Calculated and simulated effects of heterogeneous dose distributions in radiotherapy using the dose volume inhomogeneity corrected biological equivalent dose formula with special reference to prostate cancer.

The aim of this study was to evaluate and estimate the impact on the biological effective dose (BED) of irradiation delivered to a tumour during high dose rate brachytherapy with a heterogeneous dose distribution in the target volume. The calculation of BED in combination with the critical-voxel model and the LQ (linear quadratic) model was used to evaluate the effect of different combinations of heterogeneous dose distribution. The model is called the dose volume inhomogeneity corrected BED (DVIC-BED). Different random and non-random combinations of radiobiological parameters were used to test the model. A simulated clinical treatment of two 10 Gy fractions of brachytherapy was used. In the simulations 0-100% of the target volume was simulated to receive only 80% of the total dose. Different alpha/beta ratios as well as a different alpha value were used. A drastic effect on the outcome was observed especially when the ratio was low and the alpha value was high. The clinical effect is amplified when the tumour is considered to have a step dose respond curve. A 5 Gy decrease in dose corresponds to a reduction in clinical or chemical control < or =10-25% in the interval 65-85 Gy. Random production of different values has basically the same effect as above. The result stresses the importance to have control of the dose and the target volume during brachytherapy of prostate cancer. This is even more important when monotherapy with high dose rate brachytherapy is used and with a low alpha/beta ratio. The advantage of using this formula is that it is based on the LQ/BED formula and that different treatments with different fractions and treatments can be summated independently of the homogeneity of the dose distribution.

Palliation of bone pain in prostate cancer using chemotherapy and strontium-89. A randomized phase II study.

Strontium-89 is an established alternative for the alleviation of bone pain in prostate cancer. There are few data evaluating the effect on pain of palliative chemotherapy. The aim of this randomized phase II study was to assess and compare the analgesic efficacy of strontium-89 and chemotherapy (FEM=5-FU, epirubicin, and mitomycin C) in 35 patients with disseminated, hormone-refractory prostate cancer suffering from persisting bone pain despite analgesic treatment. In order to minimize the risk for imbalances regarding the two patient groups, a double-blind randomization was performed. A significant reduction in pain intensity and pain frequency was registered in both patient groups (P < 0.01 in both groups after 3 weeks). Side effects were generally mild in the strontium-89 group and significantly more severe in the FEM group. The effect of FEM on pain is surprising as chemotherapy has generally only limited effect on tumor growth in bone metastases due to prostate cancer. A possible explanation is that FEM has an inhibitory activity on the inflammatory component of metastases.

Development of dextran derivatives with cytotoxic effects in human urinary bladder cancer cell lines.

BACKGROUND: In a previous study we reported on a new approach describing intravesical instillation of charged dextran in patients with superficial bladder carcinoma. The cationic derivative showed a strong tumor-selective accumulation. To develop this approach, the present study investigates the cytotoxic effect of cationic dextran derivatives on two urinary bladder cancer cell lines (J82 and 5637). METHODS: The dextran conjugates were prepared by periodate activation and subsequent coupling by reductive amination. A fluorimetric cytotoxicity assay (FMCA) was used for the cytotoxicity assay. The tumor cells were seeded into 96-well microtiter plates and different cationic dextran derivatives were added and incubated for 72 hours. RESULTS: The results showed that cationic epirubicin-dextran had a clear inhibitory effect on the growth in both cell lines (40-95% growth inhibition). The corresponding values for epirubicin (the reference) was 90-100% inhibition. Interestingly, cationic dextran had, by itself, a growth inhibitory effect. This cytotoxic effect could be strongly enhanced to be almost equal to the reference by changing the cationic sidegroup to aminohexane. Dextran alone showed no effect. CONCLUSION: The finding that cationic dextran by itself can be made cytotoxic, together with its capacity to accumulate in superficial bladder cancer, suggests possibilities for new therapeutic constructs. Cationic dextran with different cationic side-groups and in combination with cytotoxic drugs will be studied further. The cytotoxic mechanism needs to be elucidated.

Effective oral combination metronomic chemotherapy with low toxicity for the management of castration-resistant prostate cancer.

Prostate cancer (PC) was previously believed to be a chemoresistant disease. In recent years taxane-based chemotherapy has been shown to prolong survival in patients with castration-resistant prostate cancer (CRPC). It remains to be shown, however, which type of chemotherapy provides the most beneficial effect with the least amount of side effects. Seventeen patients with chemonaive CRPC were enrolled in a pilot study evaluating an orally administered chemo-hormonal treatment regimen using a weekly sequential combination called KEES; consisting of ketoconazole in combination with cyclophosphamide or etoposide in combination with estramustine administered on alternate weeks. Prednisone was administered throughout the treatment period. Prostate-specific antigen (PSA) response and acute and chronic toxicities were evaluated. Seventeen patients with CRPC were treated; eleven patients demonstrated a median reduction in PSA of 87% (range 26-99%). Ten (59%) patients responded with a decrease in PSA >50%. Thrombocytopenia and anaemia were the most common side effects. One study fatality was reported, however, it was unclear whether this was treatment related. In conclusion, KEES may be a promising option for patients with CRPC, resulting in a clear reduction in PSA with limited toxicity. Further clinical evaluation of this metronomic chemohormonal combination is underway.

Postoperative radiotherapy after prostatectomy--a review.

PURPOSE: The management of prostate adenocarcinomas using postoperative irradiation is a controversial question. The purpose of this study was to review the literature on the subject. MATERIAL AND METHODS: A total of 417 articles dealing with postoperative radiotherapy after radical prostatectomy in English literature (1990-2002) were reviewed in aspects of effect on survival, time of irradiation, risk factors, dose and technique and side effects. RESULTS AND DISCUSSION: No randomised studies have been performed and therefore no definitive conclusive data can be made concerning the efficiency of the concept. However, postoperative radiotherapy appears to increase local control preferably in pT3/4 prostatic carcinomas with seminal vesicles involvement and/or positive margins and/or high Gleason score and high postoperative PSA level. It has not been shown to improve survival. Severe side effects are reported in a low frequency. However, postoperative irradiation can cause severe side effects and postoperative adjuvant/salvage treatments should be delivered earliest 3-6 months after surgery and the total dose delivered to the prostate bed should be 65-70 Gy. Postoperative radiotherapy induces improved local control in patients with positive surgical margins and in patients with a local relapse, preferably if the tumour is small (i.e. PSA <1-2 ng/mL).