Assessment of the radiation-equivalent of chemotherapy contributions in 1-phase radio-chemotherapy treatment of muscle-invasive bladder cancer.

PURPOSE: To estimate the radiation equivalent of the chemotherapy contribution to observed complete response rates in published results of 1-phase radio-chemotherapy of muscle-invasive bladder cancer. METHODS AND MATERIALS: A standard logistic dose-response curve was fitted to data from radiation therapy-alone trials and then used as the platform from which to quantify the chemotherapy contribution in 1-phase radio-chemotherapy trials. Two possible mechanisms of chemotherapy effect were assumed (1) a fixed radiation-independent contribution to local control; or (2) a fixed degree of chemotherapy-induced radiosensitization. A combination of both mechanisms was also considered. RESULTS: The respective best-fit values of the independent chemotherapy-induced complete response (CCR) and radiosensitization (s) coefficients were 0.40 (95% confidence interval -0.07 to 0.87) and 1.30 (95% confidence interval 0.86-1.70). Independent chemotherapy effect was slightly favored by the analysis, and the derived CCR value was consistent with reports of pathologic complete response rates seen in neoadjuvant chemotherapy-alone treatments of muscle-invasive bladder cancer. The radiation equivalent of the CCR was 36.3 Gy. CONCLUSION: Although the data points in the analyzed radio-chemotherapy studies are widely dispersed (largely on account of the diverse range of chemotherapy schedules used), it is nonetheless possible to fit plausible-looking response curves. The methodology used here is based on a standard technique for analyzing dose-response in radiation therapy-alone studies and is capable of application to other mixed-modality treatment combinations involving radiation therapy.

Radio-chemotherapy for bladder cancer: Contribution of chemotherapy on local control.

The purpose of this study was to review the magnitude of contribution of chemotherapy (CT) in the local control of muscle invasive bladder carcinoma in the studies where a combined radio-chemotherapy (RCT) was used (how much higher local control rates are obtained with RCT compared to RT alone). Studies on radiotherapy (RT) and combined RCT, neo-adjuvant, concurrent, adjuvant or combinations, reported after 1990 were reviewed. The mean complete response (CR) rates were significantly higher for the RCT studies compared to RT-alone studies: 75.9% vs 64.4% (Wilcoxon rank-sum test, P = 0.001). Eleven of the included RCT studies involved 2-3 cycles of neo-adjuvant CT, in addition to concurrent RCT. The RCT studies included the one-phase type (where a full dose of RCT was given and then assessment of response and cystectomy for non-responders followed) and the two-phase types (where an assessment of response was undertaken after an initial RCT course, followed 6 wk later by a consolidation RCT for those patients with a CR). CR rates between the two subgroups of RCT studies were 79.6% (one phase) vs 71.6% (two-phase) (P = 0.015). The average achievable tumour control rates, with an acceptable rate of side effects have been around 70%, which may represent a plateau. Further increase in CR response rates demands for new chemotherapeutic agents, targeted therapies, or modified fractionation in various combinations. Quantification of RT and CT contribution to local control using radiobiological modelling in trial designs would enhance the potential for both improved outcomes and the estimation of the potential gain.

Biologically effective dose-response relationship for breast cancer treated by conservative surgery and postoperative radiotherapy.

PURPOSE: To find a biologically effective dose (BED) response for adjuvant breast radiotherapy (RT) for initial-stage breast cancer. METHODS AND MATERIALS: Results of randomized trials of RT vs. non-RT were reviewed and the tumor control probability (TCP) after RT was calculated for each of them. Using the linear-quadratic formula and Poisson statistics of cell-kill, the average initial number of clonogens per tumor before RT and the average tumor cell radiosensitivity (alpha-value) were calculated. An alpha/beta ratio of 4 Gy was assumed for these calculations. RESULTS: A linear regression equation linking BED to TCP was derived: -ln[-ln(TCP)] = -ln(No) + alpha(*) BED = -4.08 + 0.07 (*) BED, suggesting a rather low radiosensitivity of breast cancer cells (alpha = 0.07 Gy(-1)), which probably reflects population heterogeneity. From the linear relationship a sigmoid BED-response curve was constructed. CONCLUSION: For BED values higher than about 90 Gy(4) the radiation-induced TCP is essentially maximizing at 90-100%. The relationship presented here could be an approximate guide in the design and reporting of clinical trials of adjuvant breast RT.

Use of the concept of equivalent biologically effective dose (BED) to quantify the contribution of hyperthermia to local tumor control in radiohyperthermia cervical cancer trials, and comparison with radiochemotherapy results.

PURPOSE: To express the magnitude of contribution of hyperthermia to local tumor control in radiohyperthermia (RT/HT) cervical cancer trials, in terms of the radiation-equivalent biologically effective dose (BED) and to explore the potential of the combined modalities in the treatment of this neoplasm. MATERIALS AND METHODS: Local control rates of both arms of each study (RT vs. RT+HT) reported from randomized controlled trials (RCT) on concurrent RT/HT for cervical cancer were reviewed. By comparing the two tumor control probabilities (TCPs) from each study, we calculated the HT-related log cell-kill and then expressed it in terms of the number of 2 Gy fraction equivalents, for a range of tumor volumes and radiosensitivities. We have compared the contribution of each modality and made some exploratory calculations on the TCPs that might be expected from a combined trimodality treatment (RT+CT+HT). RESULTS: The HT-equivalent number of 2-Gy fractions ranges from 0.6 to 4.8 depending on radiosensitivity. Opportunities for clinically detectable improvement by the addition of HT are only available in tumors with an alpha value in the approximate range of 0.22-0.28 Gy(-1). A combined treatment (RT+CT+HT) is not expected to improve prognosis in radioresistant tumors. CONCLUSION: The most significant improvements in TCP, which may result from the combination of RT/CT/HT for locally advanced cervical carcinomas, are likely to be limited only to those patients with tumors of relatively low-intermediate radiosensitivity.

Use of concept of chemotherapy-equivalent biologically effective dose to provide quantitative evaluation of contribution of chemotherapy to local tumor control in chemoradiotherapy cervical cancer trials.

PURPOSE: To express the magnitude of the contribution of chemotherapy to local tumor control in chemoradiotherapy cervical cancer trials in terms of the concept of the biologically effective dose. METHODS AND MATERIALS: The local control rates of both arms of each study (radiotherapy vs. radiotherapy plus chemotherapy) reported from randomized controlled trials of concurrent chemoradiotherapy for cervical cancer were reviewed and expressed using the Poisson model for tumor control probability (TCP) as TCP = exp(-exp E), where E is the logarithm of cell kill. By combining the two TCP values from each study, we calculated the chemotherapy-related log cell kill as Ec = ln[(lnTCP(Radiotherapy))/(lnTCP(Chemoradiotherapy))]. Assuming a range of radiosensitivities (alpha = 0.1-0.5 Gy(-1)) and taking the calculated log cell kill, we calculated the chemotherapy-BED, and using the linear quadratic model, the number of 2-Gy fractions corresponding to each BED. The effect of a range of tumor volumes and radiosensitivities (alpha Gy(-1)) on the TCP was also explored. RESULTS: The chemotherapy-equivalent number of 2-Gy fractions range was 0.2-4 and was greater in tumors with lower radiosensitivity. In those tumors with intermediate radiosensitivity (alpha = 0.3 Gy(-1)), the equivalent number of 2-Gy fractions was 0.6-1.3, corresponding to 120-260 cGy of extra dose. The opportunities for clinically detectable improvement are only available in tumors with intermediate radiosensitivity with alpha = 0.22-0.28 Gy(-1). The dependence of TCP on the tumor volume decreases as the radiosensitivity increases. CONCLUSION: The results of our study have shown that the contribution of chemotherapy to the TCP in cervical cancer is expected to be clinically detectable in larger and less-radiosensitive tumors.

Radiobiologic modeling of cytoprotection effects in radiotherapy.

PURPOSE: To investigate the potential for mathematical modeling of the normal tissue-sparing effects of cytoprotective agents used in conjunction with radiotherapy and chemotherapy. METHODS AND MATERIALS: The linear quadratic model was modified to include a "cytoprotection factor," in two alternative ways. The published results on the incidence of treatment-related oral mucositis in patients treated for head-and-neck carcinoma using radiotherapy alone or combined with chemotherapy were assessed against the model to determine the likely values of the cytoprotection factor required to confer a reasonable degree of cytoprotection. RESULTS: In both of the model alternatives considered, a cytoprotection factor value of < or = 0.85 was required for a clinically detectable degree of cytoprotection to be realized. A cytoprotection factor value of 0.85 would mean that the radiation sensitivity coefficients would be effectively reduced by 15% on account of the action of the cytoprotector. CONCLUSION: The incorporation of a cytoprotection factor into an existing linear quadratic method would allow a quantitative assessment of cytoprotection and could be useful in the design of future clinical studies.

Monte Carlo dosimetric evaluation of high energy vs low energy photon beams in low density tissues.

BACKGROUND AND PURPOSE: Low megavoltage photon beams are often the treatment choice in radiotherapy when low density heterogeneities are involved, because higher energies show some undesirable dosimetric effects. This work is aimed at investigating the effects of different energy selection for low density tissues. PATIENTS AND METHODS: BEAMnrc was used to simulate simple treatment set-ups in a simple and a CT reconstructed lung phantom and an air-channel phantom. The dose distribution of 6, 15 and 20 MV photon beams was studied using single, AP/PA and three-field arrangements. RESULTS: Our results showed no significant changes in the penumbra width in lung when a pair of opposed fields were used. The underdosage at the anterior/posterior tumor edge caused by the dose build-up at the lung-tumor interface reached 7% for a 5 x 5 cm AP/PA set-up. Shrinkage of the 90% isodose volume was noticed for the same set-up, which could be rectified by adding a lateral field. For the CT reconstructed phantom, the AP/PA set-up offered better tumor coverage when lower energies were used but for the three field set-up, higher energies resulted to better sparing of the lung tissue. For the air-channel set-up, adding an opposed field reduced the penumbra width. Using higher energies resulted in a 7% cold spot around the air-tissue interface for a 5 x 5 cm field. CONCLUSIONS: The choice of energy for treatment in the low density areas is not a straightforward decision but depends on a number of parameters such as the beam set-up and the dosimetric criteria. Updated calculation algorithms should be used in order to be confident for the choice of energy of treatment.

Prognostic impact of tumor volumetry in patients with locally advanced head-and-neck carcinoma (non-nasopharyngeal) treated by radiotherapy alone or combined radiochemotherapy in a randomized trial.

PURPOSE: Tumor volume (TV) is one of the main reported factors determining the outcome of treatment in head-and-neck carcinomas. In this study, the prognostic impact of TV was explored in the context of a randomized trial with the patients assigned to receive standard radiotherapy (RT) alone or RT plus platinum compounds (RT alone, RT plus cisplatin, or RT plus carboplatin). METHODS AND MATERIALS: The tumor outlines were traced and digitized on each pretreatment CT slice for each of the 101 patients studied. Taking into account the magnification factor of the scan and CT slice thickness, a computer with specifically designed software calculated the TV in cubic centimeters. RESULTS: The median overall survival for the whole group of patients was 21.6 months (95% confidence interval, 13.0-30.2) and the 3-year survival rate was 40%. The addition of platinum compounds to RT (Groups 2 and 3) significantly improved the survival rate (RT alone vs. RT plus cisplatin, hazard ratio 0.36, p = 0.002; RT alone vs. RT plus carboplatin, hazard ratio 0.53, p = 0.029). In univariate analysis, the most significant parameters for survival were treatment group, total gross tumor volume (TGTV), complete response, nodal GTV, primary GTV, and performance status. In multivariate analysis, treatment group, TGTV, gender, and primary site were independent prognostic factors for survival. A prognostic threshold of 22.8 cm(3) was detected for TGTV. Patients with a TGTV of <22.8 cm(3) were more likely to achieve a complete response and had a median survival of 45.3 months, and those with a TGTV >22.8 cm(3) had a median survival of 12.3 months (log-rank test, p = 0.0102). CONCLUSION: The prognostic significance of the TGTV was confirmed and a cutoff value of 22.8 cm(3) derived. Our data indicated that locally advanced head-and-neck carcinomas should not be treated by standard (once-daily) RT alone. Tumor size and disease subsite should be taken into account in future randomized trials to increase their statistical power.

Re-irradiation in conjunction with liposomal doxorubicin for the treatment of skin metastases of recurrent breast cancer: a radiobiological approach and 2 year of follow-up.

Thirty patients with local relapses after radical mastectomy and radiotherapy and undergoing infusion of liposomal doxorubicin (40 mg/m(2) monthly for 6 months) were randomized to receive re-irradiation. Radiotherapy was with either 17 fractions of 1.8 Gy, 5 days a week (N=15, group A) or 4 Gy plus two fractions of 3 Gy the 1st week and six fractions of 3 Gy given every second day (N=15, group B). Eight patients from group A (53.3%) and nine patients (60%) from group B demonstrating a clinically complete response (P=0.9). Grade I/II acute skin toxicity was monitored in 26.6% of patients in group A versus 73.3% in group B. The radiation schedule of group A seems superior for grade I/II acute (P=0.027) and late (P=0.015) skin toxicity. The linear quadratic model enabled the prediction of tumor response as well as normal skin reactions.