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.     

Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen ≥10 ng/ml

: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer.

: We report the biochemical freedom from disease (bNED) rates (BNED) failure in Prostate Specific Antigen (PSA) ≥ 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (<10, 10–19.9, and ≥20 ng/ml). Dose was stated to be at the center of prostate gland.

: There was significant improvement in bNED survuval for all patients divided by a dose above or below 71 Gy (p = 0.007) and a marginal improvement above or below 73 Gy (p = 0.07). Subdividing by pretreatment PSA level showed no benefit to the PSA < 10 ng/ml group at the higher dose but there was a significant improvement at 71 and 73 Gy for pretreatment PSA 10–19.9 ng/ml (p = 0.03 and 0.05, respectively) and for pretreatment PSA ≥ 20 ng/ml (p = 0.003 and 0.02, respectively).

: Increasing dose above 71 or 73 Gy did not result in improved bNED survuval for patient with pretreatment PSA < 10 ng/ml at 2 or 3 years. Further dose escalation studies may not be useful in the patients. A significant improvement in bNED survuval was noted for patients with pretreatment PSA ≥ 10 ng/ml treated above 71 of 73 Gy; further dose escalation studies are warranted.     

Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial

A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer.

A total of 305 Stage T1–T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis.

There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA ≤10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy.

An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives ≥70 Gy to <25% should be used.     

Ultrasound image fusion for external beam radiotherapy for prostate cancer

: To determine whether real-time ultrasound imaging and targeting system for the treatment of prostate cancer was feasible. The initial phase of this project included a study to develop and determined (a) software for the fusion of ultrasound images to standard x-rays obtained during simulation, and (b) the potential reduction in field size with real time imaging.

: During 13 patient simulations a transrectal ultrasound image was obtained. Orthogonal x-ray films were acquired with the rectal probe in place. Both the x-ray and ultrasound images were digitized and a fusion image was created of the prostate position in relation to the probe, bladder, and rectum. The two-dimensional area of the rectum, bladder, and prostate was determined in the lateral projection. Potential conformal blocks were designed for the lateral portals in a four-field treatment technique.

: The transrectal ultrasound probe enabled real-time prostrate imaging. The lateral field size can be reduced to 6.08 × 5.68 cm² ± 0.62 × 0.48 cm² from the standard 8 × 8 cm² field. The posterior rectal wall was physically displaced out of the lateral field. The area of the rectum included in the lateral field in 1.75 cm² ± 0.85 cm².

: The prostate position can be determined with certainty on a regular basis with transrectal ultrasonography. The amount of normal tissue in the high dose volume can be reduced. This approach may reduce acute and chronic morbidity and allow further dose escalation.     

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.     

Radiotherapy treatment for isolated loco-regional recurrence of rectosigmoid cancer following definitive surgery: Peter maccallum cancer institute experience, 1981–1990

: To assess the success of external beam radiation treatment in the management of loc-regional recurrence of rectosigmoid cancer.

: A retrospective analysis f 135 patients with locally recurrent rectosigmid cancer presenting to Peter MacCallum Cancer Institute between january 1981 and December 1990 was undertaken. Patients were treated with three different dose ranges of radiotherapy: 50–60 Gy (“Radical” group), 45 Gy (“High-dose palliative” group), and <45 Gy (“Low-dose palliative” group). Symptomatic response rates and overall survival for each group were determined.

: Symptomatic response rates of 85, 81, and 56% were achieved in the radical, high-dose palliative, and low-dose palliative groups, respectively. Estimated median survival times were 17.9, 14.8, and 9.1 months for the radical, high-dose palliative, and low-dose palliative groups, respectively.     

A dose-escalation trial with the adaptive radiotherapy process as a delivery system in localized prostate cancer: analysis of chronic toxicity

PURPOSE: To evaluate the validity of the chosen adaptive radiotherapy (ART) dose-volume constraints while testing the hypothesis that toxicity would not be greater at higher tumor dose levels. MATERIALS AND METHODS: In the ART dose escalation/selection trial, treatment was initiated with a generic planning target volume (PTV) formed as a 1-cm expansion of the clinical target volume (CTV). After the first week of therapy, the patient was replanned with a patient-specific PTV, constructed with CT and electronic portal images obtained in the first 4 days of treatment. A new multileaf collimator beam aperture was used. A minimum dose prescribed to the patient-specific PTV, ranging 70.2-79.2 Gy, was determined on the basis of the following rectal and bladder constraints: <5% of the rectal wall has a dose >82 Gy, <30% of the rectal wall has a dose >75.6 Gy, <50% of the bladder volume has a dose >75.6 Gy, and the maximum bladder dose is 85 Gy. A conformal four-field and/or intensity-modulated radiotherapy (IMRT) technique was used. Independent reviewers scored toxicities. The worst toxicity score seen was used as per the Common Toxicity Criteria grade scale (version 2). We divided the patients into three separate groups: 70.2-72 Gy, >72-75.6 Gy, and >75.6-79.2 Gy. Toxicities in each group were quantified and compared by the Pearson chi-squared test to validate our dose escalation/selection model. Grades 0, 1, 2, and 3 were censored as none vs. each category and none vs. any. RESULTS: We analyzed patients with follow-up greater than 1 year. The mean duration of follow-up was 29 months (range, 12-46 months). We report on 280 patients, mean age 72 years (range, 51-87 years). Only 60 patients received adjuvant hormones. Mean pretreatment prostate-specific antigen level was 9.3 ng/mL (range, 0.6-120 ng/mL). Mean Gleason score was 6 (range, 3-9). The lowest dose level was given to 49 patients, the intermediate dose to 131 patients, and 100 patients received the highest dose escalation. One hundred eighty-one patients (65%) were treated to a prostate field only and 99 patients (35%) to prostate and seminal vesicles. Chronic genitourinary and/or gastrointestinal categories were incontinence, persistent urinary retention, increased urinary frequency/urgency, urethral stricture, hematuria, diarrhea, rectal pain, bleeding, ulcer, fistula, incontinence, and proctitis. Toxicity at the high dose level was not different from toxicity at the intermediate or lower dose levels. No significant difference was observed in any of the individual toxicity categories. CONCLUSIONS: By applying the ART process--namely, developing a patient-specific PTV--to prostate cancer patients, significant dose escalation can be achieved without increases in genitourinary or gastrointestinal toxicity. Our data validate the rectal and bladder dose-volume constraints chosen for our three-dimensional conformal and IMRT prostrate radiotherapy planning.     

Inclusion of geometric uncertainties in treatment plan evaluation

: To correctly evaluate realistic treatment plans in terms of absorbed dose to the clinical target volume (CTV), equivalent uniform dose (EUD), and tumor control probability (TCP) in the presence of execution (random) and preparation (systematic) geometric errors.

: The dose matrix is blurred with all execution errors to estimate the total dose distribution of all fractions. To include preparation errors, the CTV is randomly displaced (and optionally rotated) many times with respect to its planned position while computing the dose, EUD, and TCP for the CTV using the blurred dose matrix. Probability distributions of these parameters are computed by combining the results with the probability of each particular preparation error. We verified the method by comparing it with an analytic solution. Next, idealized and realistic prostate plans were tested with varying margins and varying execution and preparation error levels.

: Probability levels for the minimum dose, computed with the new method, are within 1% of the analytic solution. The impact of rotations depends strongly on the CTV shape. A margin of 10 mm between the CTV and planning target volume is adequate for three-field prostate treatments given the accuracy level in our department; i.e., the TCP in a population of patients, TCP_pop, is reduced by less than 1% due to geometric errors. When reducing the margin to 6 mm, the dose must be increased from 80 to 87 Gy to maintain the same TCP_pop. Only in regions with a high-dose gradient does such a margin reduction lead to a decrease in normal tissue dose for the same TCP_pop. Based on a rough correspondence of 84% minimum dose with 98% EUD, a margin recipe was defined. To give 90% of patients at least 98% EUD, the planning target volume margin must be approximately 2.5 Σ + 0.7 σ − 3 mm, where Σ and σ are the combined standard deviations of the preparation and execution errors. This recipe corresponds accurately with 1% TCP_pop loss for prostate plans with clinically reasonable values of Σ and σ.

: The new method computes in a few minutes the influence of geometric errors on the statistics of target dose and TCP_pop in clinical treatment plans. Too small margins lead to a significant loss of TCP_pop that is difficult to compensate for by dose escalation.     

Dose-Volume Histograms for bladder and rectum

: A careful examination of the foundation upon which the concept of the Dose-Volume Histogram (DVH) is built, and the implications of this set of parameters on the clinical application and interpretation of the DVH concept has not been conducted since the introduction of DVHs as a tool for the quantitative evaluation of treatment plans. The purpose of the work presented herein is to illustrate problems with current methods of implementing and interpreting DVHs when applied to hollow anatomic structures such as the bladder and rectum.

: A typical treatment plan for external beam irradiation of a patient with prostate cancer was chosen to provide a data set from which DVH curves for both the bladder and rectum were calculated. The two organs share the property of being shells with contents that are of no clinical importance. DVHs for both organs were computed using a solid model and using a shell model. Typical treatment plans for prostate cancer were used to generate DVH curves for both models. The Normal Tissue Complication Probability (NTCP) for these organs is discussed in this context.

: For an eight-field conformal treatment plan of the prostate, a bladder DVH curve generated using the shell model is higher than the corresponding curve generated using the solid model. The shell model also has a higher NTCP. A six-field conformal treatment plan slo results in a higher DVH curve for the shell model. A treatment plan consisting of bilateral 120-degree arcs, results in a higher DVH curve for the shell model, as well as a higher NTCP.

: The DVH concept currently used in evaluation of treatment plans is problematic because current practices of defining exactly what constitutes “bladder” and “rectum.” Commonly used methods of tracing the bladder and rectum imply use of a solid structure model for DVHs. In reality, these organs are shells and the critical structure associated with NTCP is obviously and indisputably the shell, as opposed to its contents. Treatment planning algorithms for DVH computation should thus be modified to utilize the shell model for these organs.     

Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer

Purpose: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT).

Methods and Materials: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose–volume histograms. The recurrences were classified as 1) “in-field,” in which 95% or more of the recurrence volume (V_recur) was within the 95% isodose; 2) “marginal,” in which 20% to 95% of V_recur was within the 95% isodose; or 3) “outside,” in which less than 20% of V_recur was within the 95% isodose.

Results: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68–90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared.

Conclusions: The majority of local-regional recurrences after conformal and segmental IMRT were “in-field,” in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.     

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.     

Late morbidity profiles in prostate cancer patients treated to 79-84 Gy by a simple four-field coplanar beam arrangement

PURPOSE: To describe the frequency and magnitude of late GI and GU morbidity in prostate cancer patients treated to high dose levels with a simple three-dimensional conformal technique. METHODS AND MATERIALS: A total of 156 intermediate- and high-risk patients were treated between January 1, 1992 and February 28, 1999 with a simple four-field three-dimensional conformal technique to 79-84 Gy. All patients were treated with a four-field conformal technique; the prostate received 82 Gy and the seminal vesicles and periprostatic tissue 46 Gy. GI and GU toxicity was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Morbidity Grading Scale and compared using Kaplan-Meier estimates. RESULTS: The late Grade 2 GI complication rate was 9% and 38% at 3 years for patients treated with and without rectal blocking, respectively (p = 0.0004). No Grade 3 late GI complications developed. The rate of Grade 2 late GU complications was 5%, 8%, and 12% at 12, 24, and 36 months, respectively. The Grade 3 late GU complication rate was 2% at 36 months. These differences were not statistically significant. CONCLUSION: The treatment method described is a simple four-field conformal technique that can be easily implemented in the general radiation community. A dose of 79-84 Gy can be safely delivered to the prostate, with a 9% rate of late Grade 2 GI, 12% rate of late Grade 2 GU, and 2% rate of late Grade 3 GU complications.     

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.     

Lack of radiation dose response for patients with low-risk clinically localized prostate cancer: a retrospective analysis

The need for dose escalation for patients with low-risk clinically localized prostate cancer remains controversial. In this study, we report our pooled institutional experience of low-risk patients treated with a range of “standard” radiation doses to assess outcome in regard to biochemical failure and to determine whether a dose-response relationship exists within this conventional dose range.

Patients with low-risk clinically localized prostate cancer (T1 or T2a, Gleason grade ≤6, and prostate-specific antigen ≤10 ng/mL) treated at Joint Center for Radiation Therapy-affiliated institutions between October 1989 and September 1997 were retrospectively analyzed for freedom from biochemical failure. The dose was prescribed volumetrically with 95% normalization to between 5760 and 6900 cGy (6100 and 7300 cGy ICRU reference point dose). Patients were stratified into 3 groups with relatively equal numbers of patients (<6660, 6660, and >6660 cGy). To ensure that any differences in biochemical failure between patients at the lower and higher ends of the dose range used were not masked by analysis of the entire cohort, patients receiving ≤6500 cGy or ≥6800 cGy were subsequently analyzed separately. Biochemical failure was defined per the ASTRO consensus definition. The log-rank test was used to assess for differences in follow-up and time to biochemical failure. A Kaplan-Meier plot of time to biochemical failure for the initial 3 subgroups was generated.

A total of 264 patients were identified. Sixteen patients whose dose was not recorded in the database were excluded from analysis. The median follow-up was 35 months. No significant differences were found in baseline prostate-specific antigen, Gleason grade, or clinical stage among the groups. The overall actuarial rate of 5-year freedom from biochemical failure was 80.2%. By dose level, the 5-year biochemical failure-free rate was 79.2%, 78.4%, and 84.5% for <6660 cGy, 6660 cGy, and >6660 cGy, respectively. These differences were not significant. Subsequently, 45 patients receiving ≤6500 cGy were compared with 23 patients receiving ≥6800 cGy. The difference between these groups was not significant. The 5-year freedom from biochemical failure rate for the patients receiving ≤6500 cGy was 89.9%.

Within a range of doses considered standard for treatment of low-risk clinically localized prostate cancer during an 8-year period, no improvement in biochemical freedom from failure was noted with the higher doses. The overall 5-year rate of freedom from biochemical failure is consistent with that reported by others with standard and escalated external beam doses used in this low-risk population. A prospective randomized study is necessary to define the optimal dose in this patient population.     

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.     

Local excision and postoperative radiotherapy for distal rectal cancer

To assess the outcome following local excision and postoperative radiotherapy (RT) for distal rectal carcinoma.

Seventy-three patients received postoperative radiotherapy following local surgery for primary rectal carcinoma at Princess Margaret Hospital from 1983 to 1998. Selection factors for postoperative RT were patient preference, poor operative risks, and “elective” where conservative therapy was regarded as optimal therapy. Median distance of the primary lesion from the anal verge was 4 cm (range, 1–8 cm). There were 24 T1, 36 T2, and 8 T3 lesions. The T category could not be determined in 5. Of 55 tumor specimens in which margins could be adequately assessed, they were positive in 18. RT was delivered using multiple fields by 6- to 25-MV photons. Median tumor dose was 50 Gy (range, 38–60 Gy), and 62 patients received 50 Gy in 2.5-Gy daily fractions. The tumor volume included the primary with 3–5 cm margins. No patients received adjuvant chemotherapy. Median follow-up was 48 months (range, 10–165 months).

Overall 5-year survival and disease-free survival were 67% and 55%, respectively. Tumor recurrence was observed in 23 patients. There were 14 isolated local relapses; 6 patients developed local and distant disease; and 3 relapsed distantly only. For patients with T1, T2, and T3 lesions, 5-year local relapse-free rates were 61%, 75%, and 78%, respectively, and 5-year survival rates were 76%, 58%, and 33%, respectively. The 5-year local relapse-free rate was lower in the presence of lymphovascular invasion (LVI) compared to no LVI, 52% vs. 89%, p = 0.03, or where tumor fragmentation occurred during local excision compared to no fragmentation, 51% vs. 76%, p = 0.02. Eleven of 14 patients with local relapse only underwent abdominoperineal resection, 8 achieved local control, and 4 remained cancer free. The ultimate local control, including salvage surgery, was 86% at 5 and 10 years. The 5-year colostomy-free rate was 82%. There were 2 patients who experienced RTOG Grade 3 late complications, and 1 with Grade 4 complication (bowel obstruction requiring surgery).

The local relapse rate for patients with T1 disease was high compared to other series of local excision and postoperative RT. Patients with LVI or tumor fragmentation during excision have high local relapse rates and may not be good candidates for conservative surgery and postoperative RT.     

Characterization of rectal normal tissue complication probability after high-dose external beam radiotherapy for prostate cancer

PURPOSE: Conformal radiotherapy (RT) has allowed radiation dose escalation to improve the outcome of prostate cancer. With higher doses, concern exists that rectal injury may increase. This study analyzed the utility and limitations of the widely used Lyman-Kutcher- Burman (LKB) normal tissue complication probability model in projecting the hazards of rectal complication with high-dose RT. METHODS AND MATERIALS: A total of 128 patients were included in this study. These patients were treated with three-dimensional conformal RT alone at the University of Texas M.D. Anderson Cancer Center between 1992 and 1999. Patients were treated to 46 Gy with a four-field box technique followed by a six-field arrangement to boost the total dose to 78 Gy. All doses were delivered at 2 Gy/fraction to the isocenter. The minimal follow-up was 2 years. The end point for analysis was Grade 2 or worse rectal bleeding by 2 years. The LKB model was fitted to the data using the maximal likelihood method. RESULTS: Of the 128 patients, 29 experienced Grade 2 or worse rectal bleeding by 2 years. For the entire cohort, the parameters obtained from the fit of the LKB model were as follows: the volume factor was n = 3.91 (95% confidence interval [CI] 0.031 to infinity ), dose associated with 50% chance of complication for uniform whole rectal irradiation [TD50(1)] was 53.6 Gy (95% CI 50.0-75.1), and a determinant of the steepness of the dose-response curve, (m), was 0.156 (95% CI 0.036-0.271). A statistically significant difference was found in the rate of postradiation rectal bleeding in patients with hemorrhoids vs. those without hemorrhoids. The parameters obtained for the patients without hemorrhoids were as follows: n = 0.746 (95% CI 0.026 to infinity ), TD50(1) 56.7 Gy (95% CI 49.9-75.2), and m 0.092 (95% CI 0.019-0.189). CONCLUSION: Our analysis suggests a dose response for rectal bleeding probability along with a volume effect. We found that the LKB model might have limited utility in determining a large volume effect. We further suggest that LKB model should be used with caution in clinical practice.