Treatment of disseminated non-seminomatous testicular cancer: the European experience

The majority of patients with disseminated germ cell cancer can be cured with cisplatin-based combination chemotherapy. For more than a decade the gold standard regimen is cisplatin, etoposide, and bleomycin (BEP). On both sides of the Atlantic, a number of studies have been carried out to either modify the toxicity of therapy in good prognosis patients or to improve the treatment outcome by intensifying the regimen or incorporating new agents in patients with intermediate or poor prognosis disease. This review discusses the trials that have been conducted in Europe, mainly through the European Organization of Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) in the United Kingdom, as well as the studies that are currently being conducted by the collaborative groups in Europe.     

Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer.

BACKGROUND: Because of the increasing number of long-term survivors of metastatic testicular germ-cell cancer, a general concern has been secondary morbidities, especially cardiovascular risk factors. PATIENTS AND METHODS: Thirty-two patients treated with cisplatin- and doxorubicin-containing chemotherapy > or = 13 years before the time of analyses were evaluated for neuro-, oto-, pulmonary-, vascular- and gonadal toxicity including evaluation of myocardial damage and cardiovascular risk factors and analysis of microcirculation. RESULTS: Thirty percent of the patients showed abnormal left ventricle function. Elevated follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in 75% of patients were often associated with low testosterone levels. Elevated total cholesterol levels were found in 82% and higher triglyceride levels in 44% of patients, most of them were overweight. About 25% of the patients developed diastolic arterial hypertension after chemotherapy. Reduced hearing was confirmed in 23% of patients, especially at frequencies higher than 3000 Hz. Moreover, 53% of patients presented transient evoked otoacoustic emissions. In 38% of patients non-symptomatic neuropathy was detected, in 28% symptomatic neuropathy, and in 6% disabling polyneuropathy. In 80% of patients with neuropathic symptoms additional morphological and functional abnormalities were found by nailfold capillary videomicroscopy, compared to only 57% of the patients without neuropathic symptoms. CONCLUSIONS: Patients cured by cisplatin-based chemotherapy for metastatic testicular cancer have to be cognizant of their unfavorable cardiovascular risk profile, that might be a greater risk than developing a relapse or second malignancy.     

Routine chest X-rays have no additional value in the detection of relapse during routine follow-up of patients treated with chemotherapy for disseminated non-seminomatous testicular cancer.

BACKGROUND: The routine follow-up of patients with disseminated non-seminomatous testicular cancer (DNSTC) treated with the combination of orchidectomy, polychemotherapy, and if needed, resection of the residual mass, consists of regular physical examinations, chest X-rays (CXR) and tumor marker assessments. Most guidelines for this routine follow-up originate from multi-center trials. In order to estimate the value of CXR in the detection of tumor relapse after complete remission, we reviewed all patients with disseminated testicular cancer treated with chemotherapy at the University Hospital Groningen. PATIENTS AND METHODS: Three hundred and fifty-three consecutive patients with DNSTC treated between February 1977 and February 1999 at our institution were reviewed. Two hundred and ninety (82.2%) patients, who were in complete remission after cisplatin-containing chemotherapy followed by, if necessary, resection of the residual mass, entered this analysis. The follow-up schedule consisted of regular physical examinations, tumor marker assessment (lactate dehydrogenase, beta-human chorionic gonadotropin and alpha-FP) and CXR. In all patients the first diagnostic sign of tumor relapse was documented. RESULTS: During a median follow-up of 107 months (range 8-261) a tumor relapse was documented in 33 patients (11.4%). Median time to relapse was 17 months (range 6-179) after the start of chemotherapy. In 27 patients, tumor relapse was first detected by a rise in tumor markers. Two patients presented their relapse with neurological complaints. Both were diagnosed with brain metastasis. In four patients the relapse was detected by both increase in tumor markers and abnormalities in the physical examination. In none of the 33 relapsed patients was routine CXR during follow-up involved in the detection of tumor recurrence. All but one of the relapsed patients had elevated tumor markers before the start of chemotherapy. The total number of CXR made during follow-up in all 290 patients was 10 160; none were diagnostic for the detected relapses. CONCLUSIONS: These data suggest that routine CXR has no additional value in the detection of tumor relapses during follow-up after chemotherapy in the subset of patients who present their DNSTC with increased tumor markers and are in complete remission after treatment. In order to save valuable resources, CXR can be omitted from the follow-up schedule after chemotherapy for marker-positive non-seminomatous testicular cancer in complete remission.     

Long-term follow-up of non-seminomatous testicular cancer patients with mature teratoma or carcinoma at postchemotherapy surgery

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53–110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74–112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.     

Antipyrine metabolism in patients with disseminated testicular cancer and the influence of cytostatic treatment

Summary Antipyrine plasma clearance and rates of metabolite formation were measured on four occasions in eight patients with disseminated nonseminomatous testicular cancer. Antipyrine tests were performed before, during (2X), and after treatment with a combination of cisplatin (P), vinblastin (V), and bleomycin (B). Pretreatment values were compared with a male control group (n=14) matched for age and body weight. Antipyrine plasma clearance was 20% higher in patients with testicular cancer (first experiment) than in the control group. This difference was mainly due to a 35% higher clearance for production of 3-hydroxymethylantipyrine (HMA), while clearance for production of norantipyrine (NORA) and 4-hydroxyantipyrine (OHA) was not significantly different from the control group. A reduction in CL_HMA was observed after complete remission (fourth experiment), indicating that the presence of the tumor may be related to a selective increase of HMA formation. Treatment with the PVB combination resulted in a 30% increase in antipyrine plasma clearance (second and third experiments), whereas the rates of formation of the main metabolites of antipyrine were all increased to the same extent. These accelerating effects of PVB treatment persisted for at least 6 weeks after the start of the last treatment cycle.The data presented in this paper demonstrate that the presence of a testicular tumor and the use of cytostatics can have an accelerating and partially selective effect on oxidative drug-metabolizing enzyme activity in man.     

Long-term effects of chemotherapy in patients with testicular cancer.

PURPOSE: Combination chemotherapy regimens that include cisplatin (CDDP) and bleomycin (BLE) result in the cure of the majority of patients with malignant germ cell tumors of the testis. We investigated the long-term damage of such chemotherapy to renal, pulmonary, and hearing function. PATIENTS AND METHODS: Forty-three patients with disseminated testicular carcinoma were studied 1.5 to 9.3 years (median, 4.1 years) after completion of chemotherapy. All 43 patients received CDDP; of these, 39 also received BLE, 27 vinblastine (VLB), and 27 etoposide (VP-16). Mean cumulative doses of individual cytotoxic drugs administered were CDDP 483 mg/m2 (range, 189 to 1,173 mg/m2), BLE 160 mg/m2 (range, 81 to 311 mg/m2), VLB 31 mg/m2 (range, 19 to 158 mg/m2), and VP-16 667 mg/m2 (range, 242 to 1,455 mg/m2). RESULTS: In the majority of cases, values of renal, pulmonary, and hearing function were within the normal range before treatment. An initial decrease in renal, pulmonary, and hearing function was observed, with recovery of pulmonary function at late follow-up. On average, a decrease of 15% in creatinine clearance rates was observed at late follow-up. Long-term effect on audiometric function was considerable, but frequencies affected were outside the range of conversational speech. With multivariate analysis, no overall relation between the cumulative doses of the individual drugs and the loss in organ function was found; the cumulative doses of CDDP and BLE only contributed approximately 30% to the loss in renal function and vital capacity, respectively. CONCLUSION: Chemotherapy-induced pulmonary toxicity is reversible, whereas nephrotoxicity and ototoxicity are not. However, the long-term effects of chemotherapy in testicular cancer patients were minor and not invalidating.     

High-dose versus conventional-dose chemotherapy as first-salvage treatment in patients with non-seminomatous germ-cell tumors: a matched-pair analysis.

BACKGROUND: The purpose of this study was to compare high-dose chemotherapy (HDCT) with conventional-dose chemotherapy (CDCT) as first-salvage treatment in patients with relapsed or refractory non-seminomatous germ-cell tumors (NSGCT). PATIENTS AND METHODS: One hundred and ninety-three patients with relapsed or refractory NSGCT, between 1981 and 1995, were identified from two large databases. In 74 of these, intensification of first-salvage treatment by HDCT was planned. Patients were matched based on primary tumor location, response to first-line treatment, duration of this response and serum levels of the tumor markers, human chorionic gonadotrophin (HCG) and alpha-fetoprotein (AFP). Multivariate analyses were performed using event-free survival and overall survival as primary endpoints. RESULTS: Full matches on all five factors were found for 38 pairs of patients; for a further 17 pairs, matches on at least four factors could be identified. Hazard ratios in favor of HDCT were obtained between 0.72 and 0.84 [confidence interval (CI) 0.59-1.01] for event-free survival and between 0.77 and 0.83 (CI 0.60-0.99) for overall survival, depending on the type of analysis. CONCLUSIONS: The current analysis suggests a benefit from HDCT, with an estimated absolute improvement in event-free survival of between 6 and 12% and in overall survival of between 9 and 11% at 2 years. This benefit is lower than expected from previous phase I/II studies.     

High-dose versus low-dose vinblastine in cisplatin-vinblastine-bleomycin combination chemotherapy of non-seminomatous testicular cancer: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group

Two hundred fourteen patients with disseminated non-seminomatous testicular cancer were randomized to receive induction chemotherapy with cisplatin, vinblastine, and bleomycin (PVB). The randomization was for vinblastine 0.4 mg/kg/cycle or 0.3 mg/kg/cycle. The complete response (CR) rates to both regimens were identical: 68% and 71%, respectively. In addition, there was no significant difference in disease-free and overall survival. There was a significant decrease in the incidence of WBC nadirs below 1,000/microL: 29% and 13%, respectively (P = .01). Of the non-hematologic toxicities, there was a significant reduction in the incidence of mucositis: 53% and 37%, respectively (P = .006). The major prognostic factor was tumor volume. This study confirms that vinblastine 0.3 mg/kg/cycle in PVB chemotherapy is as effective and less toxic than vinblastine 0.4 mg/kg/cycle.     

Acute subjective morbidity after cisplatin-based combination chemotherapy in patients with testicular cancer: a prospective study

In a randomized trial, 22 patients with metastatic testicular cancer used low-fibre diet during and after their first cycle of cisplatin and vinblastine containing combination chemotherapy, in order to reduce the acute gastrointestinal post-treatment morbidity (Group 1). Their subjective morbidity, including aspects of general well-being, was compared to 23 comparable patients having no diet restrictions (Group 2). A third similarly composed group consisted of 10 testicular cancer patients without diet restrictions, who received etoposide (VP-16) instead of vinblastine. Low-fibre diet did not reduce the frequency or severity of the acute post-treatment gastrointestinal morbidity. Severe constipation and/or paralytic ileus was observed in 23 patients in Groups 1 and 2 and necessitated short-term hospitalization in 14. The substitution of vinblastine by etoposide resulted in a significant reduction of the acute gastrointestinal morbidity and in a considerable improvement of the patients' general well-being. It is concluded that VP-16 should be given instead of vinblastine to patients receiving cisplatin-based combination chemotherapy in order to maintain an optimal quality of life during cytostatic treatment. This study also indicates that the frequency and severity of subjective treatment-related morbidity often is underestimated by retrospective routine clinical assessment, and should preferably be assessed prospectively by frequently applied patients' questionnaires.     

Serum alpha-fetoprotein surge after the initiation of chemotherapy for non-seminomatous testicular cancer has an adverse prognostic significance.

It has been recognized that the tumour markers alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) may show a transient elevation after the initiation of chemotherapy in non-seminomatous testicular cancer. We investigated the prognostic importance of these so-called marker surges in a cohort of patients treated with cisplatin combination chemotherapy between 1983 and 1991. A total of 669 patients were studied. Of 352 patients who had an elevated AFP at the start of treatment and for whom we had data at both day 1 and day 8, 101 (29%) had a surge. Of 317 patients for whom we had data for HCG, 80 patients (25%) had a surge. It was found that an AFP surge was a strong adverse prognostic factor for progression [hazard ratio (HR) 2.28, P=0.005]. There was no statistically significant difference in survival (HR 1.65, P=0.13). There was no prognostic significance of a HCG surge, either for progression or for survival. To investigate whether a surge was an independent prognostic factor for progression and survival, multivariate Cox regression models were fitted using the independent prognostic factors for progression and survival and the surge/decline variable. An AFP surge was retained in the final model for progression. A HCG surge was of no prognostic importance for progression or survival. We conclude that an AFP surge has an adverse prognostic significance, independent of pretreatment characteristics.     

SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer

The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.     

Tumour necrosis is a postoperative prognostic marker for pancreatic cancer patients with a high interobserver reproducibility in histological evaluation

Background:

Tumour necrosis reflects the presence of hypoxia, which can be indicative of an aggressive tumour phenotype. The aim of this study was to investigate whether histological necrosis is a useful predictor of outcome in patients with pancreatic ductal carcinoma (PDC).

Methods:

We reviewed histopathological findings in 348 cases of PDC in comparison with clinicopathological information. We counted small necrotic foci (micronecrosis) as necrosis, in addition to massive necrosis that had been only defined as necrosis in previous studies. The reproducibility of identifying histological parameters was tested by asking five independent observers to blindly review 51 examples of PDC.

Results:

Both micronecrosis and massive necrosis corresponded to hypoxic foci expressing carbonic anhydrase IX detected by immunohistochemistry. Multivariate survival analysis showed that histological necrosis was an independent predictor of poor outcome in terms of both disease-free survival (DFS) and disease-specific survival (DSS) of PDC patients. In addition, metastatic status, and lymphatic, venous, and intrapancreatic neural invasion were independent prognostic factors for shorter DFS and metastatic status, margin status, lymphatic invasion, and intrapancreatic neural invasion were independent prognostic factors for DSS. The interobserver reproducibility of necrosis identification among the five independent observers was ‘almost perfect'' (κ-value of 0.87).

Conclusion:

Histological necrosis is a simple, accurate, and reproducible predictor of postoperative outcome in PDC patients.     

How safe is surveillance in patients with histologically low-risk non-seminomatous testicular cancer in a geographically extended country with limited computerised tomographic resources?

In patients with clinical stage I non-seminomatous testicular cancer only limited information is available about the administrative problems with the surveillance programme, in particular if this policy is to be implemented in a geographically extended country with limited computerised tomography (CT) resources. One hundred and two patients with non-seminomatous testicular cancer clinical stage I and low-risk histology (MRC criteria, UK) were followed by the surveillance policy for at least 1 year after orchiectomy (median 47 months, range 21-81 months). Twenty-two patients (22%) relapsed after a median time of 5 months (range 2-18 months), 14 of them in the retroperitoneal space. Serum alpha-fetoprotein and/or human chorionic gonadotrophin were elevated in eight of the 22 relapsing patients. The progression-free and cancer-corrected survival rates were 78% and 99% respectively. Patient non-compliance did not represent a major problem, whereas the regular and adequate performance of necessary CT examinations yielded some administrative difficulties. One and 3 years after orchiectomy about 50% of the relapse-free patients had no psychological problems and were satisfied with the surveillance programme, whereas 46% reported minor and 4% major psychological distress. Despite non-negligible administrative difficulties in geographically extended countries, surveillance is feasible and safe in compliant patients with low-risk non-seminomatous testicular cancer stage I. The responsible cancer centre and the local hospitals should establish a high degree of cooperation and enable adequate follow-up examinations in these patients.     

Intra-arterial chemotherapy in patients with breast cancer: a feasibility study.

The aim of this study was to assess the practicality of treating patients with various stages of breast cancer by means of regional (intra-arterial) chemotherapy. Three groups of patients received a median of four (range 2-4) cycles of combination chemotherapy: group I operable primary (n = 10); group II, locally advanced disease (n = 20); group III, recurrent locoregional disease (n = 22). The response rates (complete response, partial response and mixed response) in these groups of patients were 100% in groups I and II and 86% in group III. Morbidity included drug streaming and dysaesthesia in the hand. Patients in groups I and II had their tumours downstaged, allowing surgery to be performed. Local control was also achieved in group III when other treatment modalities had failed.     

Surgical aspects in the treatment of patients with testicular cancer.

We sit at a crossroads in the therapeutic treatment of patients with low-stage testicular cancer. The luxury of effective chemotherapy has allowed achievement of virtually 100% survival rates in patients with low-stage testicular cancer. The goal of urologists and oncologists in concert should be to minimize the long-term morbidity and to reduce the amount of therapy necessary to achieve these high survival rates. Patients with a low risk of lymphatic or disseminated metastases, such as those with low-stage tumors, without vascular invasion and with favorable histologic features (teratoma), are clearly candidates for observation protocols to be carried out in well-defined centers. It should be emphasized, however, that observation needs to be an active surveillance program for a minimum of 2 to 3 years after orchiectomy, with frequent chest roentgenography, tumor marker studies, and CT scanning. In the majority of patients with low-stage tumors, however, modified retroperitoneal lymph node dissection allows definitive staging, thus allowing treatment with a lesser amount of chemotherapy. Patients with bulky stage II disease require chemotherapy in hopes of avoiding the need for retroperitoneal lymph node dissection. In the group of patients with stage II disease with minimal retroperitoneal involvement (less than 3 cm in maximal diameter, stage IIA), approximately half of the patients can be treated by surgical approaches alone, although half will require postoperative chemotherapy. Testicular cancer at this time is one of the most successfully treated solid tumors. Although diagnostic tools are available, successful diagnosis still relies upon suspicion and physical findings. Staging techniques have improved but still have vast limitations, especially in patients with low-stage disease. By careful application of multimodal therapy, long-term survival and cure are likely in the majority of patients. Continued long-term observation is necessary, however, especially in patients with residual teratoma that has been resected. As we look to the 1990s, emphasis can be placed on finding less morbid treatments yet still maintaining the high success rates enjoyed in the treatment of this once nearly uniformly fatal tumor.