Market and patient access to new oncology products in Europe: a current, multidisciplinary perspective.

To air challenging issues related to patient and market access to new anticancer agents, the Biotherapy Development Association--an international group focused on developing targeted cancer therapies using biological agents--convened a meeting on 29 November 2007 in Brussels, Belgium. The meeting provided a forum for representatives of pharmaceutical companies and academia to interact with European regulatory and postregulatory agencies. The goal was to increase all parties' understanding of their counterparts' roles in the development, licensure, and appraisal of new agents for cancer treatment, events guided by an understanding that cancer patients should have rapid and equitable access to life-prolonging treatments. Among the outcomes of the meeting were a greater understanding of the barriers facing drug developers in an evolving postregulatory world, clarity about what regulatory and postregulatory bodies expect to see in dossiers of new anticancer agents as they contemplate licensure and reimbursement, and several sets of recommendations to optimize patients' access to innovative, safe, effective, and fairly priced cancer treatments.

Quality control of radical prostatectomy: a feasibility study.

The aim of this study was to assess whether the quality of the surgical act could be an important prognostic factor for patients undergoing radical prostatectomy. This study also aims to investigate whether the surgical quality can be assessed by any means. Questionnaires were collected from 23 different institutes including 232 radical prostatectomies (RPr) performed for T1T2 prostate cancer. Blood loss, duration of surgery, margin status, postoperative prostate specific antigen (PSA) and urinary incontinence were analysed and correlated with the yearly number of RPr performed. The mean values obtained for each parameter were very different in the various centres. The outcome in terms of tumour control and incontinence could not be related to a higher or lower number of RPr performed. Quality control of RPr is feasible on the basis of an analysis of a few parameters, such as surgical margins, postoperative PSA and incontinence, that might recognise urologists that perform better or poorer than a proposed average.

Quality of life and treatment of hormone resistant metastatic prostatic cancer. The EORTC Genito-Urinary Group.

72 patients with hormone resistant, progressing prostatic cancer completed a self-administered questionnaire to assess subjective morbidity and quality of life before they were entered into a phase III trial of estramustine (34) vs. mitomycin (38). At least one post-treatment assessment was available in 43 patients. This considerable degree of non-compliance is explained by practical problems related to completion and collection of the questionnaires in these rapidly deteriorating patients. Doctors underestimated subjective morbidity (pain, decreased performance status, nausea) in 30-50% of the cases. Decreased functional status, fatigue and pain were identified as the most frequent major morbidities before study entry. In most patients, treatment did not reduce this morbidity. The routine application of self-administered quality of life questionnaires has considerable practical problems but yields clinically worthwhile information about subjective morbidity. Simple but relevant monitoring of subjective morbidity by the patient should be mandatory in cancer trials where palliation is a major endpoint.

Sarcomatoid carcinoma of the urinary bladder. Clinicopathologic analysis of 18 cases with immunohistochemical and electron microscopic findings.

Sarcomatoid carcinoma is a rare tumor in the urinary bladder and accounts for approximately 0.3% of all bladder malignancies. In this study, the clinicopathologic findings of 18 cases are described. Distribution of sex and age and clinical symptoms are not distinctive from transitional cell carcinoma. The tumor behaves as a high-grade malignancy with advanced initial stage and unfavorable outcome. Surgery is the therapy of choice. Histological differentiation from true sarcoma may be difficult. Recognition rests on the co-existence of an overt carcinomatous component or demonstration of the epithelial nature by immunohistochemistry or electron microscopy.

Combination 186Re-HEDP and cisplatin supra-additive treatment effects in prostate cancer cells.

UNLABELLED: Radionuclide therapy has proven to be an efficacious palliative treatment for metastatic prostate cancer. Its potential therapeutic possibilities may be substantially increased by combining it with effective radiosensitizing drugs. METHODS: This study explores the radiosensitizing properties of cisplatin when combined with 186Re-labeled hydroxyethylidene diphosphonate (HEDP) in the treatment of R3327-MATLyLu prostate cancer cells in vitro. A concomitant incubation during 4 d, combining various concentrations of cisplatin (0, 0.42, 0.83 and 1.67 micromol/L) and 186Re-HEDP (0, 1.84 and 3.69 MBq/mL [0, 50 and 100 microCi/mL, respectively]) was followed by the determination of the cell numbers surviving and the replating of these cells in semisolid agar. RESULTS: The surviving fraction of clonogenic tumor cells after combination treatment clearly showed synergism when analyzed by a panel of three different published analytical methods. In addition, analysis of variance demonstrated a significant interaction between radionuclide therapy and cisplatin-based chemotherapy (P < 0.001). Treatment with 186Re-HEDP and cisplatin by sequential incubation yielded similar, but never superior results. CONCLUSION: It is concluded that radionuclide therapy in combination with cisplatin is able, in principle, to improve therapeutic success rate in metastatic prostate cancer in a more than additive way.

Nerve growth factor stimulates in vitro invasive capacity of DU145 human prostatic cancer cells.

The prevalence of nerve growth factor (NGF) production in different human prostatic tumor cell lines (DU145, PC-3, LNCaP-FGC) was investigated using a specific enzyme-linked immunosorbent assay (ELISA) and compared to that of different human and rat prostatic tissue samples. In addition, the biological effects of NGF beta addition to the human prostatic cancer cell cultures were investigated. The ELISA technique showed the DU145 cell line to secrete measurable levels of NGF in the culture medium. When neurite-outgrowth determination in a pheochromocytoma cell line was used as a bioassay, the NGF synthesized by DU145 cells was confirmed to exhibit functional biological activity. No effect of exogenously added NGF could be established on tumor cell proliferation, on the basis of either colorimetric tetrazolium-based staining assay or bromodeoxyuridine incorporation. Also the expression of prostate specific acid phosphatase was not influenced by NGF addition. However, the in vitro invasive capacity (Matrigel) of DU145 cells was significantly increased by inclusion of 50 ng or 100 ng NGF beta/ml culture medium. In view of the clinically well-known perineural invasion of prostate cancer cells, the possible involvement of NGF as a (paracrine) factor in prostatic cancer metastatic behavior should be investigated further.

Comparison of the effects of high dose Estramustine phosphate and mitomycin C on the time to progression and length of survival of patients with progressive, advanced endocrine-independent prostatic cancer: an interim analysis of EORTC-GU Group study no. 30865.

Patients with hormone escaped advanced progressive prostate cancer were randomized either to receive either high-dose Estramustine phosphate orally or Mitomycin C by i.v. injection every 6 weeks until signs of progression or death supervened. Patients on both arms progressed rapidly, with a median time to progression of 5 months and a median length of survival of only 10 months. Toxicity was very considerable in both arms.

Orchidectomy versus Zoladex plus Eulexin in patients with metastatic prostate cancer (EORTC 30853).

A total of 327 patients with metastatic prostate cancer have been randomized to either orchidectomy or treatment with goserelin (Zoladez) 3.6 mg depot preparation combined with flutamide (Eulexin) 250 mg t.i.d. in a phase III study (EORTC 30853). A small but statistically significant difference in time to subjective and objective progression of disease was found in favour of the combination treatment. However, time from objective progression to death was longer in the group initially allocated to orchidectomy. Thus no difference was found in overall survival between the two treatment groups. The clinical significance of these differences requires further follow up and analysis.

Histological grading of papillary urothelial carcinoma of the bladder: prognostic value of the 1998 WHO/ISUP classification system and comparison with conventional grading systems.

AIM: To test the prognostic value of the 1998 WHO/ISUP (World Health Organisation/International Society of Urologic Pathology) consensus classification system in Ta papillary urothelial neoplasms of the bladder. METHODS: The histological slides of 322 patients with a primary Ta tumour were classified according to the consensus classification system, and recurrence free survival (RFS) and progression free survival (PFS) were assessed for a mean follow up period of 79 months. In the same patient group, the RFS and PFS rates for the 1973 WHO grading system and a low grade/high grade system were analysed. RESULTS: Recurrent tumours were seen in all categories of the 1998 WHO/ISUP classification system and five year RFS was not significantly different between the groups (p = 0.12). The five year PFS showed a small but significant difference (p = 0.04) between papillary neoplasms of low malignant potential (PNLMP) and high grade papillary urothelial carcinomas (HGPUCs). In the 1973 WHO classification, no significant difference was found in RFS and PFS between the different grades. In the low grade/high grade classification PFS was significantly better for low grade tumours (p = 0.01). CONCLUSION: The prognostic value of the 1998 WHO/ISUP classification system is limited to predicting PFS, especially between PNLMP and HGPUC. The prognostic value of this system over other grading systems is questionable.

Abnormalities detected in metaphase chromosomes in bladder carcinoma: prognostic value and comparison with histopathological factors.

The objective of this study was to detect the incidence and prognostic value of chromosomal aberrations in metaphase chromosomes (hypodiploidy, hyperdiploidy and/or structural abnormalities) in Ta and T1 transitional cell carcinoma (TCC) of the bladder. Of 266 patients, the metaphase chromosomes of the primary tumour were studied using a direct microscopic analysis and classified into two categories: normal and abnormal. Recurrence and progression were prospectively recorded during a median follow-up period of 40 months and in a retrospective analysis compared with other prognostic factors. Chromosomal abnormalities were found in 48% of Ta tumours and in 92% of T1 tumours. In univariate analysis, chromosomal abnormalities were associated with recurrence-free survival ( P=0.03) and progression-free survival ( P=0.01). In multivariate analysis, chromosomal abnormalities (RR=1.98) and age (RR=0.64) were independent predictors of recurrence-free survival but not progression-free survival.

Ultrasound in squamous cell carcinoma of the penis; a useful addition to clinical staging? A comparison of ultrasound with histopathology.

OBJECTIVE: As part of the staging procedure in squamous cell carcinoma of the penis, we assessed the role of ultrasound examination, in particular its role in assessing the extent and the invasion into the corpora. METHODS: From 1988 until 1992, all patients referred for primary treatment underwent ultrasound assessment with a 7.5 MHz linear array small parts transducer as part of the clinical workup. All ultrasound images were reviewed by one radiologist, without knowledge of the clinical outcome and were compared with the results obtained at histopathologic examination. RESULTS: In 16 patients the primary tumor and in 1 patient a recurrent cancer after primary therapy were examined. All tumors were identified as hypoechoic lesions. Ultrasound examination in the region of the glans was not able to differentiate between invasion of the subepithelial tissue and invasion into the corpus spongiosum, but absence or presence of invasion into the tunica albuginea of the corpus cavernosum was clearly demonstrated. Accurate measurement by ultrasound of maximum tumor thickness was seen in seven of sixteen examinations. CONCLUSIONS: While ultrasound examination is inexpensive and easily done, it is not accurate enough for staging small penile cancers located at the glans penis. However, for larger tumors ultrasound can be a useful addition to physical examination by delineating reliably the anatomic relations of the tumor to structures such as the tunica albuginea, corpus cavernosum, and urethra.

Radionuclide therapy for prostate cancer lumbar metastasis prolongs symptom-free survival in a rat model.

OBJECTIVES: The present study was initiated to explore the effects of hydroxyethylidene diphosphonate labeled with rhenium 186(186Re-HEDP) treatment on the progression of lumbar skeletal metastasis in an animal model and to correlate the eventual treatment efficacy with the radioisotope tissue distribution. METHODS: The effect of 186Re-HEDP on the progression of lumbar metastasis from prostate cancer was investigated in the Copenhagen rat model. Metastatic prostate tumor deposits were induced in male rats by tail vein injection of R3327-MATLyLu prostate tumor cells under concomitant clamping of the inferior caval vein. The development of clinical symptoms such as onset of hind leg paralysis and urinary bladder swelling was monitored and related to the presence of tumor cells within histologic sections of L-5 and L-6 vertebrae. RESULTS: The 186Re-HEDP administration, given either 1 day or 8 days after surgical induction of lumbar metastasis, could significantly increase the symptom-free survival of the animals. These results were confirmed by a significant decrease in the presence of histologically detectable tumor tissue. Biodistribution studies demonstrated the uptake of the major part of the radioisotope within bone tissue. Uptake of radioactivity within the lumbar vertebrae on a microscopic scale, as shown by phosphor screen autoradiography, was concentrated in areas of bone formation and turnover. Signs of radiotoxicity, such as bone marrow replacement by fat cells and the absence of megakaryocytes, were observed. CONCLUSIONS: The results show that radionuclide treatment using 186Re-HEDP is a potentially efficacious treatment option in prostate cancer disseminated to the skeleton. The optimal treatment dose should be determined carefully and aimed at acceptable levels of myelotoxicity.

Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). EORTC GU Group and EORTC Data Center.

Maximal androgen blockade (MAB), the eradication of the effects of adrenal androgens on prostate cancer cells after castration, has been used with differing success in the treatment of prostatic carcinoma. The aim of this randomized phase III study was to compare the efficacy and side effects of bilateral orchiectomy versus a combination of a luteinizing hormone-releasing hormone agonist (LHRH-A) depot formulation, goserelin acetate (3.6 mg s.c. once every four weeks), and flutamide (250 mg three times daily), in patients with metastatic cancer. Treatment usually continued until disease progression (or for a minimum of three months). Efficacy was assessed by response, time to disease progression, and duration of survival. Clinical evaluations, standard laboratory tests, and imaging examinations were carried out regularly. A total of 327 patients were entered in this study. There was a difference in response only for prostatic acid phosphatase (PAP) with a more frequent decrease of the serum values to normal in the serum in patients assigned to MAB treatment. The MAB treatment, however, proved significantly better for time to subjective progression, time to objective progression, time to first (subjective and objective) progression, and duration of survival. The most frequent side effects for both treatments included hot flushes and gynecomastia. In conclusion, significant time to progression and survival benefits are achieved by adding flutamide to an LHRH-A regimen, probably improving the quality of life of patients with metastatic cancer.

Glutathione S-transferase activity and subunit composition in transitional cell cancer and mucosa of the human bladder.

OBJECTIVES: Clinical data indicate that drug resistance to chemotherapy may occur in all stages of transitional cell cancer (TCC). Glutathione S-transferases (GSTs) are a family of detoxification enzymes composed of four different classes, denoted alpha (GSTA), mu (GSTM), pi (GSTP), and theta (GSTT), each containing one or more homo- or heterodimeric isoforms (GSTA1-1, GSTA1-2, and so forth), GSTs play a prominent role in drug detoxification and have been associated with resistance of tumor cells to anticancer agents. GST activity and isoenzyme levels were studied in TCC and normal bladder mucosa. METHODS: Enzyme activity was studied in samples of TCC (n = 37), adjacent normal bladder mucosa (n = 37), and in bladder mucosa of control patients without TCC (n = 46). GST isoenzyme composition was studied in mucosa and TCC of 14 patients and 11 controls. RESULTS: The mucosa of patients with TCC showed GST activity (191 +/- 21 nmol/min/mg cytosolic protein), similar to the mucosa of controls (176 +/- 15 nmol/min/mg). GST activity was significantly increased in TCC (666 +/- 157 nmol/min/mg) in comparison with adjacent mucosa (P < 0.003). In mucosa samples, the levels of GSTA (A1-1, A1-2, and A2-2) were below the detection limit in 92% of the samples. GSTM (GSTM1-1) was found in 9 controls and in 7 patients with TCC but not in the other 7 patients, whereas GSTP (GSTP1-1) could be detected in all samples. The levels of GSTM1-1 and GSTP1-1 were similar in mucosa of patients and controls. The mean relative increase of GSTP1-1 levels in TCC was 4.6-fold (P < 0.002). In the 7 patients with GSTM1-1-detectable expression in adjacent normal mucosa, mean GSTM1-1 levels in TCC were increased 2.8-fold compared with mean levels in normal adjacent mucosa (P < 0.02). GSTA was measured in five samples of TCC at relatively low levels. CONCLUSIONS: Overexpression of GSTP1-1 and GSTM1-1 may suggest that in the process of TCC carcinogenesis, a selection pressure occurs, resulting in a tumor with enhanced detoxification properties, including that of therapeutic drugs.

Assessment of hormone refractory prostate cancer.

OBJECTIVES: To define guidelines for the assessment of treatment in patients with hormone-refractory prostate cancer (HRPC). METHODS: In the light of modern research, and taking new treatment options into account, the Committee essays to specify different categories of patients entering clinical trials, and to define response criteria and those endpoints that are relevant in phase III studies and in short-term follow-up. RESULTS: HRPC comprises a range of disease states with varying responsiveness to therapy and length of survival. Patients with progression as evaluated by increasing prostate-specific antigen (PSA) values alone have a more favorable prognosis than those presenting with increasing tumor spread. In the assessment of these patients, the modes of previous therapy and the kind of tumor progression must be taken into account. The benefit of treatment of HRPC is often modest. While duration of survival remains the main and ultimate endpoint, the means of measuring short-term responsiveness to therapy are limited. A minority of patients have measurable tumor lesions. Decrease of PSA or other biochemical tumor markers may indicate depression of the tumor activity, but is not always associated with prolongation of survival. A variety of new treatments in HRPC are being investigated. They affect measurable tumor parameters in different ways. CONCLUSIONS: When a new agent is to be tested, it is important to measure all possible parameters before deciding which particular ones are appropriate for future investigations of this agent. In symptomatic patients, evaluation of subjective parameters, for example, relief of pain or improvement of performance status, is often the most reliable measure of treatment effect. However, these parameters should be clearly defined.

The use of adriamycin and its derivatives in the treatment of prostatic cancer.

Adriamycin and the other anthracyclines are amongst the most effective cytotoxic agents at the clinician's disposal. At least one of the reasons for their efficacy is the large number of mechanisms by which they can induce potentially lethal damage in a dividing malignant cell. Adriamycin and epirubicin are amongst the more effective agents in advanced hormone-independent prostate cancer. When given in full doses, they produce a reasonable number of objective as well as subjective responses, but the resultant toxicity precludes their use at high dose in many patients. In a number of well-documented studies, lower doses of these agents have yielded useful subjective responses with minimal toxicity.

The chemotherapy of advanced bladder cancer.

This paper traces the development of the use of chemotherapy in the management of advanced bladder carcinoma in Europe. A number of agents, including cisplatin, methotrexate, vinblastine, adriamycin, fluorouracil and cyclophosphamide, have been investigated singly and in combination in phase II studies, and it is envisaged that an ideal combination chemotherapy regimen giving lasting complete response will ultimately be used along with limited ablative surgery in the management of localised advanced bladder cancer. Careful application of the increasing knowledge of the biology of transitional cell carcinoma and strict adherence to rigid criteria of response in the assessment of new agents appears at last to offer hope of an improvement in the prognosis of invasive bladder cancer.

Total androgen ablation: European experience. The EORTC GU Group.

Zoladex plus flutamide significantly delays the time to progression (subjective, objective, first progression) compared with orchiectomy, but no difference in survival (death from all causes or from malignant disease) could be detected. Thus, a delay in the appearance of progression has not improved survival. In fact, the duration of survival after progression tends to be shorter on Zoladex plus flutamide. There is thus no evidence to suggest any survival benefit with Zoladex plus flutamide. The quality control of our data revealed acknowledged problems in defining responses in patients with advanced prostate cancer. The review of the Bone Scan Committee provided the data for Tables 5 to 7. These data must provoke some reflections and emphasize once again the heterogeneity of the studied patient population. Table 4 on pain response after 4 weeks is just one of the many items to be analyzed by the committees for response criteria and quality of life. We expect that the other trials face similar problems. More work and patience are needed to obtain a firm answer to this clinical problem. These efforts will never be wasted, however, because the combined results of these trials will increase our knowledge of the treated history of prostate cancer and will, we hope, indicate a net treatment benefit in some subsets of patients. An individually tailored treatment for each patient selected from the anonymous mass of cases of advanced prostate cancer would be the highest reward of our continued collaboration with all the study groups.

The management of localized prostate cancer.

At this point in time, the only possibility of curing prostate cancer is through the early detection and treatment of localized disease. The large number of treatment options available for localized prostate cancer, including radical prostatectomy, radiotherapy (either external beam or interstitial), hormone therapy and watchful waiting, can be confusing for the patient. These treatments are associated with different adverse effects, further complicating the treatment decision. As there will inevitably be a trade-off between expected cure and acceptable adverse effects, it is important to discuss all options with the patient. The doctor and patient must together decide the appropriate treatment for him and his tumor.

Synergism between cisplatin and radiotherapy in an in vitro prostate tumor cell line.

BACKGROUND: A combination of local irradiation and systemic cytotoxic treatment could improve therapeutic efficacy in metastatic prostate cancer. Radiosensitization can augment the treatment response to standard doses of radiation or enable lower treatment doses to be given; thus decreasing possible side effects. Intracellular glutathione has been implicated in the mechanism of such radio- sensitizing effects. MATERIALS AND METHODS: In the present study, R3327-MATLyLu prostate tumor cells were treated with cisplatin (0.0325 microM, 0.1625 microM, 0.325 microM and control "0 microM") in combination with irradiation (2, 4, 6, 8 Gy and control "0 Gy"). The survival of clonogenic tumor cells in agar was determined. In another experiment the irradiation was carried out after a 3 hours pretreatment with cisplatin concentrations (1.63 microM, 3.25 microM, 6.5 microM and control "0 microM") both in the presence and absence of Glutathione. RESULTS: In both experimental conditions the combination of cisplatin with irradiation yielded significant supra-additive treatment effects. CONCLUSIONS: The analysis of combination treatment effects, using two different methods confirmed the existence of synergism. The presence of a high level of extracellular glutathione did not alter the radiosensitization effects observed without glutathione, suggesting that the presence of glutathione may not be a major limiting factor in the radiosensitization effects observed in these investigations.