Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue.

PURPOSE: A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low alpha/beta ratio), more typical of the surrounding late-responding normal tissue. METHODS AND MATERIALS: Earlier estimates of alpha/beta for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age. RESULTS: The estimated value of alpha/beta from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This alpha/beta value is considerably less than typical values for tumors (> or =8 Gy), and more comparable to values in surrounding late-responding normal tissues. CONCLUSIONS: This analysis provides strong supporting evidence that alpha/beta values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.     

High dose-rate brachytherapy of prostate cancer utilising Iridium-192 after-loading technique: technical and methodological aspects

The aim of this study was to focus on certain characteristic problems associated with Iridium-192 high dose-rate brachytherapy (Ir-192 HDR-BT) in combination with external beam radiation therapy (EBRT) in the treatment of patients with localised prostate cancer. Over a period of 16 years, >2,000 patients with prostate cancer have been treated in Sweden with a combination of two fractions of 10 Gy Ir-192 HDR-BT and 50 Gy of fractionated EBRT. Although this treatment is usually well tolerated, there are biological and technical factors to be considered before and during the treatment of the patient to avoid side effects or under-treatment of the target volume. Some of the problems facing the doctors are transducer stability, needle deviation, target definition, target motion, pubic arch interference, concomitant diseases and tolerance doses for different organs at risk. These problems are discussed and possible solutions are presented in this study.     

Acute genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiation therapy for localized prostate cancer: correlation between the urethral dose in HDR brachytherapy and the severity of acute genitourinary toxicity

PURPOSE: Several investigations have revealed that the alpha/beta ratio for prostate cancer is atypically low, and that hypofractionation or high-dose-rate (HDR) brachytherapy regimens using appropriate radiation doses may be expected to yield tumor control and late sequelae rates that are better or at least as favorable as those achieved with conventional radiation therapy. In this setting, we attempted treating localized prostate cancer patients with HDR brachytherapy combined with hypofractionated external beam radiation therapy (EBRT). The purpose of this study was to evaluate the feasibility of using this approach, with special emphasis on the relationship between the severity of acute genitourinary (GU) toxicity and the urethral dose calculated from the dose-volume histogram (DVH) of HDR brachytherapy. METHODS AND MATERIALS: Between September 2000 and December 2003, 70 patients with localized prostate cancer were treated by iridium-192 HDR brachytherapy combined with hypofractionated EBRT at the Gunma University Hospital. Hypofractionated EBRT was administered in fraction doses of 3 Gy, three times per week; a total dose of 51 Gy was delivered to the prostate gland and the seminal vesicles using the four-field technique. No elective pelvic irradiation was performed. After the completion of EBRT, all the patients additionally received transrectal ultrasonography (TRUS)-guided HDR brachytherapy. The fraction size and the number of fractions in HDR brachytherapy were prospectively changed, whereas the total radiation dose for EBRT was fixed at 51 Gy. The fractionation in HDR brachytherapy was as follows: 5 Gy x 5, 7 Gy x 3, 9 Gy x 2, administered twice per day, although the biologic effective dose (BED) for HDR brachytherapy combined with EBRT, assuming that the alpha/beta ratio is 3, was almost equal to 138 in each fractionation group. The planning target volume was defined as the prostate gland with 5-mm margin all around, and the planning was conducted based on computed tomography images. The number of patients in each fractionation group was as follows: 13 in the 5-Gy group; 19 in the 7-Gy group, and 38 in the 9-Gy group. The tumor stage was T1 in 10 patients, T2 in 36 patients, and T3 in 24 patients. The Gleason score was 2-6 in 11 patients, 7 in 34 patients, and 8-10 in 25 patients. Androgen ablation was performed in all the patients. The median follow-up duration was 14 months (range 3-42 months). The toxicities were graded based on the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. RESULTS: The main symptoms of acute GU toxicity were dysuria and increase in urinary frequency or nocturia. The grade distribution of acute GU toxicity in the patients was as follows: Grade 0-1, 39 patients (56%), and Grade 2-4, 31 patients (44%). One patient who developed acute urinary obstruction was classified as having Grade 4 toxicity. Comparison of the distribution of the grade of acute GU toxicity among the different fractionation groups revealed no statistically significant differences among the groups. The urethral dose in HDR brachytherapy was evaluated using the following DVH parameters: V30 (percentage of the urethral volume receiving 30% of the prescribed radiation dose), V80, V90, V100, V110, V120, V130, and V150. The V30-110 values in the patients with Grade 2-4 acute GU toxicity were significantly higher than those in patients with Grade 0-1 toxicity. On the other hand, there were no significant differences in the V120-150 values between patients with Grade 0-1 and Grade 2-4 toxicity. Regarding the influence of the number of needles implanted for the radiation therapy, patients with 11 needles or less showed a significantly higher incidence of Grade 2-4 acute GU toxicity compared with those with 12 needles or more (p < 0.05). CONCLUSIONS: It was concluded that HDR brachytherapy combined with hypofractionated EBRT is feasible for localized prostate cancer when considered from the viewpoint of acute toxicity. Increase in the fraction dose or reduction in the number of fractions in HDR brachytherapy did not affect the severity of acute GU toxicity, and the volume of urethra receiving an equal or lower radiation dose than the prescribed dose was more closely associated with the grade severity of acute GU toxicity than that receiving a higher than the prescribed dose.     

What hypofractionated protocols should be tested for prostate cancer?

PURPOSE: Recent analyses of clinical results have suggested that the fractionation sensitivity of prostate tumors is remarkably high; corresponding point estimates of the alpha/beta ratio for prostate cancer are around 1.5 Gy, much lower than the typical value of 10 Gy for many other tumors. This low alpha/beta value is comparable to, and possibly even lower than, that of the surrounding late-responding normal tissue in rectal mucosa (alpha/beta nominally 3 Gy, but also likely to be in the 4-5 Gy range). This lower alpha/beta ratio for prostate cancer than for the surrounding late-responding normal tissue creates the potential for therapeutic gain. We analyze here possible high-gain/low-risk hypofractionated protocols for prostate cancer to test this suggestion. METHODS AND MATERIALS: Using standard linear-quadratic (LQ) modeling, a set of hypofractionated protocols can be designed in which a series of dose steps is given, each step of which keeps the late complications constant in rectal tissues. This is done by adjusting the dose per fraction and total dose to maintain a constant level of late effects. The effect on tumor control is then investigated. The resulting estimates are theoretical, although based on the best current modeling with alpha/beta parameters, which are discussed thoroughly. RESULTS: If the alpha/beta value for prostate is less than that for the surrounding late-responding normal tissue, the clinical gains can be rather large. Appropriately designed schedules using around ten large fractions can result in absolute increases of 15% to 20% in biochemical control with no evidence of disease (bNED), with no increase in late sequelae. Early sequelae are predicted to be decreased, provided that overall times are not shortened drastically because of a possible risk of acute or consequential late reactions in the rectum. An overall time not shorter than 5 weeks appears advisable for the hypofractionation schedules considered, pending further clinical trial results. Even if the prostate tumor alpha/beta ratio turns out to be the same (or even slightly larger than) the surrounding late-responding normal tissue, these hypofractionated regimens are estimated to be very unlikely to result in significantly increased late effects. CONCLUSIONS: The hypofractionated regimens that we suggest be tested for prostate-cancer radiotherapy show high potential therapeutic gain as well as economic and logistic advantages. They appear to have little potential risk as long as excessively short overall times (<5 weeks) and very small fraction numbers (<5) are avoided. The values of bNED and rectal complications presented are entirely theoretical, being related by LQ modeling to existing clinical data for approximately intermediate-risk prostate cancer patients as discussed in detail.     

Prediction of the benefits from dose-escalated hypofractionated intensity-modulated radiotherapy for prostate cancer

PURPOSE: To estimate the benefits of dose escalation in hypofractionated intensity-modulated radiotherapy (IMRT) for prostate cancer, using radiobiologic modeling and incorporating positional uncertainties of organs. MATERIALS AND METHODS: Biologically based mathematical models for describing the relationships between tumor control probability (TCP) and normal-tissue complication probability (NTCP) vs. dose were used to describe some of the results available in the literature. The values of the model parameters were then used together with the value of 1.5 Gy for the prostate cancer alpha/beta ratio to predict the responses in a hypofractionated 3 Gy/fraction IMRT trial at the Christie Hospital, taking into account patient movement characteristics between dose fractions. RESULTS: Compared with the current three-dimensional conformal radiotherapy technique (total dose of 50 Gy to the planning target volume in 16 fractions), the use of IMRT to escalate the dose to the prostate was predicted to increase the TCP by 5%, 16%, and 22% for the three dose levels, respectively, of 54, 57, and 60 Gy delivered using 3 Gy per fraction while keeping the late rectal complications (>/=Grade 2 RTOG scale) at about the same level of 5%. Further increases in TCP could be achieved by reducing the uncertainty in daily target position, especially for the last stage of the trial, where up to 6% further increase in TCP should be gained. CONCLUSIONS: Dose escalation to the prostate using IMRT to deliver daily doses of 3 Gy was predicted to significantly increase tumor control without increasing late rectal complications, and currently this prediction is being tested in a clinical trial.     

Rectal bleeding after high-dose-rate brachytherapy combined with hypofractionated external-beam radiotherapy for localized prostate cancer: impact of rectal dose in high-dose-rate brachytherapy on occurrence of grade 2 or worse rectal bleeding

PURPOSE: To evaluate the incidence of Grade 2 or worse rectal bleeding after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiotherapy (EBRT), with special emphasis on the relationship between the incidence of rectal bleeding and the rectal dose from HDR brachytherapy. METHODS AND MATERIALS: The records of 100 patients who were treated by HDR brachytherapy combined with EBRT for > or =12 months were analyzed. The fractionation schema for HDR brachytherapy was prospectively changed, and the total radiation dose for EBRT was fixed at 51 Gy. The distribution of the fractionation schema used in the patients was as follows: 5 Gy x 5 in 13 patients; 7 Gy x 3 in 19 patients; and 9 Gy x 2 in 68 patients. RESULTS: Ten patients (10%) developed Grade 2 or worse rectal bleeding. Regarding the correlation with dosimetric factors, no significant differences were found in the average percentage of the entire rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose from EBRT between those with bleeding and those without. The average percentage of the entire rectal volume receiving 10%, 30%, 50%, 80%, and 90% of the prescribed radiation dose from HDR brachytherapy in those who developed rectal bleeding was 77.9%, 28.6%, 9.0%, 1.5%, and 0.3%, respectively, and was 69.2%, 22.2%, 6.6%, 0.9%, and 0.4%, respectively, in those without bleeding. The differences in the percentages of the entire rectal volume receiving 10%, 30%, and 50% between those with and without bleeding were statistically significant. CONCLUSIONS: The rectal dose from HDR brachytherapy for patients with prostate cancer may have a significant impact on the incidence of Grade 2 or worse rectal bleeding.     

Fractionation and protraction for radiotherapy of prostate carcinoma

Purpose: To investigate whether current fractionation and brachytherapy protraction schemes for the treatment of prostatic cancer with radiation are optimal, or could be improved.

Methods and Materials: We analyzed two mature data sets on radiotherapeutic tumor control for prostate cancer, one using EBRT and the other permanent seed implants, to extract the sensitivity to changes in fractionation of prostatic tumors. The standard linear-quadratic model was used for the analysis.

Results: Prostatic cancers appear significantly more sensitive to changes in fractionation than most other cancers. The estimated /β value is 1.5 Gy [0.8, 2.2]. This result is not too surprising as there is a documented relationship between cellular proliferative status and sensitivity to changes in fractionation, and prostatic tumors contain exceptionally low proportions of proliferating cells.

Conclusions: High dose rate (HDR) brachytherapy would be a highly appropriate modality for treating prostate cancer. Appropriately designed HDR brachytherapy regimens would be expected to be as efficacious as low dose rate, but with added advantages of logistic convenience and more reliable dose distributions. Similarly, external beam treatments for prostate cancer can be designed using larger doses per fraction; appropriately designed hypofractionation schemes would be expected to maintain current levels of tumor control and late sequelae, but with reduced acute morbidity, together with the logistic and financial advantages of fewer numbers of fractions.     

Response of aorta and branch arteries to experimental intraoperative irradiation

Injury to the aorta was evaluated in dogs 2 and 5 years after fractionated irradiation (EBRT), intraoperative irradiation (IORT) or a combination. Doses greater than 20 Gy IORT combined with 50 Gy EBRT given in 2 Gy fractions or 30 Gy IORT alone were accompanied by a significant risk of aneurysms or large thrombi as determined at necropsy 4 to 5 years following irradiation. Narrowing of the aorta as detected by aortography occurred at 5 years but was not detected earlier. The ED50 for aortic narrowing was 38.8 Gy IORT and 31 Gy IORT plus 50 Gy EBRT. The ED50 for branch artery injury was 24.8 Gy IORT alone and 19.4 Gy IORT plus 50 Gy EBRT. The difference in ED50s for IORT alone and IORT plus EBRT indicates that the contribution of the EBRT dose in terms of an IORT dose for aortic narrowing was 7.8 Gy and for branch artery injury was 5.4 Gy. The ED50 for incidence of small thrombi in the aorta was about 29 Gy for IORT alone and 23.5 Gy for IORT combined with EBRT. Fibrous thickening of the adventitia was measured and the effect of the 50 Gy EBRT component of a combination of EBRT and IORT was determined to be equivalent to 10 to 12 Gy IORT. Based on the various estimates, IORT doses of 10-15 Gy have an effect of 5 times or greater the amount given in 2 Gy fractions. At all EBRT doses and at lower IORT doses the intima was greatly thickened. At IORT doses of 20 Gy or above there was a dose related decrease in intimal thickness to near normal values. This was probably due to cell killing or inhibition of intimal proliferation that predominated at higher doses. Although the risk of serious vascular complications appears low following IORT of humans, this may be due to short observation times and the fact that IORT doses currently used are usually 20 Gy or less; this may be near the tolerance for late response of larger arteries. Only one dog in this study had complete rupture of the aorta causing death. Five other dogs at high IORT doses had near ruptures of the aorta but were clinically normal.     

A simple method of obtaining equivalent doses for use in HDR brachytherapy

PURPOSE: To develop a simple program that can be easily used by clinicians to calculate the tumor and late tissue equivalent doses (as if given in 2 Gy/day fractions) for different high-dose-rate (HDR) brachytherapy regimens. The program should take into account the normal tissue sparing effect of brachytherapy. METHODS AND MATERIALS: Using Microsoft Excel, a program was developed incorporating the linear-quadratic (LQ) formula to calculate the biologically equivalent dose (BED). To express the BED in terms more familiar to all clinicians, it was reconverted to equivalent doses as if given as fractionated irradiation at 2 Gy/fraction. Since doses given to normal tissues in HDR brachytherapy treatments are different from those given to tumor, a normal tissue dose modifying factor (DMF) was applied in this spreadsheet (depending on the anticipated dose to normal tissue) to obtain more realistic equivalent normal tissue effects. RESULTS: The spreadsheet program created requires the clinician to enter only the external beam total dose and dose/fraction, HDR dose, and the number of HDR fractions. It automatically calculates the equivalent doses for tumor and normal tissue effects, respectively. Generally, the DMF applied is < 1 since the doses to normal tissues are less than the doses to the tumor. However, in certain circumstances, a DMF of > 1 may need to be applied if the dose to critical normal tissues is higher than the dose to tumor. Additionally, the alpha/beta ratios for tumor and normal tissues can be changed from their default values of 10 Gy and 3 Gy, respectively. This program has been used to determine HDR doses needed for treatment of cancers of the cervix, prostate, and other organs. It can also been used to predict the late normal tissue effects, alerting the clinician to the possibility of undue morbidity of a new HDR regimen. CONCLUSION: A simple Excel spreadsheet program has been developed to assist clinicians to easily calculate equivalent doses to be used in HDR brachytherapy regimens. The novelty of this program is that the equivalent doses are expressed as if given at 2 Gy per fraction rather than as BED values and a more realistic equivalent normal tissue effect is obtained by applying a DMF. Its ease of use should promote the use of LQ radiobiological modeling to determine doses to be used for HDR brachytherapy. The program is to be used judiciously as a guide only and should be correlated with clinical outcome.     

Is alpha/beta for prostate tumors really low?

PURPOSE: Brenner and Hall's 1999 paper estimating an alpha/beta value of 1.5 Gy for prostate tumors has stimulated much interest in the question of whether this ratio (of intrinsic radiosensitivity to repair capacity) is much lower in prostate tumors than in other types of tumors that proliferate faster. The implications for possibly treating prostatic cancer using fewer and larger fractions are important. In this paper we review updated clinical data and present somewhat different calculations to estimate alpha/beta. METHODS AND MATERIALS: Seventeen clinical papers published from 1995 to 2000 were reviewed to obtain estimates of biochemical control from radiotherapy alone using external beam, I-125 implants, or Pd-103 implants. The focus was on intermediate risk patients. Three methods of estimating alpha/beta were employed. First, a simple two-step graphical comparison of isoeffective doses from external beam and implant modalities was made, to see which value of alpha/beta predicted the observed identity of biologic effect. Second, the same data were subjected to Direct Analysis (maximum likelihood estimation), from which an estimate of alpha/beta and also of the T(12) of repair of sublethal damage in the tumors (both with confidence intervals) were obtained. Third, preliminary clinical data comparing two different sizes of high-dose boost doses were analyzed in which significantly different bNED was observed at 2 years. RESULTS: The second method gave the definitive result of alpha/beta = 1.49 Gy (95% CI 1.25-1.76) and T(12) = 1.90 h (95% CI 1.42-2.86 h). The first method gave a range from 1.4 to 1.9 Gy and showed that if mean or median dose were used instead of prescribed dose, the estimate of alpha/beta would be substantially below 1 Gy. The third method, although based on early follow-up, was consistent with low values of alpha/beta in the region of 2 Gy or below. The estimate for T(12) is the first value reported for prostate tumors in situ. CONCLUSIONS: All the estimates point toward low values of alpha/beta, at least as low as the estimates of Brenner and Hall, and possibly lower than the expected values of about 3 Gy for late complications. Hypofractionation trials for intermediate-risk prostatic cancer appear to be indicated.     

Literature analysis of high dose rate brachytherapy fractionation schedules in the treatment of cervical cancer: is there an optimal fractionation schedule?

PURPOSE: A literature review and analysis was performed to determine whether or not efficacious high dose rate (HDR) brachytherapy fractionation schedules exist for the treatment of cervical cancer. METHODS AND MATERIALS: English language publications from peer reviewed journals were assessed to calculate the total contribution of dose to Point A from both the external and intracavitary portions of radiation for each stage of cervical cancer. Using the linear quadratic formula, the biologically effective dose to the tumor, using an alpha/beta = 10, was calculated to Point A (Gy10) in order to determine a dose response relationship for local control and survival. Significant complications were assessed by calculating the dose to the late-responding tissues at Point A using an alpha/beta = 3 (Gy3) as a surrogate for normal tissue tolerance, since few publications list the actual bladder and rectal doses. RESULTS: For all stages combined, the median external beam fractionation schedule to Point A was 40 Gy in 20 fractions, while the median HDR fractionation schedule was 28 Gy in 4 fractions. For stages IB, IIB, and IIIB the median biologically effective dose to Point A (Gy10) was 96, 96 and 100 Gy10s, respectively. No correlation was identified between Point A BED (Gy10s) to either survival or pelvic control. A dose response relationship could also not be identified when correlating Point A Gy3s to complications. CONCLUSION: A dose response relationship could not be identified for either tumor control nor late tissue complications. These findings do not necessarily question the validity of the linear quadratic model, as much as they question the quality of the current HDR brachytherapy literature as it is currently presented and reported. Most of the HDR publications report inadequate details of the dose fractionation schedules. Only a minority of publications report significant complications using the actuarial method. In the future, all HDR publications for the treatment of cervical cancer should provide accurate fractionation details for each stage of disease, while reporting actuarial complication rates. The optimal fractionation schedule for treating cervical cancer using HDR brachytherapy is still unknown, and presently can be based only on single institutions with significant experience.     

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.     

Bone necrosis and tumor induction following experimental intraoperative irradiation

The bone of the lumbar vertebrae of 153 dogs was examined 2 and 5 years after intraoperative irradiation (IORT), fractionated external beam irradiation (EBRT), or the combination. Groups of dogs received 15 to 55 Gy IORT only, 10 to 47.5 Gy IORT combined with 50 Gy EBRT in 2 Gy fractions or 60 to 80 Gy EBRT in 30 fractions. Six MeV electrons were used for IORT, and EBRT was done using photons from a 6 MV linear accelerator. The paraaortic region was irradiated and the ventral part of the lumbar vertebrae was in the 90% isodose level. Two years after irradiation, the dose causing significant bone necrosis as determined by at least 50% empty lacunae in the vertebral cortex was 38.2 Gy IORT alone and 32.5 Gy IORT combined with EBRT. Five years after irradiation, the dose causing 50% empty lacunae was 28.5 Gy IORT only and 14.4 Gy IORT combined with EBRT. The ED50 for lesions of the ventral vertebral artery was 21.7 Gy IORT only and 20.1 Gy IORT combined with 50 Gy EBRT 2 years after irradiation and 27.0 Gy IORT only and 20.0 Gy IORT combined with 50 Gy EBRT 5 years after irradiation. All lesions after EBRT only were mild. Eight dogs developed osteosarcomas 4 to 5 years after irradiation, one at 47.5 Gy IORT only and the remainder at 25.0 Gy IORT and above combined with 50 Gy EBRT. In conclusion, the extent of empty lacunae, indicating bone necrosis, was more severe 5 years after irradiation than after 2 years. The effect of 50 Gy EBRT in 2 Gy fractions was equivalent to about 6 Gy IORT 2 years after irradiation and to about 14 Gy 5 years after irradiation. Based on these estimates, IORT doses of 10 to 15 Gy have an effect 5 times or greater than the amount given in 2 Gy fractions. Osteosarcomas occurred in 21% of dogs which received doses greater than 25 Gy IORT. Doses of 15 to 20 Gy IORT in combination with 50 Gy EBRT in 2 Gy fractions may be near the tolerance level for late developing bone injury.     

Is single fraction 15 Gy the preferred high dose-rate brachytherapy boost dose for prostate cancer?

Background and purpose

High dose-rate (HDR) brachytherapy is most commonly administered as a boost in two or more fractions combined with external beam radiotherapy (EBRT). Our purpose is to compare outcomes with a single fraction HDR boost to that with a standard fractionated boost in intermediate risk prostate cancer.

Materials and methods

Results of two sequential phase II clinical trials are compared. The Single Fraction protocol consists of 15 Gy HDR in one fraction followed by 37.5 Gy EBRT in 15 fractions over 3 weeks; the Standard Fractionation protocol consisted of two HDR fractions each of 10 Gy, 1 week apart, followed by 45 Gy EBRT in 25 fractions. Patients had intermediate risk disease, and were well balanced for prognostic factors. Patients were followed prospectively for efficacy, toxicity and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition, and by biopsy at 2 years.

Results

The Single Fraction protocol accrued 123 patients and the Standard Fractionation protocol, 60. With a median follow-up of 45 and 72 months, respectively, the biochemical disease-free survival was 95.1% and 97.9% in the Single and Standard Fractionation trials (p = 0.3528). Two-year prostate biopsy was positive in only 4% and 8%, respectively. There was no difference in late urinary or rectal toxicity rates, or in health-related quality of life between the two protocols.

Conclusions

The Single Fraction HDR protocol results in high disease control rate and low toxicity similar to our previous protocol using two HDR insertions, with significant savings in resources. While mature results with longer follow-up are awaited, a single 15 Gy may be considered as a standard fractionation regimen in combination with EBRT for men with intermediate risk disease.     

The prediction of late rectal complications in patients treated with high dose-rate brachytherapy for carcinoma of the cervix

: The aim of this work is to invetigate an unusually high rate of late rectal complications in a group of 43 patients treated with concomitant irradiation and chemotherapy for carcinoma of the cervix between December 1988 and April 1991, with a view to identifying predictive factors.

: The biologically effective dose received by each patient to the rectal reference point defined by the International Commission of Radiation Units and Measurements, Report 38, were calculated. Radiotherapy consisted of 46 Gy external beam irradiation plus three dose-rate intracavitary treatments of 10 Gy each prescribed to point A. Cisplatin 30 mg/m² was given weekly throughout the duration of the irradiation. The results have been compared to data from 119 patients treated with irradiation alone to assess the cofounding effect of the cisplatin.

: The relationship between the biologically effective dose delivered to the rectal reference point and the development of late complications shows a strong dose-response with a threshold for complications occurring at aproximately the same biologically effective dose threshold as that found for external beam irradiation in the head and neck region. The date from the group of patients treated wihout cisplatin is comparable to the date from the first group of patients in the lower dose ranges; the higher doses were not used and thus are not available for comparison.

: Using the linear quadratic model applied to our clinical results, we have established a threshold for late rectal complications for patients treated with external beam irradiation and high dose-rate brachytherapy for carcinoma of the cervix. This threshold is consistent with similar data for external irradiation in the head and neck region.     

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.     

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.