Dose optimization of fractionated external radiation and high-dose-rate intracavitary brachytherapy for FIGO stage IB uterine cervical carcinoma

: To determine the optimal dose combination scheme of external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary radiation (ICR) for maximizing tumor control while conferring an acceptable late complication rate in the treatment of Stage IB uterine cervical cancer.

: We retrospectively analyzed 162 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB squamous cell carcinoma of the uterine cervix who received definitive RT between May 1979 and December 1990. Before HDR-ICR, all patients received EBRT to a total dose of 40–46 Gy (median 45), administered during 4–5 weeks to the whole pelvis. HDR-ICR was given 3 times weeks to a total dose of 24–51 Gy (median 39) at point A, using a dose of 3 Gy/fraction. Central shielding from EBRT was begun after the delivery using 20–45 Gy (median 40) of the external dose. The total dose to point A, calculated by adding the EBRT biologically effective dose (BED) and the ICR BED to point A, was 74.1–118.1 Gy (mean 95.2). The rectal point dose was calculated at the anterior rectal wall at the level of the cervical os. The local control rate, survival rate, and late complication rate were analyzed according to the irradiation dose and BED.

: The initial complete response rate was 99.4%. The overall 5-year survival rate and 5-year disease-free survival rate was 91.1% and 90.9%, respectively. The local failure rate was 4.9%, and the distant failure rate was 4.3%. Late complications were mild and occurred in 23.5% of patients, with 18.5% presenting with rectal complications and 4.9% with bladder complications. The mean rectal BED (the sum of the external midline BED and the ICR rectal point BED) was lower in the patients without rectal complications than in those with rectal complications (125.6 Gy vs. 142.7 Gy, p = 0.3210). The late rectal complication rate increased when the sum of the external midline BED and the rectal BED by ICR was ≥131 Gy (p = 0.1962). However, 5-year survival rates did not increase with the external midline BED (p = 0.4093). The late rectal complication rate also increased, without a change in the survival rate, when the sum of the external midline BED and the ICR point A BED was >90 Gy.

: In treating Stage IB carcinoma of the uterine cervix with HDR-ICR, using fractions of 3 Gy, it is crucial to keep the point A BED at ≤90 Gy to minimize late rectal complications without compromising the survival rate. To achieve this goal, appropriate central shielding from EBRT is needed.     

High-dose-rate intracavitary brachytherapy: results of analyses of late rectal complications

: To examine the incidence of radiation-induced late rectal complications by analyzing the data of measured rectal doses in patients with cancer of the uterine cervix treated with high-dose-rate intracavitary brachytherapy.

: We measured doses to the rectum in 105 patients with cancer of the cervix during high-dose-rate intracavitary brachytherapy with a semiconductor dosimeter that can measure five points in the rectum simultaneously. On the basis of these measurements, equivalent doses, to which the biologically equivalent doses were converted as if given as fractionated irradiation at 2 Gy/fraction, were calculated as components of the cumulative dose at five rectal points in intracavitary brachytherapy combined with the external whole pelvic dose.

: The calculated values of equivalent doses for late effects at the rectum ranged from 15 to 100 Gy (median 60 Gy for patients who did not develop complications and 76 Gy for patients who subsequently developed Grade II or III complications). When converted to a graph of absolute rectal complication probability, the data could be fitted to a sigmoid curve. The data showed a very definite dose-response relationship, with a threshold for complications at approximately 50 Gy and the curve starting to rise more steeply at approximately 60 Gy. The steepest part of the curve had a slope equivalent to approximately 4% incidence/1 Gy increase in equivalent doses.

: The radiation tolerance dose, 5% and 50% complication probability, was about 64 and 79 Gy, respectively. Our data almost agree with the prescribed dose for the rectum for the radiation tolerance doses on the basis of the recorded human and animal data. The probability of rectal complications increased drastically after the maximal rectal dose was >60 Gy.     

Are doses to ICRU reference points valuable for predicting late rectal and bladder morbidity after definitive radiotherapy in uterine cervix cancer?

AIMS AND BACKGROUND: To evaluate whether doses or dose rates at International Commission on Radiation Units (ICRU) reference points are of value for predicting risks of late rectal and bladder morbidity in patients with uterine cervical cancer who have undergone external beam radiotherapy and intracavitary irradiation. METHODS: Late rectal complications and late bladder complications were evaluated in 54 patients who were treated by external beam radiotherapy followed by intracavitary irradiation between January 1996 and December 1999. External beam radiotherapy was delivered in 1.8 Gy daily fractions to a whole pelvis dose of 50.4 Gy followed by intracavitary irradiation at total point A doses ranging from 75 Gy to 85 Gy. Intracavitary irradiation was performed with dose rates of 0.5-0.7 Gy/h to point A in most patients, but 8 patients were treated at a higher dose rate (0.83-1.15 Gy/h) to shorten the hospitalization period. Biologically effective doses for the reference points were calculated using a linear quadratic model. RESULTS: Grade 3 rectal and bladder morbidity by Radiation Therapy Oncology Group (RTOG) criteria developed in 4 patients (7.4%) and 1 (1.9%), respectively. An age of >60 years (P = 0.01) and a total dose to the rectal reference point of > or =80 Gy (P = 0.03) were found to be correlated with a higher rate of rectal morbidity. Total dose (> or =80 Gy), dose rate (> or = 0.75 Gy/h), and biologically effective doses (> or =135 Gy3) at the bladder reference point were found to be significant factors for the development of late bladder morbidity. By multivariate analysis, age was identified as the only significant factor of late rectal complications, and biologically effective doses at the bladder reference point was the only significant factor of late bladder complications. CONCLUSIONS: RTOG grade 3 late rectal and bladder morbidity developed in respectively 7.4% and 1.9% of the patients. The significant risk factors for late rectal and bladder morbidity were old age and biologically effective doses at the bladder reference point, respectively.     

High-dose-rate brachytherapy in the treatment of uterine cervix cancer. Analysis of dose effectiveness and late complications

This retrospective analysis aims to report results of patients with cervix cancer treated by external beam radiotherapy (EBR) and high-dose-rate (HDR) brachytherapy.

From September 1992 to December 1996, 138 patients with FIGO Stages II and III and mean age of 56 years were treated. Median EBR to the whole pelvis was 45 Gy in 25 fractions. Parametrial boost was performed in 93% of patients, with a median dose of 14.4 Gy. Brachytherapy with HDR was performed during EBR or following its completion with a dose of 24 Gy in four weekly fractions of 6 Gy to point A. Median overall treatment time was of 60 days. Patient age, tumor stage, and overall treatment time were variables analyzed for survival and local control. Cumulative biologic effective dose (BED) at rectal and bladder reference points were correlated with late complications in these organs and dose of EBR at parametrium was correlated with small bowel complications.

Median follow-up time was 38 months. Overall survival, disease-free survival, and local control at 5 years was 53.7%, 52.7%, and 62%, respectively. By multivariate and univariate analysis, overall treatment time up to 50 days was the only statistically significant adverse variable for overall survival (p = 0.003) and actuarial local control (p = 0.008). The 5-year actuarial incidence of rectal, bladder, and small bowel late complications was 16%, 11%, and 14%, respectively. Patients treated with cumulative BED at rectum points above 110 Gy₃ and at bladder point above 125 Gy₃ had a higher but not statistically significant 5-year actuarial rate of complications at these organs (18% vs. 12%, p = 0.49 and 17% vs. 9%, p = 0.20, respectively). Patients who received parametrial doses larger than 59 Gy had a higher 5-year actuarial rate of complications in the small bowel; however, this was not statistically significant (19% vs. 10%, p = 0.260).

This series suggests that 45 Gy to the whole pelvis combined with four fractions of 6 Gy to point A with HDR brachytherapy is an effective and safe fractionation schedule in the treatment of Stages II and III cervix cancer if realized up to 50 days. To decrease the small bowel complications, we decreased the superior border of the parametrial fields to the S2-S3 level and the total dose to 54 Gy.     

Fractionation in medium dose rate brachytherapy of cancer of the cervix

: To established an optimum fractionation for medium dose rate (MDR) brachytherapy from retrospective data of patients treated with different MDR schedules in comparison with a low dose rate (LDR) schedule.

: The study population consists of consecutive Stage IB-IIA-IIB patients who received radiotherapy alone with full dose brachytherapy plus external beam pelvic and parametrial irradiation from 1986–1993. Patients also receiving surgery or chemotherapy were excluded. The LDR group (n = 102, median follow-up: 80 months) received a median dose to Point A of 32.5 Gy fractions at 0.44 Gy/h plus 18 Gy of external whole pelvic irradiation. The MDR1 group (n = 30, median follow-up: 45 months) received a mean dose of two 32 Gy fractions at 1.68 Gy/h. An individual dose reduction of 12.5% was planned for this group according to the Manchester experience, but only a 4.8% dose reduction was achieved. The MDR2 group (n = 10, median follow-up: 36 months) received a dose of two 24 Gy fractions at 1.65 Gy/h. The MDR3 group (n = 10, median follow-up 33 months_ received a mean dose of three 15.3 Gy fractions at 1.64 Gy/h. And finally, the MDR4 group (n = 38, median follow-up: 24 months)_received six six 7.7 Gy fractions from two pulses 6 h apart in each of three insertions at 1.61 Gy/h/ The median external pelvic dose to MDR schedules was between 12 and 20 Gy. The linear quadratic (LQ) formula was used to calculate the biologically effective dose (BED) to tumor (BED) to tumor (Gy₁₀) and rectum (Gy₃), assuming T1/2 for REPAIR = 1.5 h.

: The crude central recurrence rate was 6% for LDR (mean BED - 95.4 Gy₁₀) and 10% for MDR4 (mean BED = 77.0 Gy₁₀ (p = NS). The remaining MDR groups had no recurrences. Grade 2 and 3 rectal or bladder complications were 0% for LDR (rectal BED = 109 Gy₃), 83% for MDR1 (BED = 206 Gy₃), and 30% for MDR3 (BED = 127 Gy₃). The MDR2 and MDR4 groups presented no complications (BED, 123 Gy₃, and 105 Gy₃, respectively). The LQ formula appears to correlate with late complications of the different MDR regimens. A BED above 125 Gy₃ was associated with Grade 2+3 rectal complications. Adequate central tumor control may be compromised with a tumor BED below 90–95 Gy₁₀.

: Medium dose rate brachytherapy at 1.6 Gy/h to point A has a marked dose ratre effect. Increased fractionation is the cost of overcoming the less favorable therapeutic ratio for MDR than for LDR. A larger (25%) reduction of brachytherapy dose than previously reported is also necessary. Our most recently developed schedule for Stage I–II patients is three insertions on three treatment days with six 8.0 Gy brachytherapy fractions, two on each treatment day, following or preceding an external whole pelvis dose of 18 Gy, and followed by additional external parametrial dose.     

Effect of balloon occluded arterial infusion of anticancer drugs on the prognosis of cervical cancer treated with radiation therapy

: The effect of local injection of anticancer drugs by ballon catheter, i.e., balloon occuluded arterial infusion (BOAI), on the prognosis of cervical cancer treated with radiotherapy were retrospectively estimated.

: Sixty-five patients with cervical cancer (Stage I–IV) treated by irradiation were included in the study. Among the 65 cases, 2 were in Stage I, 13 in Stage II, 40 in Stage III, and 10 in Stage IV. Patients who received surgical resection were excluded. Thirty-nine patients received BOAI and 44 received brachytherapy. Twenty-six patients were not indicated for BOAI because of insufficient renal function, hepatic complications, hemotological complications, and refusal from the patients. Cisplatin (0.9–1.7 mg/kg), Adriamycin (0.7–0.9 mg/kg), and Pepleomycin (0.4–0.6 mg/kg) were administered simultaneously into the bilateral internal iliac arteries by BOAI. External irradiation was given by 10 MV x-ray. Total dose administered to the regional lymph nodes by the external irradiation was 48.3 ± 8.7 Gy. Radium was used at brachytherapy. The dose delivered by the brachytherapy at point A was 45.3 ± 14.9 Gy. Patients without brachytherapy received 26.1 ± 19.1 Gy of boost irradiation by the external photon beam. The survival probabilities of the patients were calculated by Kaplan-Meier method.

: The 5-year survival rates of the Stage III patients with and without BOAI were 53 ± 13% and 24 ± 18%, respectively (p = 0.036). By multivariate analyses using Cox's proportional hazard model, stage and BOAI were selected as significant predictors of the prognosis. Transient bone marrow suppression was observed in about half of the patients with BOAI. No significant increase of the incidence of the late radiation damage by BOAI in rectum or in urinary bladder was observed.

: Balloon occuluded arterial infusion of anticancer drugs may improve the prognosis of the patients with cervical cancer without increasing the incidence of the late radiation damage. A larger scale prospective randomized study is desired.     

Predictive role of TDF values in late rectal recto-sigmoid complications in irradiation treatment of cervix cancer.

Radiation-induced late rectal and recto-sigmoid complications for different doses per fraction were analyzed retrospectively in 203 cases of Stage IIIB carcinoma of the uterine cervix. The patients were treated with a combination of external irradiation and a single intracavitary insertion during January 1979 to December 1983. The external irradiation was randomised to deliver by four different fractionation regimens having dose per fraction of 2 Gy, 3 Gy, 4 Gy and 5.4 Gy. The doses for various fractionations were matched with the daily regimen using the time-dose factors (TDF) model. A single intracavitary insertion delivered a dose of 22 to 24 Gy to point A using Fletcher-Suit applicator. All patients had a minimum follow-up of 30 months. Thirty nine cases of late radiation induced rectal and recto-sigmoid complications were observed. The complication rate of 8.2% for daily treatment regimen delivering 2 Gy per fraction was increased to 33.3% for once weekly treatment regimen delivering 5.4 Gy per fraction (p = 0.041). Despite similar Time-Dose Factors (TDF) values in four different treatment regimens, the complication rate increased significantly in the once weekly regimen. The analysis suggest that the Time-Dose Factors (TDF) values do not predict correctly the late normal tissue reactions for different dose fractionation schedules.     

Medium-dose-rate brachytherapy of cancer of the cervix: preliminary results of a prospectively designed schedule based on the linear-quadratic model

Purpose: To compare results and complications of our previous low-dose-rate (LDR) brachytherapy schedule for early-stage cancer of the cervix, with a prospectively designed medium-dose-rate (MDR) schedule, based on the linear-quadratic model (LQ).

Methods and Materials: A combination of brachytherapy, external beam pelvic and parametrial irradiation was used in 102 consecutive Stage Ib–IIb LDR treated patients (1986–1990) and 42 equally staged MDR treated patients (1994–1996). The planned MDR schedule consisted of three insertions on three treatment days with six 8-Gy brachytherapy fractions to Point A, two on each treatment day with an interfraction interval of 6 hours, plus 18 Gy external whole pelvic dose, and followed by additional parametrial irradiation. The calculated biologically effective dose (BED) for tumor was 90 Gy₁₀and for rectum below 125 Gy₃.

Results: In practice the MDR brachytherapy schedule achieved a tumor BED of 86 Gy₁₀ and a rectal BED of 101 Gy₃. The latter was better than originally planned due to a reduction from 85% to 77% in the percentage of the mean dose to the rectum in relation to Point A. The mean overall treatment time was 10 days shorter for MDR in comparison with LDR. The 3-year actuarial central control for LDR and MDR was 97% and 98% (p = NS), respectively. The Grades 2 and 3 late complications (scale 0 to 3) were 1% and 2.4%, respectively for LDR (3-year) and MDR (2-year).

Conclusions: LQ is a reliable tool for designing new schedules with altered fractionation and dose rates. The MDR schedule has proven to be an equivalent treatment schedule compared with LDR, with an additional advantage of having a shorter overall treatment time. The mean rectal BED Gy₃ was lower than expected.     

Late rectal complications evaluated by computed tomography-based dose calculations in patients with cervical carcinoma undergoing high-dose-rate brachytherapy

PURPOSE: To investigate the efficacy of dose calculations at the computed tomography (CT)-based rectal point (CTRP) as a predictive factor for late rectal complications in patients with cervical carcinoma who were treated with a combination of high-dose-rate intracavitary brachytherapy and external beam radiotherapy. METHODS AND MATERIALS: Ninety-two patients with uterine cervical carcinoma undergoing definitive radiotherapy alone were retrospectively analyzed. The median follow-up time for all patients was 32 months (range, 13-60 months). The cumulative biologically effective dose (BED) was calculated at the rectal reference point as defined by the International Commission on Radiation Units and Measurements Report 38 (BED(RP)) and at the CTRP (BED(CTRP)). Late rectal complications were recorded according to the Radiation Therapy Oncology Group grading system. RESULTS: The late rectal complications were distributed as follows: Grade 0, 68 patients (74%); Grade 1, 20 patients (22%); Grade 2, 4 patients (4%). Univariate analysis showed that BED(RP), BED(CTRP), RP dose/point A dose ratio, and CTRP dose/point A dose ratio were significantly correlated with late rectal complications (p < 0.05). On multivariate analysis, patients with a rectal BED(CTRP) >/=140 Gy(3) presented with significantly greater frequency of rectal complications (p = 0.031). CONCLUSIONS: The present results suggest that BED(CTRP) is a useful predictive factor for late rectal complications.     

Unique role of proximal rectal dose in late rectal complications for patients with cervical cancer undergoing high-dose-rate intracavitary brachytherapy

PURPOSE: To investigate the correlation of the radiation dose to the upper rectum, proximal to the International Commission of Radiation Units and Measurements (ICRU) rectal point, with late rectal complications in patients treated with external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary brachytherapy (ICRT) for carcinoma of the uterine cervix. METHODS AND MATERIALS: Between June 1997 and February 2001, 75 patients with cervical carcinoma completed definitive or preoperative RT and were retrospectively reviewed. Of the 75 patients, 62 with complete dosimetric data and a minimal follow-up of at least 1 year were included in this analysis. Of the 62 patients, 36 (58%) also received concurrent chemotherapy, mainly with cisplatin during EBRT. EBRT consisted of a mean of 50.1 +/- 1.3 Gy of 18-MV photons to the pelvis. A parametrial boost was given to 55 patients. Central shielding was used after 40-45 Gy of pelvic RT. HDR ICRT followed EBRT, with a median dose of 5 Gy/fraction given twice weekly for a median of four fractions. The mean dose to point A from HDR ICRT was 23.9 +/- 3.0 Gy. In addition to the placement of a rectal tube with a lead wire during ICRT, 30-40 mL of contrast medium was instilled into the rectum to demonstrate the anterior rectal wall up to the rectosigmoid junction. Late rectal complications were recorded according to the Radiation Therapy Oncology Group grading system. The maximal rectal dose taken along the rectum from the anal verge to the rectosigmoid junction and the ICRU rectal dose were calculated. Statistical tests were used for the correlation of Grade 2 or greater rectal complications with patient-related variables and dosimetric factors. Correlations among the point A dose, ICRU rectal dose, and maximal proximal rectal dose were analyzed. RESULTS: Fourteen patients (23%) developed Grade 2 or greater rectal complications. Patient-related factors, definitive or preoperative RT, and the use of concurrent chemotherapy were not associated with the occurrence of rectal complications. The maximal rectal dose during ICRT was at the proximal rectum rather than at the ICRU rectal point in 55 (89%) of 62 patients. Patients with Grade 2 or greater rectal complications had received a significantly greater total maximal proximal rectal dose from ICRT (25.6 Gy vs. 19.2 Gy, p = 0.019) and had a greater maximal proximal rectal dose/point A dose ratio (1.025 vs. 0.813, p = 0.024). In contrast, patients with and without rectal complications had a similar dose at point A (25.0 Gy vs.23.6 Gy, p = 0.107). The differences in the ICRU rectal dose (17.8 Gy vs.15.4 Gy, p = 0.065) and the ICRU rectal dose/point A dose ratio (0.71 vs. 0.66, p = 0.210) did not reach statistical significance. Patients with >62 Gy of a direct dose sum from EBRT and ICRT to the proximal rectum (12 of 29 vs. 2 of 33, p = 0.001) and >110 Gy of a total maximal proximal rectal biologic effective dose (13 of 40 vs. 1 of 22, p = 0.012) presented with a significantly increased frequency of Grade 2 or greater rectal complications. The correlations between the maximal proximal rectal dose and the ICRU rectal dose were less satisfactory (Pearson coefficient 0.375). Moreover, 11 of the 14 patients with rectal complications had colonoscopic findings of radiation colitis at the proximal rectum, the area with the maximal rectal dose. CONCLUSION: Eighty-nine percent of our patients had a maximal rectal dose from ICRT at the proximal rectum instead of the ICRU rectal point. The difference between patients with and without late rectal complications was more prominent for the proximal rectal dose than for the ICRU rectal dose. It is important and useful to contrast the whole rectal wall up to the rectosigmoid junction and to calculate the dose at the proximal rectum for patients undergoing HDR ICRT.     

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

: To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer.

: We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74–78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24–102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity.

: At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p <0.0001 for all comparisons), the absolute rectal volume appeared to be a factor only at the higher doses of 70, 75.6, and 78 Gy (p = 0.0514, 0.0016, and 0.0021, respectively). The following variables also correlated with toxicity on the univariate analysis: maximal dose to the clinical target volume, maximal dose to rectum, maximal dose to the rectum as a percentage of the prescribed dose, and maximal dose delivered to 10 cm³ of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p = 0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p <0.05 for all comparisons).

: Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup.     

Predictive value of linear-quadratic model in the treatment of cervical cancer using high-dose-rate brachytherapy

: To determine whether a dose-response relationship exists between the biologic effective dose (BED) at Point A and the bladder and rectum and the clinical outcomes in our experience with external beam radiotherapy (EBRT) and high-dose-rate brachytherapy in the treatment of cervical carcinoma.

: This was a retrospective study. A total of 49 patients with cervical cancer were treated with a combination of EBRT (median 45 Gy, range 41.4–50.4) and high-dose-rate brachytherapy (median 18 Gy; range 18–19, in two fractions). Twenty-three patients received concomitant cisplatin-based chemotherapy. The cumulative BEDs were calculated at Point A (BED10) and at bladder and rectal reference points (BED3) using the linear-quadratic equation. The BED10 values, after incorporating a time factor (BED10tf) in the formula, were also calculated.

: In patients treated with RT alone, the local failure rate was 10% (1 of 10) and 19% (3 of 16) in patients receiving a BED10 >89 Gy10 or <89 Gy10 to Point A, respectively (p = 0.2). The corresponding local failure rates were 20% (3 of 15) and 0% (0 of 8) in patients treated with concomitant chemotherapy (p = 0.3). In patients treated with RT alone, the local failure rate was 7.7% (1 of 13) and 23% (3 of 13) in patients with a BED10tf >64 Gy10 or <64 Gy10 (p = 0.1), respectively. The median BED3 values at the rectal and bladder point was 95.5 Gy3 and 103.6 Gy3, respectively. Only 1 case of Grade 2 late rectal toxicity (2%) and no late bladder toxicity occurred.

: In patients treated with RT alone, a BED10 >89 Gy and a BED10tf >64 Gy indicated a trend toward a better local control rate. This difference was not observed in patients receiving chemotherapy. A BED3 <100 Gy3 was associated with negligible late toxicity. Although the BED10 in our study was about 10–15 Gy10 less than that in the published data, the 4-year local control rate of 80% and 83% and disease-free survival rate of 75% and 70% with and without chemotherapy, respectively, compare well with the rates in other studies in the literature.     

High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients

To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT).

Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6–60 months).

Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of ≥ late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of ≥ late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively.

These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.     

The “Critical volume tolerance method” for estimating the limits of dose escalation during three-dimensional conformal radiotherapy for prostate cancer

: To describe the “Critical Volume Tolerance” (CVT) method for defining normal tissue tolerance during 3D-based dose escalation studies for prostate cancer.

: The CVT method predicts the tolerance to radiation for “in series”-type functional units based on the assumption that tolerance depends on a critical threshold “low-volume high-dose region.” The data used for describing this model were generated from 3D analysis of randomly selected patients with prostate cancer. Commonly used coplanar frou- and six-field conformal (SFC) techniques were chosen as the comparison techniques. For purposes of comparison, rectal tolerance was assumed to be reached following whole pelvic irradiation using a four-field box technique to 50 Gy, followed by a conedown boost to 70 Gy using bilateral 9 × 9 cm 120 degree arcs as popularized by investigators from Stanford University (SUH).

: Based on the average dose volume histograms for the patients studied, the maximum safe increase in dose for the SFC technique compared to the SUH technique, would be 10% if 30% of the rectal volume was the critical dose limiting volume (CVT = 30%), 5%if the CVT = 10%, or greater than 20% if the CVT = 40%. Commonly used four-field conformal techniques would not be expected to allow significant escalation of the dose without increasing the risk of complications.

: The CVT method is relatively simple, and data general based on it can be used to support normal tissue complication probability equations. The CVT method can be verified or modified as partial tolerance data become available. Based on the CVT model, sophisticated treatment techniques should allow a modest increase in the total dose of radiation delivered to the prostate without an increase in late complications.     

The prediction of late rectal complications following the treatment of uterine cervical cancer by high-dose-rate brachytherapy

PURPOSE: This study aimed to correlate patient, treatment, and dosimetric factors with the risk of late rectal sequelae in patients with uterine cervical cancer treated with external beam radiation therapy (EBRT) and high dose rate intracavitary brachytherapy (HDRICB). METHODS AND MATERIALS: From September 1992 to December 1995, a total of 128 patients with uterine cervical cancer, who were treated and survived more than 12 months, were evaluated. After EBRT with 40-44 Gy/20-22 Fr/4-5 weeks to the whole pelvis, the dose was boosted up to 54-58 Gy with central shielding for patients with bilateral parametria of Stage IIb or greater. HDRICB consisted of three to four insertions at doses of 5-7.2 Gy (to Point A) at intervals of 1 week. Patient and treatment factors were analyzed using logistic regression analysis and the cumulative rectal biologic equivalent dose (CRBED) was calculated. RESULTS: After 30-75 months of follow-up (median, 43 months), 38 patients (29.7%) had late rectal sequelae. Patients who had Stage IIb-IVa disease, cumulative rectal dose (external RT + total ICRU rectal dose) greeater than 65 Gy, or age greater than 70 years had a high risk of developing late rectal sequelae. When 110 Gy was used as the cut-off value, 19.6% (10 of 51) of patients whose CRBED was less than 110 Gy had rectal complications, while 36.4% (28/77) of patients whose CRBED was greater than 110 Gy developed rectal complications. CONCLUSION: Risk factors of late rectal complications were advanced stage, age greater than 70 years, and cumulative rectal dose of greater than 65 Gy.     

Treatment planning and dosimetry for the Harvard-MIT Phase I clinical trial of cranial neutron capture therapy

: A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain.

: Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons. The study began with a prescribed biologically weighted dose of 8.8 RBE (relative biologic effectiveness) Gy, escalated in compounding 10% increments, and ended at 14.2 RBE Gy. BPA-f was infused at a dose 250–350 mg/kg body weight. Treatments were planned using MacNCTPlan and MCNP 4B. Irradiations were delivered as one, two, or three fields in one or two fractions.

: Peak biologically weighted normal tissue dose ranged from 8.7 to 16.4 RBE Gy. The average dose to brain ranged from 2.7 to 7.4 RBE Gy. Average tumor dose was estimated to range from 14.5 to 43.9 RBE Gy, with a mean of 25.7 RBE Gy.

: We have demonstrated that BPA-f-mediated NCT can be precisely planned and delivered in a carefully controlled manner. Subsequent clinical trials of boron neutron capture therapy at Harvard and MIT will be initiated with a new high-intensity, high-quality epithermal neutron beam.     

Dose response and latency for radiation-induced fibrosis, edema, and neuropathy in breast cancer patients

: To study the incidence of various forms of late normal tissue injuries to determine the latency and dose-response relationships.

: We retrospectively analyzed the clinical records of 150 breast cancer patients treated with radiotherapy after mastectomy in the mid to late 1960s. None of the patients had received chemotherapy as a part of their primary treatment. Radiotherapy was delivered to the parasternal, axillary, and supraclavicular lymph node regions. Almost all the patients continued to be checked at regular 3-month to 1-year intervals at our Oncology Department. Detailed records were available for the entire 34 years of the follow-up period. The patients were divided into 3 groups. The prescribed dose was either 11 × 4 Gy (treated with ⁶⁰Co photons) or 11 × 4 Gy or 14–15 × 3 Gy (treated with both ⁶⁰Co photons and electrons). The dose recalculation at the brachial plexus where the axillary and supraclavicular beams overlapped was performed in the early 1970s and expressed in cumulative radiation effect (CRE) units. It varied widely among the individual patients. The received dose has now been converted to biologic effective dose₃ units, and from that into the equivalent dose in 2-Gy fractions to plot the dose-response relationships.

: We present a comparison of the latency and frequency of fibrosis, edema, brachial plexus neuropathy, and paralysis in the three different subgroups and the total group. Dose-response relationships are shown at 5, 10, and 30 years after irradiation.

: The use of large daily fractions, combined with hotspots from overlapping fields, was the cause of the complications. Clear dose-response curves were seen for late radiation injuries. The incidence seen at 5 years did not represent the full spectrum of injuries. Doses that seem safe at 5 years can lead to serious complications later.     

Late radiation effects to the rectum and bladder in gynecologic cancer patients: the comparison of LENT/SOMA and RTOG/EORTC late-effects scoring systems

To test the correlation of LENT/SOMA and RTOG/EORTC late-effect scales for rectum and bladder, 116 cases with gynecologic malignancies that were treated with radiotherapy were assessed with both scales.

All cases had been treated at least 6 months before the date of assessment with external beam radiotherapy (50–54 Gy to midline) and 1–2 fractions of HDR brachytherapy (2 × 8.5 Gy to point-A for 32 inoperable cases; 1 × 9.25 Gy to 5–9 mm from the ovoid surface for 84 postoperative cases). The patients were questioned with both scales, and the correlation between the two scales was analyzed by Spearman’s rho (rank correlation) test.

There were 64 cases with uterine cervix carcinoma and 52 cases with endometrium carcinoma, The overall (external + brachy) doses to ICRU points were 57.8 ± 3.8 Gy for rectum and 59.3 ± 4.9 Gy for bladder. The statistical analysis of LENT/SOMA and RTOG/EORTC scales revealed a very good correlation for rectum (r = 0.81; p < 0.01) and a good correlation for bladder (r = 0.72; p < 0.01).

The LENT/SOMA system is a further step on the reporting of late radiation effects. Some modifications will improve its precision, and multicentric randomized studies are needed to test its validity.     

The radiobiology of prostate cancer including new aspects of fractionated radiotherapy

Total radiation dose is not a reliable measure of biological effect when dose-per-fraction or dose-rate is changed. Large differences in biological effectiveness (per gray) are seen between the 2 Gy doses of external beam radiotherapy and the large boost doses given at high dose-rate from afterloading sources. The effects are profoundly different in rapidly or slowly proliferating tissues, that is for most tumors versus late complications. These differences work the opposite way round for prostate tumors versus late complications compared with most other types of tumor. Using the Linear-Quadratic formula it is aimed to explain these differences, especially for treatments of prostate cancer. The unusually slow growth rate of prostate cancers is associated with their high sensitivity to increased fraction size, so a large number of small fractions, such as 35 or 40 "daily" doses of 2 Gy, is not an optimum treatment. Theoretical modeling shows a stronger enhancement of tumor effect than of late complications for larger (and fewer) fractions, in prostate tumors uniquely. Biologically Effective Doses and Normalized Total Doses (in 2 Gy fraction equivalents) are given for prostate tumor, late rectal reactions, and--a new development--acute rectal mucosa. Tables showing the change of fraction-size sensitivity (the alpha/beta ratio) with proliferation rates of tissues lead to the association of slow cell doubling times in prostate tumors with small alpha/beta ratios. Clinical evidence to confirm this biological expectation is reviewed. The alpha/beta ratios of prostate tumors appear to be as low as 1.5 Gy (95% confidence interval 1.3-1.8 Gy), in contrast with the value of about 10 Gy for most other types of tumor. The important point is that alpha/beta =1.5 Gy appears to be significantly less than the alpha/beta =3 Gy for late complications in rectal tissues. Such differences are also emerging from recent clinical results. From this important difference stems the superior schedules of, for example, 20 fractions of 3 Gy, or 10 fractions of 4.7 Gy, or 5 fractions of 7 Gy, which can all give tumor results equivalent to 80-90 Gy in 2 Gy fractions, while keeping late complications equivalent to only 72 Gy in 2 Gy fractions. Combination treatments of external beam (EBRT) and brachytherapy boost doses (25F x 2 Gy plus 2 x 10 Gy) can give higher biological tumor effects than any EBRT using daily 2 Gy doses, and with acceptable late complications. Monotherapy by brachytherapy for low-risk cancer prostate using two to four fractions in a few days can give even higher biological effects on the tumors.     

A pilot study of topical intrarectal application of amifostine for prevention of late radiation rectal injury

Clinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken.

Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, Karnofsky performance status ≥70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy in 20 patients and 73.8 Gy in 9 patients. Therapy was delivered using a 4-field technique with three-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. Amifostine was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most patients underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up.

All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 patients (33%) developed rectal bleeding (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 patients developed Grade 1 and Grade 2 telangiectasia, respectively. This was mostly confined to the anterior rectal wall. No visible mucosal edema, ulcerations, or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four patients (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific proctitis (n = 1), diverticular disease of the sigmoid colon (n = 1), rectal polyp (n = 1), and ulcerative colitis (n = 1). Symptoms developed significantly more often in patients receiving 500–1000 mg than in patients receiving 1500–2500 mg amifostine (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test).

Intrarectal application of amifostine is feasible and well tolerated. Systemic absorption of amifostine and its metabolites is negligible, and close monitoring of patients is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.