C Burman

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.

Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer

PURPOSE To compare acute and late toxicities of high-dose radiation for prostate cancer delivered by either conventional three-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS Between September 1992 and February 1998, 61 patients with clinical stage T1c- T3 prostate cancer were treated with 3D-CRT and 171 with IMRT to a prescribed dose of 81 Gy. To quantitatively evaluate the differences between conventional 3D-CRT and IMRT, 20 randomly selected patients were planned concomitantly by both techniques and the resulting treatment plans were compared. Acute and late radiation-induced morbidity was evaluated in all patients and graded according to the Radiation Therapy Oncology Group toxicity scale. RESULTS Compared with conventional 3D-CRT, IMRT improved the coverage of the clinical target volume (CTV) by the prescription dose and reduced the volumes of the rectal and bladder walls carried to high dose levels (P<0.01), indicating improved conformality with IMRT. Acute and late urinary toxicities were not significantly different for the two methods. However, the combined rates of acute grade 1 and 2 rectal toxicities and the risk of late grade 2 rectal bleeding were significantly lower in the IMRT patients. The 2-year actuarial risk of grade 2 bleeding was 2% for IMRT and 10% for conventional 3D-CRT (P<0.001). CONCLUSIONS The data demonstrate the feasibility and safety of high-dose IMRT for patients with localized prostate cancer and provide a proof-of-principle that this method improves dose conformality relative to tumor coverage and exposure to normal tissues.

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.

The deep inspiration breath-hold technique in the treatment of inoperable non–small-cell lung cancer☆

PURPOSE Conventional radiotherapeutic techniques are associated with lung toxicity that limits the treatment dose. Motion of the tumor during treatment requires the use of large safety margins that affect the feasibility of treatment. To address the control of tumor motion and decrease the volume of normal lung irradiated, we investigated the use of three-dimensional conformal radiation therapy (3D-CRT) in conjunction with the deep inspiration breath-hold (DIBH) technique. METHODS AND MATERIALS In the DIBH technique, the patient is initially maintained at quiet tidal breathing, followed by a deep inspiration, a deep expiration, a second deep inspiration, and breath-hold. At this point the patient is at approximately 100% vital capacity, and simulation, verification, and treatment take place during this phase of breath-holding. RESULTS Seven patients have received a total of 164 treatment sessions and have tolerated the technique well. The estimated normal tissue complication probabilities decreased in all patients at their prescribed dose when compared to free breathing. The dose to which patients could be treated with DIBH increased on average from 69.4 Gy to 87.9 Gy, without increasing the risk of toxicity. CONCLUSIONS The DIBH technique provides an advantage to conventional free-breathing treatment by decreasing lung density, reducing normal safety margins, and enabling more accurate treatment. These improvements contribute to the effective exclusion of normal lung tissue from the high-dose region and permit the use of higher treatment doses without increased risks of toxicity.

Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms.

PURPOSE AND OBJECTIVE Late rectal bleeding is a potentially dose limiting complication of three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. The frequency of late rectal bleeding has been shown to increase as the prescription dose rises above 70 Gy. The purpose of this study is to identify features of the cumulative dose-volume histogram (DVH) for the rectal wall that correlate with late rectal bleeding after 3D-CRT for prostate cancer. METHODS AND MATERIALS Follow-up information on rectal bleeding is available for 261 and 315 patients treated using 3D-CRT at Memorial Sloan-Kettering Cancer Center for Stage T1c-T3 prostate cancer with minimum target doses of 70.2 and 75.6 Gy, respectively. All patients in this study were treated with a coplanar 6-field technique (2 lateral and 4 oblique fields). Patients were classified as having rectal bleeding if they bled (> or = Grade 2) before 30 months, and nonbleeding (< or = Grade 1) if they were without bleeding at 30 months, using the RTOG morbidity scale. Rectal bleeding was observed in 13 and 38 of the patients treated at 70.2 and 75.6 Gy, respectively. Treatment plans were analyzed for 39 nonbleeding and 13 bleeding patients receiving 70.2 Gy, and 83 nonbleeding and 36 bleeding patients receiving 75.6 Gy. Dose-volume histograms (DVHs) for the anatomic rectal wall were calculated. Average DVHs of the bleeding and nonbleeding patients were generated, and a permutation test was used to assess the significance of differences between them, for each dose group. The confounding effect of total rectal wall volume (V(RW)) was removed by calculating the average differences in DVHs between all combinations of bleeding and nonbleeding patients with similar V(RW)s. Finally, multivariate analysis using logistic regression was performed to test the significance of the DVH variables in the presence of anatomic, geometric, and medical variables previously found to correlate with rectal bleeding in a companion analysis of the same patients. RESULTS The area under the average percent volume DVH for the rectal wall of patients with bleeding was significantly higher than those of patients without bleeding in both dose groups (p = 0.02, 70.2 Gy; p < 0.0001, 75.6 Gy). However, small V(RW)s were associated with rectal bleeding (p = 0.06, 70.2 Gy; p < 0.01, 75.6 Gy), resulting in an increase in average percent volumes exposed to all doses for patients with rectal bleeding. For patients with similar V(RW)s, rectal bleeding was significantly correlated with the volumes exposed to 46 Gy in both dose groups (p = 0.02, 70.2 Gy; p = 0.005, 75.6 Gy, tolerance in V(RW): 5 ccs). For the 75.6 Gy dose group, the percent volume receiving 77 Gy was significantly correlated with rectal bleeding (p < 0.005). Bivariate analysis using logistic regression, including V(RW) together with a single DVH variable, showed good agreement with the above analysis. Multivariate analysis revealed a borderline significant correlation of the percent volume receiving 71 Gy in the 70.2 Gy dose group. It also showed that the DVH variables were highly correlated with geometric and dosimetric variables previously found to correlate with rectal bleeding in multivariate analysis. CONCLUSION Significant volume effects were found in the probability of late rectal bleeding for patients undergoing 3D-CRT for prostate cancer with prescription doses of 70.2 and 75.6 Gy. The percent volumes exposed to 71 and 77 Gy in the 70.2 and 75.6 Gy dose groups respectively were significantly correlated with rectal bleeding. The independent correlation of small V(RW) with rectal bleeding may indicate the existence of a functional reserve for the rectum. The independent association with larger percent volumes exposed to intermediate doses ( approximately 46 Gy) seen in both dose groups may indicate that a large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.

Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma.

The current study was undertaken to evaluate the incidence and predictors of late toxicity in patients with localized prostate carcinoma treated with high dose three‐dimensional conformal radiotherapy (3D‐CRT).

LATE RECTAL TOXICITY AFTER CONFORMAL RADIOTHERAPY OF PROSTATE CANCER (I): MULTIVARIATE ANALYSIS AND DOSE-RESPONSE

PURPOSE The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. METHODS AND MATERIALS Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy-13 patients, 75. 6 Gy-36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy-39 patients, 75.6 Gy-83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. RESULTS A dose response for >/= Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with >/= Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p < 0.02), and 2) smaller anatomically defined rectal wall volume (p < 0.05). After 75.6 Gy, the following factors were significant: 1) smaller anatomically defined rectal wall volume (p < 0.01), 2) higher rectal D(max) (p < 0.01), 3) enclosure of rectal contour by Iso50 (p < 0.01), 4) patient age (p = 0.02), and 5) history of diabetes mellitus (p = 0.04). In addition to these five factors, acute rectal toxicity was also significantly correlated (p = 0.05) with late rectal bleeding when patients from both dose groups were combined in multivariate analysis. CONCLUSION A multivariate logistic regression model is presented which describes the probability of developing late rectal bleeding after conformal irradiation of prostate cancer. Late rectal bleeding correlated with factors which may indicate that a greater fractional volume of rectal wall was exposed to high dose, such as smaller rectal wall volume, inclusion of the rectum within the 50% isodose on the isocenter slice, and higher rectal D(max).

Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy

PURPOSE To analyze acute lung toxicity data of non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy in terms of dosimetric variables, location of dose within subvolumes of the lungs, and models of normal-tissue complication probability (NTCP). METHODS AND MATERIALS Dose distributions of 49 non-small-cell lung cancer patients treated in a dose escalation protocol between 1992 and 1999 were analyzed (dose range: 57.6-81 Gy). Nine patients had RTOG Grade 3 or higher acute lung toxicity. Correlation with dosimetric and physical variables, as well as Lyman and parallel NTCP models, was assessed. Lungs were evaluated as a single structure, as superior and inferior halves (to assess significance of dose to upper and lower lungs), and as ipsilateral and contralateral lungs. RESULTS For the whole lung, Grade 3 or higher pneumonitis was significantly correlated (p <or= 0.05) with mean dose and Lyman and parallel model indices (d(eff) and f(dam)). It was significantly correlated with these indices and with V20 for the ipsilateral lung and with mean dose and d(eff) for the inferior half of the lungs. Dosimetric and NTCP model quantities for the superior half of the lungs and contralateral lung were not significantly correlated (p > 0.5 for superior lung indices, and >0.1 for contralateral lung indices studied). CONCLUSIONS For these patients, commonly used dosimetric and NTCP models are significantly correlated with >or= Grade 3 pneumonitis. Equivalently strong correlations are found in the lower portion of the lungs and the ipsilateral lung, but not in the upper portion or contralateral lung.

Promising survival with three-dimensional conformal radiation therapy for non-small cell lung cancer

PURPOSE Local failure is a major obstacle to the cure of locally advanced non small-cell lung cancer. Three-dimensional conformal radiation therapy (3-DCRT) selects optimal treatment parameters to increase dose to tumor and reduce normal tissue dose, potentially representing an enhancement of the therapeutic ratio of radiation therapy for lung cancer. We performed this analysis of 45 non-small cell lung cancer patients treated with 3-DCRT alone, to evaluate the ability of computer derived lung dose volume histograms to predict serious pulmonary toxicity, to assess the feasibility of this approach, and to examine the resulting survival. METHODS There were 28 males (62%) and 17 females (38%). The median age was 65 (range: 38-82). Tumor stage was Stage I/II in 13%, IIIa in 42%, and IIIb in 44%. The histology was squamous in 44%, adenocarcinoma in 36%, and other non-small cell histologies in the others. Only 47% of patients. had combined favorable prognostic factors (i.e. KPS < or = 80, and < or = 5% wt. loss). The median dose of radiation to gross disease was 70.2 Gy (range: 52.2-72 Gy) delivered in fractions of 1.8 Gy, 5 days per week. RESULTS Seven patients did not complete 3-DCRT due to disease progression outside the port. Follow-up data are mature: the median follow up of the 6 survivors is 43.5 months (35-59). Thoracic progression occurred in 46%. Median survival (all 45 patients.) is 15.7 months and survival is 32% at 2 years and 12% at 59 months. Pulmonary toxicity > or = grade 3 occurred in 9% of patients. Dose volume histograms were available in 31 patients and showed a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or higher pulmonary toxicity occurred in 38% (3/8) of patients with > 30% of lung volume receiving > or = 25 Gy, versus 4% (1/23) of patients with < or = 30% lung receiving > or = 25 Gy (P = 0.04). Grade 3 or higher pulmonary toxicity occurred in 29% (4/14) of patients with a predicted pulmonary normal tissue complication probability of 12% or higher versus 0% (0/17) in patients with a predicted probability of less than 12% (P = 0.03). CONCLUSIONS Despite adverse prognostic criteria median survival is encouraging and may be higher than some combined modality approaches. Dose volume histogram parameters may be useful to determine the maximum dose for individual patients and thereby permit avoidance of toxicity.

Three-dimensional conformal radiation therapy in locally advanced carcinoma of the prostate: Preliminary results of a phase I dose-escalation study☆☆☆

PURPOSE The acute morbidity of doses of 64.8-75.6 Gy and preliminary observations of late complications and tumor response using 3-dimensional conformal radiation therapy in carcinoma of the prostate are assessed. METHODS AND MATERIALS 123 patients (Stage A2-12, B1-17, B2-43, C-51) were irradiated to the prostate and seminal vesicles using a 3-dimensional conformal radiation therapy technique. The median follow-up time was 15.2 months. The minimum tumor dose was 64.8-66.6 Gy in 49 patients, 70.2 Gy in 46, and 75.6 Gy in 28. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading system. RESULTS This technique of 3-dimensional conformal radiation therapy was well-tolerated with minimal acute morbidity. Only 32% of patients had grade 2 or 3 acute morbidity requiring short-term medication for relief of urinary symptoms or diarrhea. Only one patient (0.8%) has so far developed a severe (grade 4) late complication. Serum prostate specific antigen concentrations normalized in 67% of patients (64/96) within 1-14 months (median 4.5 months) after treatment and were progressively decreasing at last measurement in an additional 22% (21/96). Abnormal rising prostate specific antigen levels were observed in 15 patients, 11 of whom have already developed other evidence of relapsing disease. CONCLUSION Acute toxicity for the doses tested with this 3-dimensional conformal radiation therapy technique is reduced compared to traditional treatment techniques, and the initial tumor response as assessed by prostate specific antigen measurement is highly encouraging with prostate specific antigen levels returning to normal in the majority of patients. Based on these results, a further increase of the dose to 81 Gy has been implemented in accordance with the schema of an ongoing Phase I dose-escalation study.