Showing papers in "International Journal of Radiation Oncology Biology Physics in 2002"

Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy.

Abstract: Purpose: In this work, three-dimensional (3D) motion of lung tumors during radiotherapy in real time was investigated. Understanding the behavior of tumor motion in lung tissue to model tumor movement is necessary for accurate (gated or breath-hold) radiotherapy or CT scanning. Methods: Twenty patients were included in this study. Before treatment, a 2-mm gold marker was implanted in or near the tumor. A real-time tumor tracking system using two fluoroscopy image processor units was installed in the treatment room. The 3D position of the implanted gold marker was determined by using real-time pattern recognition and a calibrated projection geometry. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within a certain volume. The system provided the coordinates of the gold marker during beam-on and beam-off time in all directions simultaneously, at a sample rate of 30 images per second. The recorded tumor motion was analyzed in terms of the amplitude and curvature of the tumor motion in three directions, the differences in breathing level during treatment, hysteresis (the difference between the inhalation and exhalation trajectory of the tumor), and the amplitude of tumor motion induced by cardiac motion. Results: The average amplitude of the tumor motion was greatest (12 ± 2 mm [SD]) in the cranial-caudal direction for tumors situated in the lower lobes and not attached to rigid structures such as the chest wall or vertebrae. For the lateral and anterior-posterior directions, tumor motion was small both for upper- and lower-lobe tumors (2 ± 1 mm). The time-averaged tumor position was closer to the exhale position, because the tumor spent more time in the exhalation than in the inhalation phase. The tumor motion was modeled as a sinusoidal movement with varying asymmetry. The tumor position in the exhale phase was more stable than the tumor position in the inhale phase during individual treatment fields. However, in many patients, shifts in the exhale tumor position were observed intra- and interfractionally. These shifts are the result of patient relaxation, gravity (posterior direction), setup errors, and/or patient movement. The 3D trajectory of the tumor showed hysteresis for 10 of the 21 tumors, which ranged from 1 to 5 mm. The extent of hysteresis and the amplitude of the tumor motion remained fairly constant during the entire treatment. Changes in shape of the trajectory of the tumor were observed between subsequent treatment days for only one patient. Fourier analysis revealed that for 7 of the 21 tumors, a measurable motion in the range 1–4 mm was caused by the cardiac beat. These tumors were located near the heart or attached to the aortic arch. The motion due to the heartbeat was greatest in the lateral direction. Tumor motion due to hysteresis and heartbeat can lower treatment efficiency in real-time tumor tracking-gated treatments or lead to a geographic miss in conventional or active breathing controlled treatments. Conclusion: The real-time tumor tracking system measured the tumor position in all three directions simultaneously, at a sampling rate that enabled detection of tumor motion due to heartbeat as well as hysteresis. Tumor motion and hysteresis could be modeled with an asymmetric function with varying asymmetry. Tumor motion due to breathing was greatest in the cranial-caudal direction for lower-lobe unfixed tumors.

Flat-panel cone-beam computed tomography for image-guided radiation therapy

Abstract: Purpose: Geometric uncertainties in the process of radiation planning and delivery constrain dose escalation and induce normal tissue complications. An imaging system has been developed to generate high-resolution, soft-tissue images of the patient at the time of treatment for the purpose of guiding therapy and reducing such uncertainties. The performance of the imaging system is evaluated and the application to image-guided radiation therapy is discussed. Methods and Materials: A kilovoltage imaging system capable of radiography, fluoroscopy, and cone-beam computed tomography (CT) has been integrated with a medical linear accelerator. Kilovoltage X-rays are generated by a conventional X-ray tube mounted on a retractable arm at 90° to the treatment source. A 41 × 41 cm 2 flat-panel X-ray detector is mounted opposite the kV tube. The entire imaging system operates under computer control, with a single application providing calibration, image acquisition, processing, and cone-beam CT reconstruction. Cone-beam CT imaging involves acquiring multiple kV radiographs as the gantry rotates through 360° of rotation. A filtered back-projection algorithm is employed to reconstruct the volumetric images. Geometric nonidealities in the rotation of the gantry system are measured and corrected during reconstruction. Qualitative evaluation of imaging performance is performed using an anthropomorphic head phantom and a coronal contrast phantom. The influence of geometric nonidealities is examined. Results: Images of the head phantom were acquired and illustrate the submillimeter spatial resolution that is achieved with the cone-beam approach. High-resolution sagittal and coronal views demonstrate nearly isotropic spatial resolution. Flex corrections on the order of 0.2 cm were required to compensate gravity-induced flex in the support arms of the source and detector, as well as slight axial movements of the entire gantry structure. Images reconstructed without flex correction suffered from loss of detail, misregistration, and streak artifacts. Reconstructions of the contrast phantom demonstrate the soft-tissue imaging capability of the system. A contrast of 47 Hounsfield units was easily detected in a 0.1-cm-thick reconstruction for an imaging exposure of 1.2 R (in-air, in absence of phantom). The comparison with a conventional CT scan of the phantom further demonstrates the spatial resolution advantages of the cone-beam CT approach. Conclusions: A kV cone-beam CT imaging system based on a large-area, flat-panel detector has been successfully adapted to a medical linear accelerator. The system is capable of producing images of soft tissue with excellent spatial resolution at acceptable imaging doses. Integration of this technology with the medical accelerator will result in an ideal platform for high-precision, image-guided radiation therapy.

Prostate cancer radiation dose response: results of the m. d. anderson phase iii randomized trial

Abstract: Purpose: 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. Methods and Materials: 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. Results: 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. Conclusion: 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

Relative biological effectiveness (RBE) values for proton beam therapy.

Abstract: Purpose: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of 1.0 or 1.1, since the available evidence has been interpreted as indicating that the magnitude of RBE variation with treatment parameters is small relative to our abilities to determine RBEs. As substantial clinical experience and additional experimental determinations of RBE have accumulated and the number of proton radiation therapy centers is projected to increase, it is appropriate to reassess the rationale for the continued use of a generic RBE and for that RBE to be 1.0–1.1. Methods and Materials: Results of experimental determinations of RBE of in vitro and in vivo systems are examined, and then several of the considerations critical to a decision to move from a generic to tissue-, dose/fraction-, and LET-specific RBE values are assessed. The impact of an error in the value assigned to RBE on normal tissue complication probability (NTCP) is discussed. The incidence of major morbidity in proton-treated patients at Massachusetts General Hospital (MGH) for malignant tumors of the skull base and of the prostate is reviewed. This is followed by an analysis of the magnitude of the experimental effort to exclude an error in RBE of ≥10% using in vivo systems. Results: The published RBE values, using colony formation as the measure of cell survival, from in vitro studies indicate a substantial spread between the diverse cell lines. The average value at mid SOBP (Spread Out Bragg Peak) over all dose levels is ≈1.2, ranging from 0.9 to 2.1. The average RBE value at mid SOBP in vivo is ≈1.1, ranging from 0.7 to 1.6. Overall, both in vitro and in vivo data indicate a statistically significant increase in RBE for lower doses per fraction, which is much smaller for in vivo systems. There is agreement that there is a measurable increase in RBE over the terminal few millimeters of the SOBP, which results in an extension of the bioeffective range of the beam in the range of 1–2 mm. There is no published report to indicate that the RBE of 1.1 is low. However, a substantial proportion of patients treated at ≈2 cobalt Gray equivalent (CGE)/fraction 5 or more years ago were treated by a combination of both proton and photon beams. Were the RBE to be erroneously underestimated by ≈10%, the increase in complication frequency would be quite serious were the complication incidence for the reference treatment ≥3% and the slope of the dose response curves steep, e.g., a γ50 ≈ 4. To exclude ≥1.2 as the correct RBE for a specific condition or tissue at the 95% confidence limit would require relatively large and multiple assays. Conclusions: At present, there is too much uncertainty in the RBE value for any human tissue to propose RBE values specific for tissue, dose/fraction, proton energy, etc. The experimental in vivo and clinical data indicate that continued employment of a generic RBE value and for that value to be 1.1 is reasonable. However, there is a local “hot region” over the terminal few millimeters of the SOBP and an extension of the biologically effective range. This needs to be considered in treatment planning, particularly for single field plans or for an end of range in or close to a critical structure. There is a clear need for prospective assessments of normal tissue reactions in proton irradiated patients and determinations of RBE values for several late responding tissues in laboratory animal systems, especially as a function of dose/fraction in the range of 1–4 Gy.

High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients

Abstract: Purpose 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). Methods and materials 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). Results 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. Conclusions 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.

Analysis of radiation-induced liver disease using the Lyman NTCP model.

Abstract: Purpose : To describe the dose—volume tolerance for radiation-induced liver disease (RILD) using the Lyman—Kutcher—Burman (LKB) normal tissue complication probability (NTCP) model. Methods and Materials : A total of 203 patients treated with conformal liver radiotherapy and concurrent hepatic arterial chemotherapy were prospectively followed for RILD. Normal liver dose—volume histograms and RILD status for these patients were used as input data for determination of LKB model parameters. A complication was defined as Radiation Therapy Oncology Group Grade 3 or higher RILD ≤4 months after completion of radiotherapy. A maximal likelihood analysis yielded best estimates for the LKB NTCP model parameters for the liver for the entire patient population. A multivariate analysis of the potential factors associated with RILD was also completed, and refined LKB model parameters were obtained for patient subgroups with different risks of RILD. Results : Of 203 patients treated with focal liver irradiation, 19 developed RILD. The LKB NTCP model fit the complication data for the entire group. The “n” parameter was larger than previously described, suggesting a strong volume effect for RILD and a correlation of NTCP with the mean liver dose. No cases of RILD were observed when the mean liver dose was Conclusion : These data demonstrate that the liver exhibits a large volume effect for RILD, suggesting that the mean liver dose may be useful in ranking radiation plans. The inclusion of clinical factors, especially the diagnosis of primary hepatobiliary cancer vs. liver metastases, improves the estimation of NTCP over that obtained solely by the use of dose—volume data. These findings should facilitate the application of focal liver irradiation in future clinical trials.

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

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

A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases.

Abstract: Purpose: Data collected from 10 institutions were reviewed to compare survival probabilities of patients with newly diagnosed brain metastases managed initially with radiosurgery (RS) alone vs. RS + whole brain radiotherapy (WBRT). Methods and Materials: A database was created from raw data submitted from 10 institutions on patients treated with RS for brain metastases. The major exclusion criteria were resection of a brain metastasis and interval from the end of WBRT until RS >1 month (to try to ensure that the up-front intent was to combine RS + WBRT and that RS was not given for recurrent brain metastases). Survival was estimated using the Kaplan-Meier method from the date of first treatment for brain metastases until death or last follow-up. Survival times were compared for patients managed initially with RS alone vs. RS + WBRT using the Cox proportional hazards model to adjust for known prognostic factors or Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class. Results: Out of 983 patients, 31 were excluded because treatment began after 6/1/98; 159 were excluded because brain metastases were resected; 179 were excluded because there was an interval >1 month from WBRT until RS; and 45 were excluded for other reasons. Of the 569 evaluable patients, 268 had RS alone initially (24% of whom ultimately had salvage WBRT), and 301 had RS + up-front WBRT. The median survival times for patients treated with RS alone initially vs. RS + WBRT were 14.0 vs. 15.2 months for RPA Class 1 patients, 8.2 vs. 7.0 months for Class 2, and 5.3 vs. 5.5 months for Class 3, respectively. With adjustment by RPA class, there was no survival difference comparing RS alone initially to RS + up-front WBRT ( p = 0.33, hazard ratio=1.09). Conclusions: Omission of up-front WBRT does not seem to compromise length of survival in patients treated with RS for newly diagnosed brain metastases.

Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head-and-neck cancer.

Abstract: Purpose:To objectively assess swallowing function after an intensive chemoradiation regimen for locally advanced head-and-neck cancer and to assess the clinical implications of swallowing dysfunction. Patients and Methods:Twenty-nine patients with nonresectable Stage IV head-and-neck cancer participated in a Phase I study of radiation, 70 Gy/7 weeks, concurrent with weekly gemcitabine. Because of a high rate of mucosal toxicity, reduced drug doses were delivered to subsequent patient groups: 300, 150, 50, and 10 mg/m 2 /week. Twenty-six of these patients underwent prospective evaluation of swallowing function with videofluoroscopy and esophagogram. Studies were performed pretherapy, early post-therapy (1–3 months), and late post-therapy (6–12 months). Results:Complete tests were performed pretherapy in 22 patients, early post-therapy in 20, and late post-therapy in 13. Twenty-five patients had at least one post-therapy study. Post-therapy dysfunction was characterized by reduced inversion of the epiglottis, delayed swallow initiation and uncoordinated timing of the propulsion of the bolus, opening of the cricopharyngeal muscle, and closure of the larynx, all of which promoted aspiration during and after the swallow. In addition, reduced base-of-tongue retraction with reduced contact to the posterior pharyngeal wall and incomplete cricopharyngeal relaxation resulted in pooling in the pyriform sinuses and vallecula of residue, which was frequently aspirated after the swallow. Post-therapy aspirations were typically "silent," eliciting no cough reflex, or the cough was delayed and noneffective in expelling the residue. Aspiration was observed in 3 patients (14%) in the pretherapy studies, in 13 (65%) in the early post-therapy studies, and in 8 (62%) in the late post-therapy studies (aspiration rates post-therapy vs. pretherapy: p = 0.0002). Six patients had pneumonia requiring hospitalization 1–14 months after therapy (median: 2.5 months), being the likely cause of death in 2 patients. Five cases of pneumonia occurred among 17 patients who had demonstrated aspiration in the post-therapy studies, compared with no cases of pneumonia among 8 patients who had not demonstrated aspiration ( p = 0.1). Of the 4 patients who had not undergone any post-therapy study, 1 developed pneumonia. Mucositis scores, prolonged tube feeding, presence of tracheostomy tube, and gemcitabine doses were not found to be related to aspiration or pneumonia risk. Conclusions:After intensive chemoradiotherapy, significant objective swallowing dysfunction is prevalent. It promotes aspiration, which may not elicit a cough reflex and may be associated with pneumonia. Aspiration pneumonia may be an underdocumented complication of chemoradiotherapy for head-and-neck cancer. Future studies should examine whether routine post-therapy videofluoroscopy and training aspirating patients in safe swallowing strategies can reduce this risk.

Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy ≥72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1–T2 prostate cancer

Abstract: Purpose To review the biochemical relapse-free survival (bRFS) rates after treatment with permanent seed implantation (PI), external beam radiotherapy (EBRT) Methods and materials The study population comprised 2991 consecutive patients treated at the Cleveland Clinic Foundation or Memorial Sloan Kettering at Mercy Medical Center. All cases had pretreatment prostate-specific antigen (iPSA) levels and biopsy Gleason scores (bGSs). Neoadjuvant androgen deprivation for ≤6 months was given in 622 cases (21%). No adjuvant therapy was given after local therapy. RP was used for 1034 patients (35%), EBRT 0.2 for RP cases and three consecutive rising PSA levels (American Society for Therapeutic Radiology Oncology consensus definition) for all other cases. A multivariate analysis for factors affecting the bRFS rates was performed using the following variables: clinical T stage, iPSA, bGS, androgen deprivation, year of treatment, and treatment modality. The multivariate analysis was repeated excluding the EBRT Results The 5-year bRFS rate for RP, EBRT p p p p p p p p = 0.001) to be the only independent predictors of relapse. Treatment modality ( p = 0.95), clinical T stage ( p = 0.09), and androgen deprivation ( p = 0.56) were not independent predictors for failure. Conclusion The biochemical failure rates were similar among PI, high-dose (≥72 Gy) EBRT, COMB, and RP for localized prostate cancer. The outcomes were significantly worse for low-dose (

Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies.

Abstract: Purpose: To describe our initial clinical experience with intensity-modulated whole pelvic radiotherapy (IM-WPRT) in women with gynecologic malignancies. Methods and Materials: Between February 2000 and August 2001, 40 gynecology patients underwent IM-WPRT. After fabrication of customized immobilization, all patients underwent contrast-enhanced CT, and a clinical target volume was contoured consisting of the upper vagina, parametria, uterus (if present), and presacral and pelvic lymph node regions. The clinical target volume was expanded by 1 cm to create a planning target volume (PTV). Using commercially available software, 7- or 9-field, 6-MV, coplanar IM-WPRT plans were generated for all patients. The worst acute gastrointestinal and genitourinary toxicity during treatment was scored on a 4-point scale: 0, none; 1, mild, no medications required; 2, moderate, medications required; and 3, severe, treatment breaks or cessation, hospitalization. As a comparison, acute toxicities in 35 previously treated conventional WPRT patients were analyzed. No significant differences were noted in the clinicopathologic and treatment factors between the two groups. Results: IM-WPRT plans provided excellent PTV coverage, with considerable sparing of the surrounding normal tissues. On average, 98.1% of the PTV received the prescription dose. The average percentage of the PTV receiving 110% and 115% of the prescription dose was 9.8% and 0.2%, respectively. IM-WPRT was well tolerated, with no patient developing Grade 3 toxicity. Grade 2 acute gastrointestinal toxicity was less common in the IM-WPRT group (60 vs. 91%, p = 0.002) than in the conventional WPRT group. Moreover, the percentage of IM-WPRT and WPRT patients requiring no or only infrequent antidiarrheal medications was 75% and 34%, respectively (p = 0.001). Although less Grade 2 genitourinary toxicity was seen in the IM-WPRT group (10% vs. 20%), this difference was not statistically significant (p = 0.22). Conclusion: IM-WPRT is a promising approach in gynecology patients. IMRT planning resulted in excellent PTV coverage, with considerable sparing of normal tissues. Treatment was well tolerated and associated with less acute gastrointestinal sequelae than conventional WPRT. Longer follow-up and more patients are needed, however, to evaluate the full merits of this novel approach.

Optimization of intensity-modulated radiotherapy plans based on the equivalent uniform dose

Abstract: Purpose : The equivalent uniform dose (EUD) for tumors is defined as the biologically equivalent dose that, if given uniformly, will lead to the same cell kill in the tumor volume as the actual nonuniform dose distribution. Recently, a new formulation of EUD was introduced that applies to normal tissues as well. EUD can be a useful end point in evaluating treatment plans with nonuniform dose distributions for three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. In this study, we introduce an objective function based on the EUD and investigate the feasibility and usefulness of using it for intensity-modulated radiotherapy optimization. Methods and Materials : We applied the EUD-based optimization to obtain intensity-modulated radiotherapy plans for prostate and head-and-neck cancer patients and compared them with the corresponding plans optimized with dose-volume-based criteria. Results : We found that, for the same or better target coverage, EUD-based optimization is capable of improving the sparing of critical structures beyond the specified requirements. We also found that, in the absence of constraints on the maximal target dose, the target dose distributions are more inhomogeneous, with significant hot spots within the target volume. This is an obvious consequence of unrestricted maximization target cell kill and, although this may be considered beneficial for some cases, it is generally not desirable. To minimize the magnitude of hot spots, we applied dose inhomogeneity constraints to the target by treating it as a “virtual” normal structure as well. This led to much-improved target dose homogeneity, with a small, but expected, degradation in normal structure sparing. We also found that, in principle, the dose-volume objective function may be able to arrive at similar optimum dose distributions by using multiple dose-volume constraints for each anatomic structure and with considerably greater trial-and-error to adjust a large number of objective function parameters. Conclusion : The general inference drawn from our investigation is that the EUD-based objective function has the advantages that it needs only a small number of parameters and allows exploration of a much larger universe of solutions, making it easier for the optimization system to balance competing requirements in search of a better solution.

Issues in respiratory motion compensation during external-beam radiotherapy.

Abstract: Purpose: To investigate how respiration influences the motion of lung and pancreas tumors and to relate the observations to treatment procedures intended to improve dose alignment by predicting the moving tumor’s position from external breathing indicators. Methods and materials: Breathing characteristics for five healthy subjects were observed by optically tracking the displacement of the chest and abdomen, and by measuring tidal air volume with a spirometer. Fluoroscopic imaging of five radiotherapy patients detected the motion of lung and pancreas tumors synchronously with external breathing indicators. Results: The external and fluoroscopic data showed a wide range of behavior in the normal breathing pattern and its effects on the position of lung and pancreas tumors. This included transient phase shifts between two different external measures of breathing that diminished to zero over a period of minutes, modulated phase shifts between tumor and chest wall motion, and other complex phenomena. Conclusions: Respiratory compensation strategies that infer tumor position from external breathing signals, including methods of beam gating and dynamic beam tracking, require three-dimensional knowledge of the tumor’s motion trajectory as well as the ability to detect and adapt to transient and continuously changing characteristics of respiratory motion during treatment.

Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors.

Abstract: Purpose : To assess the potential influence of improved dose distribution with proton beams compared to conventional or intensity-modulated (IM) X-ray beams on the incidence of treatment-induced secondary cancers in pediatric oncology. Methods and Materials : Two children, one with a parameningeal rhabdomyosarcoma (RMS) and a second with a medulloblastoma, were used as models for the purpose of this study. After defining the target and critical structures, treatment plans were calculated and optimized, four for the RMS case (conventional X-ray, IM X-rays, protons, and IM protons) and three for the irradiation of the spinal axis in medulloblastoma (conventional X-ray, IM X-rays, protons). Secondary cancer incidence was estimated using a model based on Publication No. 60 of the International Commission on Radiologic Protection. This model allowed estimation of absolute risks of secondary cancer for each treatment plan based on dose-volume distributions for the nontarget organs. Results : Proton beams reduced the expected incidence of radiation-induced secondary cancers for the RMS patient by a factor of ≥2 and for the medulloblastoma case by a factor of 8 to 15 when compared with either IM or conventional X-ray plans. Conclusions : The potential for a significant reduction in secondary cancers with pediatric cancers after using proton beams (forward planned or IM) in the treatment of RMS and MBD in children and adolescents represents an additional argument supporting the development of proton therapy for most radiotherapy indications in pediatric oncology.

Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer study 22845 with the Medical Research Council study BRO4: An interim analysis

Abstract: Purpose: There is no consensus on the treatment strategy for adult patients with cerebral low-grade glioma. The diagnosis and primary treatment are usually undertaken by surgery. Some investigators doubt the efficacy of postoperative radiotherapy (RT), whereas others advise routine postoperative RT. We report the primary results of a multicenter randomized trial on this controversy. Methods and Materials: From 24 European centers, 311 adult patients with low-grade glioma were randomized centrally after surgery from March 1986 through September 1997, between the two arms of the trial. The irradiated group received 54 Gy in 6 weeks. The other patients did not receive any treatment after surgery until the tumor showed progression, defined as clinical-neurologic deterioration and evidence of progressive tumor on imaging. Results: Of 290 eligible and assessable patients (93%), the irradiated group showed a significant (log-rank p = 0.02) improvement in time to progression but not in overall survival, with a median follow-up of 5 years. The 5-year estimate was, respectively, 63% vs. 66% (overall survival) and 44% vs. 37% (time to progression) for the treated and control arms. Different treatment modalities, including RT, were undertaken for the 85 controls when a progressive tumor was noted. Conclusion: Early postoperative conventional RT such as that used for this protocol appears to improve the time to progression or progression-free survival, but not overall survival, for patients with low-grade glioma. (C) 2002 Elsevier Science Inc.

Inclusion of geometric uncertainties in treatment plan evaluation

Abstract: Purpose : 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. Materials and Methods : 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. Results : 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, TCPpop, 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 TCPpop. Only in regions with a high-dose gradient does such a margin reduction lead to a decrease in normal tissue dose for the same TCPpop. 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% TCPpop loss for prostate plans with clinically reasonable values of Σ and σ. Conclusion : The new method computes in a few minutes the influence of geometric errors on the statistics of target dose and TCPpop in clinical treatment plans. Too small margins lead to a significant loss of TCPpop that is difficult to compensate for by dose escalation.

Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer ☆

Abstract: Purpose : Hypoxia-inducible factors HIF1α and HIF2α (HIFαs) regulate the expression of a variety of genes encoding proteins related to angiogenesis and to anaerobic metabolism of cells exposed to hypoxic stress. Their putative role as markers of clinically relevant hypoxia and, therefore, as predictors of response to chemoradiotherapy is herein examined. Patients and Methods : Using immunohistochemistry, we assessed the expression of HIFαs in normal head-neck mucosa and in 75 cancer specimens from patients with locally advanced squamous cell head-and-neck cancer (SCHNC), treated with concurrent carboplatin chemoradiotherapy. Results : Head-and-neck mucosa from normal individuals did not show any HIF1α or HIF2α reactivity. SCHNC showed a varying expression of HIFαs ranging through negative reactivity, to weak or focally strong cytoplasmic reactivity, or to strong diffuse cytoplasmic/nuclear reactivity. Fifty-two percent and 33% of cancer samples showed the latter expression pattern for HIF1α and HIF2α, respectively, and were considered to bear “high” HIF reactivity. Bone/cartilage involvement was more frequent in tumors with high HIF1α expression (p = 0.05). HIF1α and HIF2α overexpression were significantly associated with high microvessel density (p = 0.002 and 0.02, respectively) and with VEGF expression (p = 0.01 and 0.005, respectively). HIF1α was related to high thymidine phosphorylase expression (p = 0.03), whereas VEGF/KDR-activated tumor vasculature was significantly more frequent in HIF2α-overexpressing tumors (p = 0.02). High HIF1α and HIF2α were associated with incomplete response to chemoradiation (p = 0.007 and p = 0.02, respectively). In univariate analysis, high HIF1α and HIF2α expression were significantly associated with poor local relapse-free survival (p = 0.003 and 0.003, respectively) and with poor overall survival (p = 0.05 and 0.001, respectively). In multivariate models, HIF2α expression was an independent prognostic factor. In biopsies performed after the delivery of 20 Gy of radiotherapy, upregulation of HIFαs was noted in some cases. Conclusions : It is concluded that the overexpression of HIFαs in SCHNC is related to locally aggressive behavior, to intensification of angiogenesis, and to an important resistance to carboplatin chemoradiotherapy.

Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy

Abstract: Purpose: To present our clinical experience using intensity-modulated radiation therapy (IMRT) to improve dose uniformity and treatment efficacy in patients with early-stage breast cancer treated with breast-conserving therapy. Methods and Materials: A total of 281 patients with Stage 0, I, and II breast cancer treated with breast-conserving therapy received whole breast RT after lumpectomy using our static, multileaf collimator (sMLC) IMRT technique. The technical and practical aspects of implementing this technique on a large scale in the clinic were analyzed. The clinical outcome of patients treated with this technique was also reviewed. Results: The median time required for three-dimensional alignment of the tangential fields and dosimetric IMRT planning was 40 and 45 min, respectively. The median number of sMLC segments required per patient to meet the predefined dose-volume constraints was 6 (range 3–12). The median percentage of the treatment given with open fields (no sMLC segments) was 83% (range 38–96%), and the median treatment time was Conclusion: The use of intensity modulation with our sMLC technique for tangential whole breast RT is an efficient method for achieving a uniform and standardized dose throughout the whole breast. Strict dose-volume constraints can be readily achieved resulting in both uniform coverage of breast tissue and a potential reduction in acute and chronic toxicities. Because the median number of sMLC segments required per patient is only 6, the treatment time is equivalent to conventional wedged-tangent treatment techniques. As a result, widespread implementation of this technology can be achieved with minimal imposition on clinic resources and time constraints.

The impact of 18 FDG-PET on target and critical organs in CT-based treatment planning of patients with poorly defined non-small-cell lung carcinoma: a prospective study☆

Abstract: Purpose : To prospectively study the impact of coregistering 18F-fluoro-deoxy-2-glucose hybrid positron emission tomographic (FDG-PET) images with CT images on the planning target volume (PTV), target coverage, and critical organ dose in radiation therapy planning of non-small-cell lung carcinoma. Methods and Materials : Thirty patients with poorly defined tumors on CT, referred for radical radiation therapy, underwent both FDG-PET and CT simulation procedures on the same day, in radiation treatment position. Image sets were coregistered using external fiducial markers. Three radiation oncologists independently defined the gross tumor volumes, using first CT data alone and then coregistered CT and FDG-PET data. Standard margins were applied to each gross tumor volume to generate a PTV, and standardized treatment plans were designed and calculated for each PTV. Dose-volume histograms were used to evaluate the relative effect of FDG information on target coverage and on normal tissue dose. Results : In 7 of 30 (23%) cases, FDG-PET information changed management strategy from radical to palliative. In 5 of the remaining 23 (22%) cases, new FDG-avid nodes were found within 5 cm of the primary tumor and were included in the PTV. The PTV defined using coregistered CT and FDG-PET would have been poorly covered by the CT-based treatment plan in 17–29% of cases, depending on the physician, implying a geographic miss had only CT information been available. The effect of FDG-PET on target definition varied with the physician, leading to a reduction in PTV in 24–70% of cases and an increase in 30–76% of cases. The relative change in PTV ranged from 0.40 to 1.86. On average, FDG-PET information led to a reduction in spinal cord dose but not in total lung dose, although large differences in dose to the lung were seen for a few individuals. Conclusion : The coregistration of planning CT and FDG-PET images made significant alterations to patient management and to the PTV. Ultimately, changes to the PTV resulted in changes to the radiation treatment plans for the majority of cases. Where possible, we would recommend that FDG-PET data be integrated into treatment planning of non-small-cell lung carcinoma, particularly for three-dimensional conformal techniques.

Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients

Abstract: Purpose: To evaluate the impact of tumor response; tumor and nodal downstaging; and cTNM, yTNM (clinical stage after chemoradiation, based on preoperative imaging), and pTNM classifications on long-term outcome in patients with rectal cancer treated with preoperative 5-fluorouracil (5-FU)-based concurrent chemoradiation. Methods and Materials: Between January 1990 and March 1998, 165 consecutive patients with locally advanced extraperitoneal cancer of the rectum were treated with preoperative chemoradiation. Four patients had a cT2 lesion (2.5%), 120 had a cT3 lesion (74.5%), and 41 had a cT4 lesion (23%). The nodal involvement at combined imaging was cN0 in 21%, cN1 in 41%, cN2 in 34%, and cN3 in 4%. Preoperative chemoradiation was delivered according to 1 of 3 schedules: ( 1 ) FUMIR-T3 (from 1990 to 1995) for patients with cT3N0-2 or cT2N1-2 rectal carcinoma (82 patients): 37.8 Gy (1.8 Gy/fraction) plus 5-FU, 1 g/m 2 /d on Days 1–4, continuous infusion, and mitomycin-C, 10 mg/m 2 /d on Day 1; ( 2 ) FUMIR-T4 (from 1990 to 1999) for patients with cT4N0-3 or cT3-4N3 rectal carcinoma (40 patients): 45 Gy (1.8 Gy/fraction) plus 5-FU, 1 g/m 2 /d on Days 1–4 and 29–32, continuous infusion, and mitomycin-C, 10 mg/m 2 /d on Days 1 and 29; and ( 3 ) PLAFUR-4 (from 1995 to 1998) for patients with cT3N0-2 or cT2N1-2 rectal carcinoma (42 patients): 50.4 Gy (1.8 Gy/fraction) plus 5-FU, 1 g/m 2 /d on Days 1–4 and 29–32, continuous infusion, and cisplatin, 60 mg/m 2 /d on Days 1 and 29. Four to five weeks after chemoradiation, patients were reevaluated for clinical response by imaging studies (CT scan, transrectal ultrasonography, barium enema, liver ultrasonography, chest X-rays) and restaged (yTNM). Surgery was performed 6–8 weeks after chemoradiation. Adjuvant chemotherapy (5-FU + l-folinic acid) was delivered to 26 patients in the FUMIR-T4 protocol group. Local control (LC), freedom from distant metastases (FDM), disease-free survival, and overall survival (OS) were evaluated according to the clinical response and cTNM, yTNM, and pTNM classification. The median follow-up was 67 months. Results: The 5-year survival rate was 100% for cT2, 77% for cT3, and 62% for cT4 ( p = 0.0497); after chemoradiation, it ranged between 81% and 91% for pT0-pT2 and dropped to 66% for pT3 and 47% for pT4 ( p = 0.014). The 5-year local control rate was, at the first staging, 84% for cT3 and 72% for cT4; after chemoradiation, the pT stage correlated significantly with LC ( p = 0.0012): 100% for pT0, 83% for pT1, 88% for pT2, 79% for pT3, and 46% for pT4. N stage was statistically significant in predicting FDM and OS at any staging step. A significant impact of tumor response, tumor downstaging, and nodal downstaging on LC, FDM, disease-free survival, and OS was also recorded. If the residual tumor, before surgery, had a tumor index Conclusion: After preoperative chemoradiation, clinical response and tumor/nodal pathologic downstaging showed a close correlation with improved outcomes. The better 5-year survival and local control in pT0-2 patients regardless of their initial stage seems to confirm a heterogeneity in rectal cancer patients. The responder population showed a behavior similar to rectal cancer diagnosed at Stage cT1-2 and treated with conservative surgery alone. Additional studies aimed at improving local tumor response seem justified. Trials of sphincter-saving surgery after a major response are warranted.

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer.

Abstract: 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.

Defining A radiotherapy target with positron emission tomography

Abstract: Purpose F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is now considered the most accurate clinical staging study for non–small-cell lung cancer (NSCLC) and is also important in the staging of multiple other malignancies. Gross tumor volume (GTV) definition for radiotherapy, however, is typically based entirely on computed tomographic data. We performed a series of phantom studies to determine an accurate and uniformly applicable method for defining a GTV with FDG-PET. Methods and materials A model-based method was tested by a phantom study to determine a threshold, or unique cutoff of standardized uptake value based on body weight (standardized uptake value [SUV]) for FDG-PET based GTV definition. The degree to which mean target SUV, background FDG concentration, and target volume influenced that GTV definition were evaluated. A phantom was constructed consisting of a 9.0-L cylindrical tank. Glass spheres with volumes ranging from 12.2 to 291.0 cc were suspended within the tank, with a minimum separation of 4 cm between the edges of the spheres. The sphere volumes were selected based on the range of NSCLC patient tumor volumes seen in our clinic. The tank and spheres were filled with a variety of known concentrations of FDG in several experiments and then scanned using a General Electric Advance PET scanner. In the initial experiment, six spheres with identical volumes were filled with varying concentrations of FDG (mean SUV = 1.85 ∼ 9.68) and suspended within a background bath of FDG at a similar concentration to that used in clinical practice (0.144 μCi/mL). The second experiment was identical to the first, but was performed at 0.144 and 0.036 μCi/mL background concentrations to determine the effect of background FDG concentration on sphere definition. In the third experiment, six spheres with volumes of 12.2 to 291.0 cc were filled with equal concentrations of FDG and suspended in a standard background FDG concentration of 0.144 μCi/mL. Sphere images in each experiment were auto-contoured (simulating a GTV) using the threshold SUV that yielded a volume matching that of the known sphere volume. A regressive function was constructed to represent the relationship between the threshold SUV and the mean target SUV. This function was then applied to define the GTV of 15 NSCLC patients. The GTV volumes were compared to those determined by a fixed image intensity threshold proposed by other investigators. Results There was a strong linear relationship between the threshold SUV and the mean target SUV. The linear regressive function derived was: threshold SUV = 0.307 × (mean target SUV) + 0.588. The background concentration and target volume indirectly affect the threshold SUV by way of their influence on the mean target SUV. We applied the linear regressive function, as well as a fixed image intensity threshold (42% of maximum intensity) to the sphere phantoms and 15 patients with NSCLC. The results indicated that a much smaller deviation occurred when the threshold SUV regressive function was utilized to estimate the phantom volume as compared to the fixed image intensity threshold. The average absolute difference between the two methods was 21% with respect to the true phantom volume. The deviation became even more pronounced when applied to true patient GTV volumes, with a mean difference between the two methods of 67%. This was largely due to a greater degree of heterogeneity in the SUV of tumors over phantoms. Conclusions An FDG-PET-based GTV can be systematically defined using a threshold SUV according to the regressive function described above. The threshold SUV for defining the target is strongly dependent on the mean target SUV of the target, and can be uniquely determined through the proposed iteration process.

What hypofractionated protocols should be tested for prostate cancer

Abstract: Purpose: Recent analyses of clinical results have suggested that the fractionation sensitivity of prostate tumors is remarkably high; corresponding point estimates of the / ratio for prostate cancer are around 1.5 Gy, much lower than the typical value of 10 Gy for many other tumors. This low / value is comparable to, and possibly even lower than, that of the surrounding late-responding normal tissue in rectal mucosa (/ nominally 3 Gy, but also likely to be in the 4 –5 Gy range). This lower / 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 / parameters, which are discussed thoroughly. Results: If the / 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 / 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. © 2003 Elsevier Inc. Hypofractionation, Prostate tumors, Approximately intermediate-risk, Reduced total doses.

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

Abstract: 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 ≤ 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 ≥ 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.

Craniopharyngioma: The St. Jude Children's Research Hospital experience 1984-2001

Abstract: Purpose: To review our institution's experience in the treatment of craniopharyngioma and assess the merits of initial therapy with limited surgery and irradiation. Methods and Materials: The data of 30 patients (median age 8.6 years) with a diagnosis of craniopharyngioma between April 1984 and September 1997 were reviewed. Their course of treatment, neurologic, endocrine, and cognitive function, and quality of life at last follow-up were compared. Results: Fifteen patients were initially treated with surgery (8 required irradiation after relapse) and 15 with limited surgery and irradiation (2 required additional treatment for tumor progression). Only 1 patient died of tumor progression. The surgery group lost a mean of 9.8 points in full-scale IQ, and the combined-modality group lost only 1.25 points ( p n = 9) lost a mean of 13.1 points ( p p t test). Conclusions: The acute neurologic, cognitive, and endocrine effects of surgery often affect long-term function and quality of life. Our experience suggests that limited surgery and radiotherapy cause lesser or comparable sequelae. Diabetes insipidus was the only endocrine deficiency that differed substantially in frequency between the two groups. Newer radiation planning and delivery techniques may make a combined-modality approach a good initial option for most patients.

Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT)

Abstract: Purpose: We present a novel three-dimensional conformal radiation therapy (3D-CRT) technique to treat the lumpectomy cavity, plus a 1.5-cm margin, in patients with early-stage breast cancer and study its clinical feasibility. Methods and Materials: A 3D-CRT technique for partial-breast irradiation was developed using archived CT scans from 7 patients who underwent an active breathing control study. The clinical feasibility of this technique was then assessed in 9 patients who were prospectively enrolled on an Investigational Review Board-approved protocol of partial-breast irradiation. The prescribed dose was 34 Gy in 5 patients and 38.5 Gy in 4 patients, delivered in 10 fractions twice daily over 5 consecutive days. The impact of both breathing motion and patient setup uncertainty on clinical target volume (CTV) coverage was studied, and an appropriate CTV-to-PTV (planning target volume) margin was calculated. Results: By adding a CTV-to-PTV “breathing-only” margin of 5 mm, 98%–100% of the CTV remained covered by the 95% isodose surface at the extremes of normal inhalation and normal exhalation. The “total” CTV-to-PTV margin employed to accommodate organ motion and setup error (10 mm) was found to be sufficient to accommodate the observed uncertainty in the delivery precision. Patient tolerance was excellent, and acute toxicity was minimal. No skin changes were noted during treatment, and at the initial 4–8-week follow-up visit, only mild localized hyperpigmentation and/or erythema was observed. No instances of symptomatic radiation pneumonitis have occurred. Conclusions: Accelerated partial-breast irradiation using 3D-CRT is technically feasible, and acute toxicity to date has been minimal. A CTV-to-PTV margin of 10 mm seems to provide coverage for most patients. However, more patients and additional studies will be needed to validate the accuracy of this margin, and longer follow-up will be needed to assess acute and chronic toxicity, tumor control, and cosmetic results.

Evaluation of respiratory movement during gated radiotherapy using film and electronic portal imaging

Abstract: Purpose: To evaluate the effectiveness of a commercial system 1 in reducing respiration-induced treatment uncertainty by gating the radiation delivery. 1Varian Medical Systems, Inc., Palo Alto, CA. Methods and Materials: The gating system considered here measures respiration from the position of a reflective marker on the patient's chest. Respiration-triggered planning CT scans were obtained for 8 patients (4 lung, 4 liver) at the intended phase of respiration (6 at end expiration and 2 at end inspiration). In addition, fluoroscopic movies were recorded simultaneously with the respiratory waveform. During the treatment sessions, gated localization films were used to measure the position of the diaphragm relative to the vertebral bodies, which was compared to the reference digitally reconstructed radiograph derived from the respiration-triggered planning CT. Variability was quantified by the standard deviation about the mean position. We also assessed the interfraction variability of soft tissue structures during gated treatment in 2 patients using an amorphous silicon electronic portal imaging device. Results: The gated localization films revealed an interfraction patient-averaged diaphragm variability of 2.8 ± 1.0 mm (error bars indicate standard deviation in the patient population). The fluoroscopic data yielded a patient-averaged intrafraction diaphragm variability of 2.6 ± 1.7 mm. With no gating, this intrafraction excursion became 6.9 ± 2.1 mm. In gated localization films, the patient-averaged mean displacement of the diaphragm from the planning position was 0.0 ± 3.9 mm. However, in 4 of the 8 patients, the mean (over localization films) displacement was >4 mm, indicating a systematic displacement in treatment position from the planned one. The position of soft tissue features observed in portal images during gated treatments over several fractions showed a mean variability between 2.6 and 5.7 mm. The intrafraction variability, however, was between 0.6 and 1.4 mm, indicating that most of the variability was due to patient setup errors rather than to respiratory motion. Conclusions: The gating system evaluated here reduces the intra- and interfraction variability of anatomy due to respiratory motion. However, systematic displacements were observed in some cases between the location of an anatomic feature at simulation and its location during treatment. Frequent monitoring is advisable with film or portal imaging.

Measurement of tumor volume by PET to evaluate prognosis in patients with advanced cervical cancer treated by radiation therapy.

Abstract: Purpose: This study evaluated the usefulness of tumor volume measurement with positron emission tomography (PET) in patients with advanced cervical cancer treated by radiation therapy. Methods and Materials: Fifty-one patients underwent PET before treatment. Primary tumor volume was determined, and volume, FIGO stage, and presence of lymph nodes on the PET study were compared to progression-free survival (PFS) and overall survival (OS). Results: Tumor volume, lymph node disease, and stage were predictive of PFS, whereas volume and lymph node involvement predicted OS. Lymph node status did not correlate with volume. Dividing patients according to whether the tumor volume was more or less than 60 cm 3 predicted PFS and OS. Separation of patients with tumor volumes ≤60 cm 3 and no lymph node disease vs. any other combination was strongly predictive of PFS and OS. Conclusions: The following conclusions were drawn regarding patients with advanced cervical cancer treated with radiation therapy: ( 1 ) Tumor volume can be accurately measured by PET; ( 2 ) Tumor volume separates patients with a good prognosis from those with a poorer prognosis; ( 3 ) A subset of patients with relatively small tumors and no lymph node involvement does remarkably well; ( 4 ) Tumor volume does not correlate with the presence of lymph node disease.

Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy.

Abstract: Purpose: ( 1 ) To determine whether exposure of phosphatidylserine (PS) occurs on vascular endothelium in solid tumors in mice. ( 2 ) To determine whether PS exposure can be induced on viable endothelial cells in tissue culture by conditions present in the tumor microenvironment. Methods and Materials: Externalized PS in vivo was detected by injecting mice with a monoclonal anti-PS antibody and examining frozen sections of tumors and normal tissues for anti-PS antibody bound to vascular endothelium. Apoptotic cells were identified by anti-active caspase-3 antibody or by TUNEL assay. PS exposure on cultured endothelial cells was determined by 125 I-annexin V binding. Results: Anti-PS antibody bound specifically to vascular endothelium in six tumor models. The percentage of PS-positive vessels ranged from 4% to 40% in different tumor types. Vascular endothelium in normal organs was unstained. Very few tumor vessels expressed apoptotic markers. Hypoxia/reoxygenation, acidity, inflammatory cytokines, thrombin, or hydrogen peroxide induced PS exposure on cultured endothelial cells without causing loss of viability. Conclusions: Vascular endothelial cells in tumors, but not in normal tissues, externalize PS. PS exposure might be induced by tumor-associated oxidative stress and activating cytokines. PS is an abundant and accessible marker of tumor vasculature and could be used for tumor imaging and therapy.

Secondary neutron dose during proton therapy using spot scanning

Abstract: Purpose: During proton radiotherapy, secondary neutrons are produced by nuclear interactions in the material in the beam line before and after entering the patient. The dose equivalent deposited by these neutrons is usually not considered in routine treatment planning. In this study, we estimated the neutron dose in patients from a spot scanning beam line by performing measurements and Monte Carlo simulations. Methods and Materials: Measurements of the secondary neutron dose were performed during irradiation of a water phantom with 177-MeV protons using a Bonner sphere and CR39 etch detectors. Additionally, Monte Carlo simulations were performed using the FLUKA code. Results: A comparison of our measurements with measurements taken at a beam line using the scatter foil technique shows a dose advantage of at least 10 for the spot scanning technique. In the region of the Bragg peak, the neutron dose equivalent can reach for a medium-sized target volume approximately 1% of the treatment dose. Neutron doses expected in healthy tissues of the patient (in the not-treated volume) are for large and medium target volumes, approximately 0.004 Sv and 0.002 Sv per treatment Gy, respectively. Conclusions: We conclude from the measurements and simulations that the dose deposited by secondary neutrons during proton radiotherapy using the spot scanning technique can be neglected in the treatment region. In the healthy tissue, the dose coming from neutrons (0.002 Sv per treatment Gy) is approximately a factor of two larger than during photon treatment (0.001 Sv). These contributions to the integral dose from neutrons are still very low when compared to the dose sparing that can be achieved by using a proton beam instead of photons.