Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma

Purpose

Based on improvements of progression-free survival (PFS), new agents for metastatic renal cell carcinoma (mRCC) have been approved. It is assumed that one of the benefits is a delay in health-related quality of life (HRQoL) deterioration as a result of a delay in progression of disease. However, little data are available supporting this relationship. This study aims to provide insight into the most important determinants of HRQoL (including progression of disease) of patients with mRCC.

Methods

A patient registry (PERCEPTION) was created to evaluate treatment of patients with (m)RCC in the Netherlands. HRQoL was measured, using the EORTC QLQ-C30 and EQ-5D-5L, every 3 months in the first year of participation in the study, and every 6 months in the second year. Participation started as soon as possible following a diagnosis of (m)RCC. Random effects models were used to study associations between HRQoL and patient and disease characteristics, symptoms and treatment.

Results

Eighty-seven patients with mRCC completed 304 questionnaires. The average EORTC QLQ-C30 global health status was 69 (SD, 19) before progression and 61 (SD, 22) after progression of disease. Similarly, the average EQ-5D utility was 0.75 (SD, 0.19) before progression and 0.66 (SD, 0.30) after progression of disease. The presence of fatigue, pain, dyspnoea, and the application of radiotherapy were associated with significantly lower EQ-5D utilities.

Conclusions

Key drivers for reduced HRQoL in mRCC are disease symptoms. Since symptoms increase with progression of disease, targeted therapies that increase PFS are expected to postpone reductions in HRQoL in mRCC.

     

Prevention of febrile leucopenia after chemotherapy in high-risk breast cancer patients: no significant difference between granulocyte-colony stimulating growth factor or ciprofloxacin plus amphotericin B.

In a prospective randomized trial, 40 stage IV breast cancer patients undergoing intermediate high-dose chemotherapy (cyclophosphamide, 5-fluorouracil plus epirubicin or methotrexate), received either recombinant human G-CSF (rhG-CSF, group I) or ciprofloxacin and amphotericin B (CAB, group II) for prevention of febrile leucopenia (FL). In group I, seven of 18 patients developed FL (after 10/108 courses); in group II, seven of 22 patients (7/98 courses) (P = NS). Median hospitalization duration and costs were not different. RhG-CSF was 6.6 times more expensive per course than CAB. In conclusion, prophylactic CAB has similar efficacy to rhG-CSF in this setting, and is more cost-effective.     

i(12p)-negative testicular germ cell tumors. A different group?

Cytogenetic analysis was performed of three seminomas, two primary nonseminomas, and two mature residual teratomas following chemotherapy, all lacking i(12p). Testicular germ cell tumors without an i(12p) may represent a subgroup of germ cell tumors, also in their clinical course, compared with those having i(12p).     

The distribution of drug-efflux pumps, P-gp, BCRP, MRP1 and MRP2, in the normal blood-testis barrier and in primary testicular tumours

The drug-efflux pumps P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are present in the blood-testis barrier (BTB) and may hamper the delivery of cytotoxic drugs to the testis. The precise localisation of P-gp and MRP1 in testicular tissue and the presence of the efflux pumps MRP2 and breast cancer resistance protein (BCRP) in the BTB are unknown. We therefore studied the localisation of these pumps in the BTB in normal testis (n = 12), in non-seminoma (n = 10) seminoma (n = 10), and testicular lymphoma (n = 9). Slides were scored semi-quantitatively for P-gp, MRP1, MRP2 and BCRP and blood vessels with factor VIII antibody. In normal testis, P-gp and BCRP were strongly expressed by myoid cells and luminal capillary endothelial wall and P-gp also by Leydig cells. MRP1 was observed at the basal side of Sertoli cells and on Leydig cells. MRP2 was only weakly expressed by myoid cells. Seminomas and non-seminomas expressed P-gp and/or BCRP and/or MRP1, lymphomas strongly expressed P-gp, weakly expressed BCRP and did not or showed weak expression of MRP1. There was very little staining for MRP2 in the tumours. Newly formed vessels in all tumours only expressed P-gp and BCRP. P-gp, BCRP and MRP1 are present in different cell layers of the normal testis, suggesting the optimal protection of spermatogenesis. In germ cell tumours, this expression pattern may explain the chemoresistance observed to P-gp, BCRP and MRP1 substrates. In germ cell tumours and testicular lymphomas, P-gp and BCRP expression by tumour cells and by newly formed vessels may also contribute to chemoresistance. These findings underscore the importance of removing the affected testis in cases of primary germ cell tumours and testicular lymphomas, irrespective of whether the patient has already undergone chemotherapy.     

Clinical value of circulating endothelial cell detection in oncology

Given the importance of tumor vasculature in tumor biology and as a target for treatment, there is an increasing need for biomarkers that reflect effects impacting tumor vasculature accurately. Circulating endothelial cells (CECs) increase in number as a result of vascular damage in cancer and several other diseases. CEC count constitutes a promising tool for monitoring disease activity with potential to assess prognosis and response to treatment. Here, we address the current state-of-the-art of CEC enumeration as a biomarker in clinical oncology. We focus on technical issues concerning CEC detection, review results from clinical studies and explore future potential applications.     

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.     

High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.     

High dose etoposide for brain metastases of small cell lung cancer. A phase II study. The EORTC Lung Cancer Cooperative Group

Symptomatic brain metastases are found in about 40% of patients with small cell lung cancer. Cranial irradiation is the first line treatment for this form of metastatic disease. Frequently brain metastases recur after this treatment or develop after prophylactic cranial irradiation. For these patients no effective antitumour therapy is available. In this study the efficacy of high dose etoposide 1.5 g m-2 was evaluated. In 10 (43%) out of 23 evaluable patients a response was seen. Toxicity was severe with five aplasia-related deaths. For palliative purposes this regimen is too toxic in heavily pretreated patients.     

Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care

The group of soft tissue sarcomas in adult patients is a heterogeneous group with more than 40 different subtypes. While local treatment remains the mainstay for localized disease, systemic chemotherapy can importantly contribute in the treatment of advanced soft tissue sarcoma. For patients with metastatic disease, chemotherapy is a palliative treatment in the vast majority of the cases. In this setting, toxicity should not outweigh the potential benefits resulting from chemotherapy. In patients with locally advanced disease too extensive for local treatment, systemic chemotherapy can contribute to cure, provided that tumor shrinkage renders subsequent optimal local treatment possible. In these cases, chemotherapeutic regimens yielding the highest response rates achievable should be used. In the last decades, several randomized studies have aimed to determine whether combination regimens yield benefit over single-agent treatment in terms of response rate and overall survival. This review addresses the current available data on chemotherapy for adult patients with soft tissue sarcoma, excluding gastrointestinal stromal tumor, the Ewing-like sarcomas, and other small blue round cell tumors. In addition, it is increasingly recognized that future research in soft tissue sarcoma should focus on the identification of tumor factors that can serve as targets for treatment and that the diverse tumor subtypes should be analyzed separately for their sensitivity to systemic treatment. This review also focuses on these and other strategies that will hopefully lead to better out comes in this disease entity in the near future.     

The potential of statins as part of anti-cancer treatment

Statins are known to reduce mortality related to cardiovascular diseases. In recent years, evidence has accumulated that statins also exert anti-tumour activity for which numerous potential underlying mechanisms of action have been suggested. Accordingly, several case-control studies showed a reduction in cancer incidence in patients treated with statins. Furthermore, statins interact synergistically with several anti-tumour treatments in preclinical studies. Until now, only a few clinical studies are available that explore the optimal dose, feasibility, and efficacy of statins applied as single agents to control the growth of existing tumours. Studies investigating statins as part of a multi-drug regimen are completely lacking. Nevertheless, the interesting pre-clinical anti-tumour activity of statins combined with a favourable toxicity profile warrant their further development as anti-tumour agents, in particular as part of multi-drug regimens.