Michael Goitein

Tolerance of normal tissue to therapeutic irradiation

The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.

Fitting of normal tissue tolerance data to an analytic function

During external beam radiotherapy, normal tissues are irradiated along with the tumor. Radiation therapists try to minimize the dose of normal tissues while delivering a high dose to the target volume. Often this is difficult and complications arise due to irradiation of normal tissues. These complications depend not only on the dose but also on volume of the organ irradiated. Lyman has suggested a four-parameter empirical model which can be used to represent normal tissue response under conditions of uniform irradiation to whole and partial volumes as a function of the dose and volume irradiated. In this paper, Lymans model has been applied to a compilation of clinical tolerance data developed by Emami et al. The four parameters to characterize the tissue response have been determined and graphical representations of the derived probability distributions are presented. The model may, therefore, be used to interpolate clinical data to provide estimated normal tissue complication probabilities for any combination of dose and irradiated volume for the normal tissues and end points considered.

Histogram reduction method for calculating complication probabilities for three-dimensional treatment planning evaluations

New tools are needed to help in evaluating 3-D treatment plans because of the large volume of data. One technique which may prove useful is the application of complication probability calculations. A method of calculating complication probabilities for inhomogeneously irradiated normal tissues is presented in this paper. The method uses clinical estimates of tolerance doses for a few discreet conditions of uniform partial organ irradiation, an empirical fit of a continuous function to these data, and a technique (the effective volume method) for transforming nonuniform dose-volume histograms into equivalent uniform histograms. The behavior of the effective volume histogram reduction method for various boundary conditions is reviewed. The use of complication probabilities in evaluating treatment plans is presented, using examples from an NCI 3-D treatment planning contract.

Advanced prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone☆

PURPOSE Following a thorough Phase I/II study, we evaluated by a Phase III trial high versus conventional dose external beam irradiation as mono-therapy for patients with Stage T3-T4 prostate cancer. Patient outcome following standard dose radiotherapy or following a 12.5% increase in total dose to 75.6 Cobalt Gray Equivalent (CGE) using a conformal perineal proton boost was compared for local tumor control, disease-free survival, and overall survival. METHODS AND MATERIALS Stage T3-T4, Nx, N0-2, M0 patients received 50.4 Gy by four-field photons and were randomized to receive either an additional 25.2 CGE by conformal protons (arm 1--the high dose arm, 103 patients, total dose 75.6 CGE) or an additional 16.8 Gy by photons (arm 2--the conventional dose arm, 99 patients, total dose 67.2 Gy). Actuarial overall survival (OS), disease-specific survival (DSS), total recurrence-free survival (TRFS), (clinically free, prostate specific antigen (PSA) less than 4ng/ml and a negative prostate rebiopsy, done in 38 patients without evidence of disease) and local control (digital rectal exam and rebiopsy negative) were evaluated. RESULTS The protocol completion rate was 90% for arm 1 and 97% for arm 2. With a median follow-up of 61 months (range 3 to 139 months) 135 patients are alive and 67 have died, 20 from causes other than prostate cancer. We found no significant differences in OS, DSS, TRFS or local control between the two arms. Among those completing randomized treatment (93 in arm 1 and 96 in arm 2), the local control at 5 and 8 years for arm 1 is 92% and 77%, respectively and is 80% and 60%, respectively for arm 2 (p = .089) and there are no significant differences in OS, DSS, and TRFS. The local control for the 57 patients with poorly differentiated (Gleason 4 or 5 of 5) tumors at 5 and 8 years for arm 1 is 94% and 84% and is 64% and 19% on arm 2 (p = 0.0014). In patients whose digital rectal exam had normalized following treatment and underwent prostate rebiopsy there was a lower positive rebiopsy rate for arm 1 versus arm 2 patients (28 vs. 45%) and also for those with well and moderately differentiated tumors versus poorly differentiated tumors (32 and 50%). These differences were not statistically significant. Grade 1 and 2 rectal bleeding is higher (32 vs. 12%, p = 0.002) as may be urethral stricture (19 vs. 8%, p = 0.07) in the arm 1 versus arm 2. CONCLUSIONS An increase in prostate tumor dose by external beam of 12.5% to 75.6 CGE by a conformal proton boost compared to a conventional dose of 67.2 Gy by a photon boost significantly improved local control only in patients with poorly differentiated tumors. It has increased late radiation sequelae, and as yet, has not increased overall survival, disease-specific survival, or total recurrence-free survival in any subgroup. These results have led us to test by a subsequent Phase III trial the potential beneficial effect on local control and disease-specific survival of a 12.5% increase in total dose relative to conventional dose in patients with T1, T2a, and T2b tumors.

Multi-dimensional treatment planning: II. Beam's eye-view, back projection, and projection through CT sections

Three features of a fully three-dimensional treatment planning program are presented: (1) The beams-eye-view provides the user with an accurate reproduction of anatomic features from the viewpoint of a treatment source. The source can be moved to any feasible position relative to the patient, permitting a choice which allows sensitive organs to be excluded from the beam. In this view a field defining aperture can readily be designed. (2) Back-projection of such an aperture shows the parts of the original transverse CT sections, or reconstructed sagittal or coronal sections, which may be covered by the selected beam. (3) Projection through the CT data from any desired origin provides an alignment film simulation which can be used to confirm accuracy of treatment, as well as help establish anatomic relationships relative to the margins of a treatment field.

ACCURACY OF RADIATION FIELD ALIGNMENT IN CLINICAL PRACTICE

We present an analysis of simulator and portal films of 71 patients. Twenty-five were analyzed retrospectively, 39 prospectively, but without changing routine filming practice, and 7 had daily portal films taken. Treatment-to-treatment variations in anatomy with respect to the field were determined by comparing sequential portal films. The standard deviation of the variations was approximately normally distributed with an average value of 3 mm independent of site and field shaping technique. Discrepancies between the portal and simulator films were greater and depended on the site of treatment. The mean worst-case discrepancy averaged over all sites was 7.7 mm; the lowest value was 3.5 mm in the head and neck region; the highest value was 9.2 mm in the thorax.

A pencil beam algorithm for proton dose calculations

The sharp lateral penumbra and the rapid fall-off of dose at the end of range of a proton beam are among the major advantages of proton radiation therapy. These beam characteristics depend on the position and characteristics of upstream beam-modifying devices such as apertures and compensating boluses. The extent of separation, if any, between these beam-modifying devices and the patient is particularly critical in this respect. We have developed a pencil beam algorithm for proton dose calculations which takes accurate account of the effects of materials upstream of the patient and of the air gap between them and the patient. The model includes a new approach to picking the locations of the pencil beams so as to more accurately model the penumbra and to more effectively account for the multiple-scattering effects of the media around the point of interest. We also present a faster broad-beam version of the algorithm which gives a reasonably accurate penumbra. Predictions of the algorithm and results from experiments performed in a large-field proton beam are presented. In general the algorithm agrees well with the measurements.

Dose-volume histograms

A plot of a cumulative dose-volume frequency distribution, commonly known as a dose-volume histogram (DVH), graphically summarizes the simulated radiation distribution within a volume of interest of a patient which would result from a proposed radiation treatment plan. DVHs show promise as tools for comparing rival treatment plans for a specific patient by clearly presenting the uniformity of dose in the target volume and any hot spots in adjacent normal organs or tissues. However, because of the loss of positional information in the volume(s) under consideration, it should not be the sole criterion for plan evaluation. DVHs can also be used as input data to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). The sensitivity of TCP and NTCP calculations to small changes in the DVH shape points to the need for an accurate method for computing DVHs. We present a discussion of the methodology for generating and plotting the DVHs, some caveats, limitations on their use and the general experience of four hospitals using DVHs.

Long-term results of proton beam irradiated uveal melanomas

The first 128 consecutive patients with uveal melanomas treated with proton beam irradiation were studied in order to evaluate survival and visual acuity status of patients with relatively long-term follow-up. The median follow-up was 5.4 years, and no patient was lost to follow-up. All tumors showed regression. The most recent visual acuity was 20/40 or better in 35% and 20/100 or better in 58%. Eight eyes were enucleated because of complications. Metastasis developed in 26 patients (20.5%) from 3 months to 7 years after treatment. Results indicate that proton irradiation is quite successful for achieving local control of uveal melanomas. A large proportion of the treated eyes maintained useful vision. Five-year follow-up data indicate that proton irradiation has no deleterious effect on the likelihood of the development of metastasis.

Definitive radiation therapy for chordoma and chondrosarcoma of base of skull and cervical spine.

: Proton-beam radiation therapy has been developed for the treatment of chordomas or sarcomas of bone or soft tissue that abut the central nervous system. The authors report the results of treatment of 10 patients, six with chordoma, three with chondrosarcoma, and one with a neurofibrosarcoma. Local control has been achieved for all patients (with, however, one marginal failure) with a follow-up period ranging from 2 months to 6 years. High doses of radiation, up to 76 Cobalt Gray Equivalents (CGE), have been delivered without significant morbidity. In particular, no neurological sequelae have been observed.