Mark A. Ritter

Is α/β for prostate tumors really low?

Abstract Purpose: Brenner and Halls 1999 paper estimating an α/β 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 α/β. 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 α/β 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 α/β predicted the observed identity of biologic effect. Second, the same data were subjected to Direct Analysis (maximum likelihood estimation), from which an estimate of α/β 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 α/β = 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 α/β would be substantially below 1 Gy. The third method, although based on early follow-up, was consistent with low values of α/β 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 α/β, 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.

Image guidance for precise conformal radiotherapy

PURPOSE To review the state of the art in image-guided precision conformal radiotherapy and to describe how helical tomotherapy compares with the image-guided practices being developed for conventional radiotherapy. MATERIALS AND METHODS Image guidance is beginning to be the fundamental basis for radiotherapy planning, delivery, and verification. Radiotherapy planning requires more precision in the extension and localization of disease. When greater precision is not possible, conformal avoidance methodology may be indicated whereby the margin of disease extension is generous, except where sensitive normal tissues exist. Radiotherapy delivery requires better precision in the definition of treatment volume, on a daily basis if necessary. Helical tomotherapy has been designed to use CT imaging technology to plan, deliver, and verify that the delivery has been carried out as planned. The image-guided processes of helical tomotherapy that enable this goal are described. RESULTS Examples of the results of helical tomotherapy processes for image-guided intensity-modulated radiotherapy are presented. These processes include megavoltage CT acquisition, automated segmentation of CT images, dose reconstruction using the CT image set, deformable registration of CT images, and reoptimization. CONCLUSIONS Image-guided precision conformal radiotherapy can be used as a tool to treat the tumor yet spare critical structures. Helical tomotherapy has been designed from the ground up as an integrated image-guided intensity-modulated radiotherapy system and allows new verification processes based on megavoltage CT images to be implemented.

Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406

PURPOSE A prospective Phase I dose escalation study was conducted to determine the maximally-tolerated radiation dose in men treated with three-dimensional conformal radiation therapy (3D CRT) for localized prostate cancer. This is a preliminary report of toxicity encountered on the 3DOG/RTOG 9406 study. METHODS AND MATERIALS Each participating institution was required to implement data exchange with the RTOG 3D quality assurance (QA) center at Washington University in St. Louis. 3D CRT capabilities were strictly defined within the study protocol. Patients were registered according to three stratification groups: Group 1 patients had clinically organ-confined disease (T1,2) with a calculated risk of seminal vesicle invasion of < 15%. Group 2 patients had clinical T1,2 disease with risk of SV invasion > or = 15%. Group 3 (G3) patients had clinical local extension of tumor beyond the prostate capsule (T3). All patients were treated with 3D techniques with minimum doses prescribed to the planning target volume (PTV). The PTV margins were 5-10 mm around the prostate for patients in Group 1 and 5-10 mm around the prostate and SV for Group 2. After 55.8 Gy, the PTV was reduced in Group 2 patients to 5-10 mm around the prostate only. Minimum prescription dose began at 68.4 Gy (level I) and was escalated to 73.8 Gy (level II) and subsequently to 79.2 Gy (level III). This report describes the acute and late toxicity encountered in Group 1 and 2 patients treated to the first two study dose levels. Data from RTOG 7506 and 7706 allowed calculation of the expected probability of observing a > or = grade 3 late effect more than 120 days after the start of treatment. RTOG toxicity scores were used. RESULTS Between August 23, 1994 and July 2, 1997, 304 Group 1 and 2 cases were registered; 288 cases were analyzable for toxicity. Acute toxicity was low, with 53-54% of Group 1 patients having either no or grade 1 toxicity at dose levels I and II, respectively. Sixty-two percent of Group 2 patients had either none or grade 1 toxicity at either dose level. Few patients (0-3%) experienced a grade 3 acute bowel or bladder toxicity, and there were no grade 4 or 5 toxicities. Late toxicity was very low in all patient groups. The majority (81-85%) had either no or mild grade 1 late toxicity at dose level I and II, respectively. A single late grade 3 bladder toxicity in a Group 2 patient treated to dose level II was recorded. There were no grade 4 or 5 late effects in any patient. Compared to historical RTOG controls (studies 7506, 7706) at dose level I, no grade 3 or greater late effects were observed in Group 1 and Group 2 patients when 9.1 and 4.8 events were expected (p = 0.003 and p = 0.028), respectively. At dose level II, there were no grade 3 or greater toxicities in Group 1 patients and a single grade 3 toxicity in a Group 2 patient when 12.1 and 13.0 were expected (p = 0.0005 and p = 0.0003), respectively. Multivariate analysis demonstrated that the relative risk of developing acute bladder toxicity was 2.13 if the percentage of the bladder receiving > or = 65 Gy was more than 30% (p = 0.013) and 2.01 if patients received neoadjuvant hormonal therapy (p = 0.018). The relative risk of developing late bladder complications also increased as the percentage of the bladder receiving > or = 65 Gy increased (p = 0.026). Unexpectedly, there was a lower risk of late bladder complications as the mean dose to the bladder and prescription dose level increased. This probably reflects improvement in conformal techniques as the study matured. There was a 2.1 relative risk of developing a late bowel complication if the total rectal volume on the planning CT scan exceeded 100 cc (p = 0.019). CONCLUSION Tolerance to high-dose 3D CRT has been better than expected in this dose escalation trial for Stage T1,2 prostate cancer compared to low-dose RTOG historical experience. With strict quality assurance standards and review, 3D CRT can be safely studied in a co

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.

Prostate-specific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer.

PURPOSE A study of preradiation and postradiation, serial serum prostate-specific antigen (PSA) levels was performed in patients who had clinically localized prostate cancer. The prognostic value of the PSA in pretreatment evaluation and posttreatment follow-up was assessed. PATIENTS AND METHODS Sixty-three patients who presented with clinically localized prostate cancer and who were treated with external-beam radiation therapy were followed-up for a median of 25 months. A serum PSA and physical examination were performed at 3-month intervals, and a bone scan was done yearly. An increase in PSA triggered an additional metastatic workup. Prostate rebiopsy was performed for new, palpable nodules or for a serial increase in PSA in the context of a negative metastatic workup. RESULTS Forty-one patients remained recurrence-free and 22 recurred clinically, 15 distantly and seven locally. The PSA was the strongest, independent, pretreatment prognostic indicator (P = .019) among pretreatment PSA, stage, and grade, but lost significance when the serum prostatic acid phosphatase (PAP) status was included. The initial rate of the PSA decrease after radiation (median half-life, 2.6 months) failed to predict outcome. Recurrence-free patients reached postradiation PSA levels that were equivalent to those reported in disease-free male populations; failure of the PSA to reach such normal levels was a multivariate predictor of subsequent failure (P less than .037). All clinicopathologic documentations of failure were preceded by an increase in PSA levels during follow-up. Delayed versus early PSA increase was associated with clinically localized versus metastatic first recurrence. CONCLUSIONS The serum PSA is an independent pretreatment and posttreatment predictor of outcome. Additionally, for a median follow-up of 25 months, delayed PSA failure is associated with clinically localized rather than metastatic recurrence, a relationship that may help in selection for local salvage therapy.

Helical Tomotherapy: An Innovative Technology and Approach to Radiation Therapy

Helical tomotherapy represents both a novel radiation treatment device and an innovative means of delivering radiotherapy. The helical tomotherapy unit itself is essentially a hybrid between a linear accelerator and a helical CT scanner for the purpose of delivering intensity-modulated radiation therapy (IMRT). The imaging capacity conferred by the CT component allows targeted regions to be visualized prior to, during, and immediately after each treatment. The megavoltage CT (MVCT) images supplant the port-films used in conventional radiotherapy, providing unprecedented anatomical detail. Image-guidance through MVCT will allow the development and refinement of the concept of “adaptive radiotherapy”, the reconstruction of the actual daily delivered dose (as opposed to planned dose) accompanied by prescription and delivery adjustments when appropriate. In addition to this unique feature, helical tomotherapy appears capable of further improvements over 3-dimensional conformal radiation therapy and non-helical IMRT in the specific avoidance of critical normal structures, i.e. “conformal avoidance”, the counterpart of conformal radiation therapy. Based on radiobiological principles that exploit the physical advantages of helical tomotherapy, several dosimetric and clinical investigations are underway.

Rectal dose sparing with a balloon catheter and ultrasound localization in conformal radiation therapy for prostate cancer

BACKGROUND AND PURPOSE To compare the rectal wall and bladder volume in the high dose region with or without the use of a balloon catheter with both three-dimensional (3D)-conformal and intensity modulated radiation therapy (CRT, IMRT) approaches in the treatment of prostate cancer. MATERIAL AND METHODS Five patients with a wide range of prostate volumes and treated with primary external beam radiation therapy for localized prostate cancer were selected for analysis. Pinnacle treatment plans were generated utilizing a 3D conformal six-field design and an IMRT seven coplanar-field plan with a novel, three-step optimization and with ultrasound localization. Separate plans were devised with a rectal balloon deflated or air inflated with and without inclusion of the seminal vesicles (SV) in the target volume. The prescription dose was 76Gy in 38 fractions of 2Gy each. Cumulative dose-volume histograms (DVHs) were analyzed for the planning target volume (PTV), rectal wall, and bladder with an inflated (60cc air) or deflated balloon with and without SV included. The volumes of rectal wall and bladder above 60, 65, and 70Gy with each treatment approach were evaluated. RESULTS Daily balloon placement was well-tolerated with good patient positional reproducibility. Inflation of the rectal balloon in all cases resulted in a significant decrease in the absolute volume of rectal wall receiving greater than 60, 65, or 70Gy. The rectal sparing ratio (RSR), consisting of a structures high dose volume with the catheter inflated, divided by the volume with the catheter deflated, was calculated for each patient with and without seminal vesicle inclusion for 3D-CRT and IMRT. For 3D-CRT, RSRs with SV included were 0.59, 0.59, and 0.56 and with SV excluded were 0.60, 0.58, and 0.54 at doses of greater than 60, 65, and 70Gy, respectively. Similarly, for IMRT, the mean RSRs were 0.59, 0.59, and 0.63 including SV and 0.71, 0.66, and 0.67 excluding SV at these same dose levels, respectively. Averaged over all conditions, inflation of the rectal balloon resulted in a significant reduction in rectal volume receiving > or =65Gy to a mean ratio of 0.61 (P=0.01) or, in other words, a mean fractional high dose rectal sparing of 39%. There was a slight overall increase to 1.13 in the relative volume of bladder receiving at least 65Gy; however, this was not significant (P=0.6). Use of an endorectal balloon with a non-image-guided 3D-CRT plan produced about as much rectal dose sparing as a highly conformal, image-guided IMRT approach without a balloon. However, inclusion of a balloon with IMRT produced further rectal sparing still. CONCLUSION These results indicate that use of a rectal balloon with a 3D-CRT plan incorporating typical treatment margins will produce significant high dose rectal sparing that is comparable to that achieved by a highly conformal IMRT with ultrasound localization. Further sparing is achieved with the inclusion of a balloon catheter in an IMRT plan. Thus, in addition to a previously reported advantage of prostate immobilization, the use of a rectal displacement balloon during daily treatment results in high dose rectal wall sparing during both modestly and highly conformal radiotherapy. Such sparing could assist in controlling and limiting rectal toxicity during increasingly aggressive dose escalation.

Clinical Implementation of Adaptive Helical Tomotherapy: A Unique Approach to Image-Guided Intensity Modulated Radiotherapy

Image-guided IMRT is a revolutionary concept whose clinical implementation is rapidly evolving. Methods of executing beam intensity modulation have included individually designed compensators, static multi-leaf collimators (MLC), dynamic MLC, and sequential (serial) tomotherapy. We have developed helical tomotherapy as an innovative solution to overcome some of the limitations of other IMRT systems. The unique physical design of helical tomotherapy allows the realization of the concepts of adaptive radiotherapy and conformal avoidance. In principle, these advances should improve normal tissue sparing and permit dose reconstruction and verification, thereby allowing significant biologically effective dose escalation. Recent radiobiological findings can be translated into altered fractionation schemes that aim to improve the local control and long-term survival. This strategy is being tested at the University of Wisconsin using helical tomotherapy with its highly precise delivery and verification system along with meticulous and practical forms of immobilization. Innovative techniques such optical guidance, respiratory gating, and ultrasound assessments are being designed and tailored for helical tomotherapy use. The intrinsic capability of helical tomotherapy for megavoltage CT (MVCT) imaging for IMRT image-guidance is being optimized. The unique features of helical tomotherapy might allow implementation of image-guided IMRT that was previously impossible or impractical. Here we review the technological, physical, and radiobiological rationale for the ongoing and upcoming clinical trials that will use image-guided IMRT in the form of helical tomotherapy; and we describe our plans for testing our hypotheses in a rigorous prospective fashion.

COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial.

BACKGROUND COX-2 is overexpressed in some cancers, including prostate cancer; however, little is known about the effect of COX-2 overexpression on outcome in radiation-treated patients with prostate cancer. We aimed to study COX-2 overexpression and outcome in a well-defined cohort of men who received treatment with short-term androgen deprivation (STAD) plus radiotherapy or long-term androgen deprivation (LTAD) plus radiotherapy. METHODS Men with prostate cancer who had participated in the Radiation Therapy Oncology Group (RTOG) 92-02 trial and for whom sufficient diagnostic tissue was available for immunohistochemical staining and image analysis of COX-2 expression were enrolled in this study. Patients in the 92-02 trial had been randomly assigned to treatment with STAD plus radiotherapy or LTAD plus radiotherapy. Multivariate analyses by Cox proportional hazards models were done to assess whether associations existed between COX-2 staining intensity and the RTOG 92-02 primary endpoints of biochemical failure (assessed by the American Society for Therapeutic Radiology and Oncology [ASTRO] and Phoenix criteria), local failure, distant metastasis, cause-specific mortality, overall mortality, and any failure. FINDINGS 586 patients with sufficient diagnostic tissue for immunohistochemical staining and image analysis of COX-2 expression were included in this study. In the multivariate analyses, the intensity of COX-2 staining as a continuous covariate was an independent predictor of distant metastasis (hazard ratio [HR] 1.181 [95% CI 1.077-1.295], p=0.0004); biochemical failure by two definitions (ASTRO HR 1.073 [1.018-1.131], p=0.008; Phoenix HR 1.073 [1.014-1.134], p=0.014); and any failure (HR 1.068 [1.015-1.124], p=0.011). The higher the expression of COX-2, the greater the chance of failure. As a dichotomous covariate, COX-2 overexpression seemed to be most discriminating of outcome for those who received STAD compared with those who received LTAD. INTERPRETATION To our knowledge, this is the first study to establish an association of COX-2 expression with outcome in patients with prostate cancer who have had radiotherapy. Increasing COX-2 expression was significantly associated with biochemical failure, distant metastasis, and any failure. COX-2 inhibitors might improve patient response to radiotherapy in those treated with or without androgen deprivation. Our findings suggest that LTAD might overcome the effects of COX-2 overexpression. Therefore, COX-2 expression might be useful in selecting patients who need LTAD.

A Comprehensive Assessment by Tumor Site of Patient Setup Using Daily MVCT Imaging From More Than 3,800 Helical Tomotherapy Treatments

PURPOSE To assess patient setup corrections based on daily megavoltage CT (MVCT) imaging for four anatomic treatment sites treated on tomotherapy. METHOD AND MATERIALS Translational and rotational setup corrections, based on registration of daily MVCT to planning CT images, were analyzed for 1,179 brain and head and neck (H&N), 1,414 lung, and 1,274 prostate treatment fractions. Frequencies of three-dimensional vector lengths, overall distributions of setup corrections, and patient-specific distributions of random and systematic setup errors were analyzed. RESULTS Brain and H&N had lower magnitude positioning corrections and smaller variations in translational setup errors but were comparable in roll rotations. Three-dimensional vector translational shifts of larger magnitudes occurred more frequently for lung and prostate than for brain and H&N treatments, yet this was not observed for roll rotations. The global systematic error for prostate was 4.7 mm in the vertical direction, most likely due to couch sag caused by large couch extension distances. Variations in systematic errors and magnitudes of random translational errors ranged from 1.6 to 2.6 mm for brain and H&N and 3.2 to 7.2 mm for lung and prostate, whereas roll rotational errors ranged from 0.8 degrees to 1.2 degrees for brain and H&N and 0.5 degrees to 1.0 degrees for lung and prostate. CONCLUSIONS Differences in setup were observed between brain, H&N, lung, and prostate treatments. Patient setup can be improved if daily imaging is performed. This analysis can assess the utilization of daily image guidance and allows for further investigation into improved anatomic site-specific and patient-specific treatments.