:Active surveillance, adjuvant carboplatin or radiotherapy are equally accepted options for CS I seminoma but they result in different relapse rates and patterns. Usually relapses occur within the first 2(–6) years. Routinely performed follow-up using computerized tomography (CT) after adjuvant treatment yield only low detection rates of recurrences. Therefore, there is no evidence to maintain routine examinations every 3–4 months. After treatment of stage IIA/B, detection rates of relapses or progression identified solely by routinely performed CT during follow-up are low.Conclusion:Considering lifelong cure rates of up to 99% for patients treated for seminoma CS I–IIA/B, the negative impact of unnecessary ionizing radiation exposure has to be considered. The presented recommendations for various follow-up scenarios for early stage seminoma strongly promote the restrictive use of imaging procedures that utilize ionizing radiation (especially CT), due to its potential to induce secondary malignancies.ZusammenfassungZiel:Empfehlungen für die Nachbeobachtung nach Primärtherapie von Patienten mit testikulärem Seminom der klinischen Stadien (CS) I und IIA/B auf Basis aktueller publizierter Evidenz und ergänzender Expertenmeinung.Material und Methodik:Eine interdisziplinäre multinationale Arbeitsgruppe von Urologen, internistischen Onkologen und Strahlentherapeuten analysierte die publizierten Empfehlungen zur Nachsorge von Patienten mit testikulären Keimzellmalignomen unterschiedlicher Stadien. Mit Blick auf radioonkologische Aspekte wurden Nachsorgeempfehlungen für seminomatöse Hodentumoren in Frühstadien, zu deren Heilung die Radiotherapie beiträgt, aktualisiert. Dabei wurden Ausmaß, Frequenz und Zeiträume bildgebender Verlaufskontrollen bezüglich Rückfallmuster, Risikofaktoren und Art der Rückfalldetektion untersucht.Ergebnisse:Aktive Surveillance, adjuvante Carboplatin- oder Radiotherapie gelten als gleichwertige Optionen beim Seminom Stadium I mit jeweils unterschiedlichen Rückfallraten und -mustern. Die allermeisten Rückfälle erfolgen in den ersten 2(–6) Jahren. 3–4 monatlich routinemäßig erfolgende CT-Kontrollen nach adjuvanter Therapie führen zu nur sehr niedrigen Detektionsraten. Nach kurativer Radiotherapie wegen CS IIA/B sind die mit alleiniger CT diagnostizierten Rückfall- oder Progressionsraten ebenfalls niedrig.Schlussfolgerungen:Da bis zu 99% der Patienten mit Seminom im Frühstadium dauerhaft geheilt werden, sind insbesondere negative Auswirkungen durch Expositionen mit ionisierender Strahlung bei Nachbeobachtungsuntersuchungen zu beachten. Die hier für die unterschiedlichen Szenarien und Stadien differenzierten praxisorientierten Empfehlungen zielen auf einen restriktiven Einsatz von radiologischen Bildgebungsverfahren ab. Damit sollen Strahlenexpositionen im Rahmen der Nachbeobachtung reduziert werden, da diese zur Entwicklung von Sekundärmalignomen beitragen können.