Showing papers in "International Journal of Radiation Oncology Biology Physics in 2000"

The probability of correct target dosage: dose-population histograms for deriving treatment margins in radiotherapy

Abstract: Purpose: To provide an analytical description of the effect of random and systematic geometrical deviations on the target dose in radiotherapy and to derive margin rules. Methods and Materials: The cumulative dose distribution delivered to the clinical target volume (CTV) is expressed analytically. Geometrical deviations are separated into treatment execution (random) and treatment preparation (systematic) variations. The analysis relates each possible preparation (systematic) error to the dose distribution over the CTV and allows computation of the probability distribution of, for instance, the minimum dose delivered to the CTV. Results: The probability distributions of the cumulative dose over a population of patients are called dose-population histograms in short. Large execution (random) variations lead to CTV underdosage for a large number of patients, while the same level of preparation (systematic) errors leads to a much larger underdosage for some of the patients. A single point on the histogram gives a simple "margin recipe." For example, to ensure a minimum dose to the CTV of 95% for 90% of the patients, a margin between CTV and planning target volume (PTV) is required of 2.5 times the total standard deviation (SD) of preparation (systematic) errors (Σ) plus 1.64 times the total SD of execution (random) errors (σ′) combined with the penumbra width, minus 1.64 times the SD describing the penumbra width (σ p ). For a σ p of 3.2 mm, this recipe can be simplified to 2.5 Σ + 0.7 σ′. Because this margin excludes rotational errors and shape deviations, it must be considered as a lower limit for safe radiotherapy. Conclusion: Dose-population histograms provide insight into the effects of geometrical deviations on a population of patients. Using a dose-probability based approach, simple algorithms for choosing margins were derived.

Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05.

Abstract: Purpose: To determine the maximum tolerated dose of single fraction radiosurgery in patients with recurrent previously irradiated primary brain tumors and brain metastases. Methods and Materials: Adults with cerebral or cerebellar solitary non-brainstem tumors ≤ 40 mm in maximum diameter were eligible. Initial radiosurgical doses were 18 Gy for tumors ≤ 20 mm, 15 Gy for those 21–30 mm, and 12 Gy for those 31–40 mm in maximum diameter. Dose was prescribed to the 50–90% isodose line. Doses were escalated in 3 Gy increments providing the incidence of irreversible grade 3 (severe) or any grade 4 (life threatening) or grade 5 (fatal) Radiation Therapy Oncology Group (RTOG) central nervous system (CNS) toxicity (unacceptable CNS toxicity) was Results: Between 1990–1994, 156 analyzable patients were entered, 36% of whom had recurrent primary brain tumors (median prior dose 60 Gy) and 64% recurrent brain metastases (median prior dose 30 Gy). The maximum tolerated doses were 24 Gy, 18 Gy, and 15 Gy for tumors ≤ 20 mm, 21–30 mm, and 31–40 mm in maximum diameter, respectively. However, for tumors Conclusions: The maximum tolerated doses of single fraction radiosurgery were defined for this population of patients as 24 Gy, 18 Gy, and 15 Gy for tumors ≤ 20 mm, 21–30 mm, and 31–40 mm in maximum diameter. Unacceptable CNS toxicity was more likely in patients with larger tumors, whereas local tumor control was most dependent on the type of recurrent tumor and the treatment unit.

Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality.

Abstract: Purpose: The goals of this study were to survey and summarize the advances in imaging that have potential applications in radiation oncology, and to explore the concept of integrating physical and biological conformality in multidimensional conformal radiotherapy (MD-CRT). Methods and Materials: The advances in three-dimensional conformal radiotherapy (3D-CRT) have greatly improved the physical conformality of treatment planning and delivery. The development of intensity-modulated radiotherapy (IMRT) has provided the “dose painting” or “dose sculpting” ability to further customize the delivered dose distribution. The improved capabilities of nuclear magnetic resonance imaging and spectroscopy, and of positron emission tomography, are beginning to provide physiological and functional information about the tumor and its surroundings. In addition, molecular imaging promises to reveal tumor biology at the genotype and phenotype level. These developments converge to provide significant opportunities for enhancing the success of radiotherapy. Results: The ability of IMRT to deliver nonuniform dose patterns by design brings to fore the question of how to “dose paint” and “dose sculpt”, leading to the suggestion that “biological” images may be of assistance. In contrast to the conventional radiological images that primarily provide anatomical information, biological images reveal metabolic, functional, physiological, genotypic, and phenotypic data. Important for radiotherapy, the new and noninvasive imaging methods may yield three-dimensional radiobiological information. Studies are urgently needed to identify genotypes and phenotypes that affect radiosensitivity, and to devise methods to image them noninvasively. Incremental to the concept of gross, clinical, and planning target volumes (GTV, CTV, and PTV), we propose the concept of “biological target volume” (BTV) and hypothesize that BTV can be derived from biological images and that their use may incrementally improve target delineation and dose delivery. We emphasize, however, that much basic research and clinical studies are needed before this potential can be realized. Conclusions: Whereas IMRT may have initiated the beginning of the end relative to physical conformality in radiotherapy, biological imaging may launch the beginning of a new era of biological conformality. In combination, these approaches constitute MD-CRT that may further improve the efficacy of cancer radiotherapy in the new millennium. © 2000 Elsevier Science Inc. Biological imaging, Conformal radiotherapy.

Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy

Abstract: In 1997, the National Cancer Institute (NCI) led an effort to revise and expand the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent, radiation, and surgical criteria into a comprehensive and standardized system. Representatives from the Radiation Therapy Oncology Group (RTOG) participated in this process in an effort to improve acute radiation related criteria and to achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and includes more than 260 individual adverse events with more than 100 of these applicable to acute radiation effects. One of the advantages of the revised criteria for radiation oncology is the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system. A pilot study conducted by the RTOG indicated the new criteria are indeed more comprehensive and were preferred by research associates. CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities.

Physical aspects of a real-time tumor-tracking system for gated radiotherapy

Abstract: Purpose: To reduce uncertainty due to setup error and organ motion during radiotherapy of tumors in or near the lung, by means of real-time tumor tracking and gating of a linear accelerator Methods and Materials: The real-time tumor-tracking system consists of four sets of diagnostic X-ray television systems (two of which offer an unobstructed view of the patient at any time), an image processor unit, a gating control unit, and an image display unit The system recognizes the position of a 20-mm gold marker in the human body 30 times per second using two X-ray television systems The marker is inserted in or near the tumor using image guided implantation The linear accelerator is gated to irradiate the tumor only when the marker is within a given tolerance from its planned coordinates relative to the isocenter The accuracy of the system and the additional dose due to the diagnostic X-ray were examined in a phantom, and the geometric performance of the system was evaluated in 4 patients Results: The phantom experiment demonstrated that the geometric accuracy of the tumor-tracking system is better than 15 mm for moving targets up to a speed of 40 mm/s The dose due to the diagnostic X-ray monitoring ranged from 001% to 1% of the target dose for a 20-Gy irradiation of a chest phantom In 4 patients with lung cancer, the range of the coordinates of the tumor marker during irradiation was 25–53 mm, which would have been 96–384 mm without tracking Conclusion: We successfully implemented and applied a tumor-tracking and gating system The system significantly improves the accuracy of irradiation of targets in motion at the expense of an acceptable amount of diagnostic X-ray exposure

TGF-β1 and radiation fibrosis: a master switch and a specific therapeutic target?

Abstract: Radiation fibrosis is a frequent sequel of therapeutic or accidental radiation overexposure in normal human tissues. One of the main fundamental problems yet unsolved in fibrotic tissues is the origin of the chronic activation of myofibroblasts within these tissues. It has been postulated that this chronic activation results from a continuous production of activating factors. In this context, fibrosis could be defined as a wound where continuous signals for tissue repair are emitted. Cytokines and growth factors probably play a central role in this process. Among them, transforming growth factor-β1 (TGF-β1) is considered as a master switch for the fibrotic program. This review discusses recent evidence on the critical role played by TGF-β in the initiation, development, and persistence of radiation fibrosis. It summarizes the results concerning this factor after irradiation of various tissues and cells, with an emphasis on superficial fibrosis, including skin and subcutaneous tissues. Finally, recent data concerning the treatment of established fibrotic disorders of various etiology are presented, as well as the possible mechanisms involved in fibrosis regression, which show that the TGF-β pathway may constitute a specific target for antifibrotic agents.

Pancreatic tumors show high levels of hypoxia.

Abstract: Purpose: Because of the dismal outcomes of conventional therapies for pancreatic carcinomas, we postulated that hypoxia may exist within these tumors. Methods and Materials: Seven sequential patients with adenocarcinomas of the pancreas consented to intraoperative measurements of tumor oxygenation using the Eppendorf (Hamburg, Germany) polargraphic electrode. Results: All 7 tumors demonstrated significant tumor hypoxia. In contrast, adjacent normal pancreas showed normal oxygenation. Conclusion: Tumor hypoxia exists within pancreatic cancers.

Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.

Abstract: Purpose: Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer. Methods and Materials: At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The twodimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (mmol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint. Results: Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n 5 25). Other sites included oropharynx (n 5 5), hypopharynx (n 5 3), and oral cavity (n 5 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 mmol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries ( <0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 mmol/g vs. 4.8 mmol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage. Discussion: Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes. © 2001 Elsevier Science Inc.

Four-dimensional treatment planning and fluoroscopic real-time tumor tracking radiotherapy for moving tumor.

Abstract: Purpose: To achieve precise three-dimensional (3D) conformal radiotherapy for mobile tumors, a new radiotherapy system and its treatment planning system were developed and used for clinical practice. Methods and Materials: We developed a linear accelerator synchronized with a fluoroscopic real-time tumor tracking system by which 3D coordinates of a 2.0-mm gold marker in the tumor can be determined every 0.03 second. The 3D relationships between the marker and the tumor at different respiratory phases are evaluated using CT image at each respiratory phase, whereby the optimum phase can be selected to synchronize with irradiation (4D treatment planning). The linac is triggered to irradiate the tumor only when the marker is located within the region of the planned coordinates relative to the isocenter. Results: The coordinates of the marker were detected with an accuracy of ± 1 mm during radiotherapy in the phantom experiment. The time delay between recognition of the marker position and the start or stop of megavoltage X-ray irradiation was 0.03 second. Fourteen patients with various tumors were treated by conformal radiotherapy with a “tight” planning target volume (PTV) margin. They were surviving without relapse or complications with a median follow-up of 6 months. Conclusion: Fluoroscopic real-time tumor tracking radiotherapy following 4D treatment planning was developed and shown to be feasible to improve the accuracy of the radiotherapy for mobile tumors.

Respiratory gated irradiation system for heavy-ion radiotherapy

Abstract: Purpose: In order to reduce the treatment margin of the moving target due to breathing, we developed a gated irradiation system for heavy-ion radiotherapy. Methods and Materials: The motion of a patient due to respiration is detected by the motion of the body surface around the chest wall. A respiratory sensor was developed using an infrared light spot and a position-sensitive detector. A timing signal to request a beam is generated in response to the respiration waveform, and a carbon beam is extracted from the synchrotron using a RF-knockout method. CT images for treatment planning are taken in synchronization with the respiratory motion. For patient positioning, digitized fluoroscopic images superimposed with the respiration waveform were used. The relation between the respiratory sensor signal and the organ motion was examined using digitized video images from fluoroscopy. The performance of our gated system was demonstrated by using the moving phantom, and dose profiles were measured in the direction of phantom motion. Results: The timing of gate-on is set at the end of the expiratory phase, because the motion of the diaphragm is slower and more reproducible than during the inspiratory phase. The signal of the respiratory sensor shows a phase difference of 120 milliseconds between lower and upper locations on the chest wall. The motion of diaphragm is delayed by 200 milliseconds from the respiration waveform at the lower location. The beam extraction system worked according to the beam on/off logic for gating, and the gated CT scanner performed well. The lateral penumbra size of the dose profile along the moving axis was distinguishably decreased by the gated irradiation. The ratio of the nongated to gated lateral fall-off was 4.3, 3.5, and 2.0 under the stroke of 40.0, 29.0, and 13.0 mm respectively. Conclusion: We developed a total treatment system of gated irradiation for heavy-ion radiotherapy. We found that with this system the target margin along the body axis could be decreased to 5–10 mm although the target moved twice or three times. Over 150 patients with lung or liver cancer had already been treated by this gated irradiation system by the end of July 1999.

The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix

Abstract: Purpose: This report presents guidelines for using high-dose-rate (HDR) brachytherapy in the management of patients with cervical cancer, taking into consideration the current availability of resources in most institutions. Methods: Members of the American Brachytherapy Society (ABS) with expertise in HDR brachytherapy for cervical cancer performed a literature review, supplemented their clinical experience to formulate guidelines for HDR brachytherapy of cervical cancer. Results: The ABS strongly recommends that definitive irradiation for cervical carcinoma must include brachytherapy as a component. Each institution should follow a consistent treatment policy when performing HDR brachytherapy, including complete documentation of treatment parameters and correlation with clinical outcome, such as pelvic control, survival, and complications. The goals are to treat Point A to at least a total low-dose-rate (LDR) equivalent of 80–85 Gy for early stage disease and 85–90 Gy for advanced stage. The pelvic sidewall dose recommendations are 50–55 Gy for early lesions and 55–65 Gy for advanced ones. The relative doses given by external beam radiation therapy (EBRT) vs. brachytherapy depend upon the initial volume of disease, the ability to displace the bladder and rectum, the degree of tumor regression during pelvic irradiation, and institutional preference. As with LDR brachytherapy, every attempt should be made to keep the bladder and rectal doses below 80 Gy and 75 Gy LDR equivalent doses, respectively. Interstitial brachytherapy should be considered for patients with disease that cannot be optimally encompassed by intracavitary brachytherapy. While recognizing that many efficacious HDR fractionation schedules exist, some suggested dose and fractionation schemes for combining the EBRT with HDR brachytherapy for each stage of disease are presented. These recommendations are intended only as guidelines, and the suggested fractionation schemes have not been thoroughly tested. The responsibility for the medical decisions ultimately rests with the treating radiation oncologist. Conclusion: Guidelines are established for HDR brachytherapy for cervical cancer. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies. These guidelines will be modified, as image-based treatment becomes more widely available.

Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial

Abstract: Objective: To compare early and late side effects in prostate cancer patients with Stage T1b–T3 disease randomized to receive 70 Gy or 78 Gy. Methods: There were 189 patients randomized with a minimum follow-up of 2 years, that were available for this analysis. All patients were initially treated with a 4-field box to an isocenter dose of 46 Gy at 2 Gy per fraction. In the 70-Gy arm, treatment was continued to a reduced volume using a 4-field box technique. In the 78-Gy arm, treatment was continued to a reduced volume using a conformal 6-field arrangement. Side effects were graded on a 1–4 scale, adapted from Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. Results: No significant differences in acute rectal or bladder toxicity were seen between the two treatment techniques ( p > 0.6 for all comparisons). The 5-year Kaplan–Meier risks of Grade 2 or higher late bladder toxicity were 20% and 9% for 70-Gy and 78-Gy groups, respectively (log rank, p = 0.8). The 5-year risks of Grade 2 or higher late rectal toxicity were 14% and 21% for 70 Gy and 78 Gy, respectively ( p = 0.4). Dose–volume histogram analysis of the 78-Gy patients showed a significant correlation between the percentage of rectum irradiated to 70 Gy or greater and the likelihood of developing late rectal complications. Patients with more than 25% of the rectum receiving 70 Gy or greater had a 5-year risk of Grade 2 or higher complications of 37% compared to 13% for patients with 25% or less ( p = 0.05). All three Grade 3 complications occurred when greater than 30% of the rectum received 70 Gy or more. Conclusion: The overall rate of complications was similar in both treatment arms. However, there is evidence for a significant increase in late rectal complications when more than 25% of the rectum received 70 Gy or greater. This parameter may serve as a benchmark for the design of future three-dimensional conformal trials.

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

Abstract: 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.

Evaluation of microscopic tumor extension in non–small-cell lung cancer for three-dimensional conformal radiotherapy planning

Abstract: Purpose: One of the most difficult steps of the three-dimensional conformal radiotherapy (3DCRT) is to define the clinical target volume (CTV) according to the degree of local microscopic extension (ME). In this study, we tried to quantify this ME in non–small-cell lung cancer (NSCLC). Material and Methods: Seventy NSCLC surgical resection specimens for which the border between tumor and adjacent lung parenchyma were examined on routine sections. This border was identified with the naked eye, outlined with a marker pen, and the value of the local ME outside of this border was measured with an eyepiece micrometer. The pattern of histologic spread was also determined. Results: A total of 354 slides were examined, corresponding to 176 slides for adenocarcinoma (ADC) and 178 slides for squamous cell carcinoma (SCC). The mean value of ME was 2.69 mm for ADC and 1.48 mm for SCC ( p = 0.01). The usual 5-mm margin covers 80% of the ME for ADC and 91% for SCC. To take into account 95% of the ME, a margin of 8 mm and 6 mm must be chosen for ADC and SCC, respectively. Aerogenous dissemination was the most frequent pattern observed for all groups, followed by lymphatic invasion for ADC and interstitial extension for SCC. Conclusion: The ME was different between ADC and SCC. The usual CTV margin of 5 mm appears inadequate to cover the ME for either group, and it must be increased to 8 mm and 6 mm for ADC and SCC, respectively, to cover 95% of the ME. This approach is obviously integrated into the overall 3DCRT procedure and with other margins.

Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies

Abstract: Purpose: To evaluate the ability of intensity-modulated radiation therapy (IMRT) to reduce the volume of small bowel irradiated in women with gynecologic malignancies receiving whole pelvic radiotherapy (WPRT). Methods and Materials: Ten women with cervical (5) or endometrial (5) cancer undergoing WPRT were selected for this analysis. A planning CT scan of each patient was obtained following administration of oral, i.v., and rectal contrast. The clinical target volume (CTV) was defined as the proximal vagina, parametrial tissues, uterus (if present), and regional lymph nodes. The CTV was expanded uniformly by 1 cm in all directions to produce a planning target volume (PTV). The bladder, rectum, and small bowel were also delineated in each patient. Two plans were created: a standard “4-field box” with apertures shaped to the PTV in each beam’s eye view and an IM-WPRT plan designed to conform to the PTV while minimizing the volume of normal tissues irradiated. Both plans were normalized to deliver 45 Gy to the PTV. Isodose distributions and dose–volume histograms (DVH) were compared. Results: The IM-WPRT plan reduced the volume of small bowel irradiated in all 10 patients at doses above 30 Gy. At the prescription dose, the average volume of small bowel irradiated was reduced by a factor of two (17.4 vs. 33.8%, p = 0.0005). In addition, the average volume of rectum and bladder irradiated at the prescription dose was reduced by 23% in both cases (p = 0.0002 and p = 0.0005, respectively). The average PTV doses delivered by the conventional and IM-WPRT plans were 47.8 Gy and 47.4 Gy, respectively. Corresponding maximum doses were 50.0 Gy and 54.8 Gy, respectively. However, on average, only 3.2% of the PTV received greater than 50.0 Gy in the IM-WPRT plans. Conclusion: Our results suggest that IM-WPRT is an effective means of reducing the volume of small bowel irradiated in women with gynecologic malignancies receiving WPRT. This approach potentially offers a method for reducing small bowel complications in patients with gynecologic malignancies.

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91.

Abstract: Purpose: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT ’91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. Methods and Materials: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine (“Philadelphia protocol”). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). Results: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4–62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70 ± 0.08; for patients with residual disease: 0.72 ±0.06; without residual disease: 0.68 ± 0.09; M0: 0.72 ± 0.04; M1: 0.65 ± 0.12; and M2/3: 0.30 ± 0.15. For all randomized patients without M2/3 disease: 0.65± 0.05 (arm I) and 0.78 ± 0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60 ± 0.13 and 0.64 ± 0.14, respectively, but patients between 6 and 18 years: 0.62 ± 0.09 and 0.84 ± 0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). Conclusions: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Radiosurgery for brain metastases: a score index for predicting prognosis

Abstract: Purpose: To analyze a prognostic score index for patients with brain metastases submitted to stereotactic radiosurgery (the Score Index for Radiosurgery in Brain Metastases [SIR]). Methods and Materials: Actuarial survival of 65 brain metastases patients treated with radiosurgery between July 1993 and December 1997 was retrospectively analyzed. Prognostic factors included age, Karnofsky performance status (KPS), extracranial disease status, number of brain lesions, largest brain lesion volume, lesions site, and receiving or not whole brain irradiation. The SIR was obtained through summation of the previously noted first five prognostic factors. Kaplan-Meier actuarial survival curves for all prognostic factors, SIR, and recursive partitioning analysis (RPA) (RTOG prognostic score) were calculated. Survival curves of subsets were compared by log-rank test. Application of the Cox model was utilized to identify any correlation between prognostic factors, prognostic scores, and survival. Results: Median overall survival from radiosurgery was 6.8 months. Utilizing univariate analysis, extracranial disease status, KPS, number of brain lesions, largest brain lesion volume, RPA, and SIR were significantly correlated with prognosis. Median survival for the RPA classes 1, 2, and 3 was 20.19 months, 7.75 months, and 3.38 months respectively ( p = 0.0131). Median survival for patients, grouped under SIR from 1 to 3, 4 to 7, and 8 to 10, was 2.91 months, 7.00 months, and 31.38 months respectively ( p = 0.0001). Using the Cox model, extracranial disease status and KPS demonstrated significant correlation with prognosis ( p = 0.0001 and 0.0004 respectively). Multivariate analysis also demonstrated significance for SIR and RPA when tested individually ( p = 0.0001 and 0.0040 respectively). Applying the Cox Model to both SIR and RPA, only SIR reached independent significance ( p = 0.0004). Conclusions: Systemic disease status, KPS, SIR, and RPA are reliable prognostic factors for patients with brain metastases submitted to radiosurgery. Applying SIR and RPA classifications to our patients' data, SIR demonstrated better accuracy in predicting prognosis. SIR should be further tested with larger patient accrual and for all patients with brain metastases subjected or not to stereotactic radiosurgery.

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer.

Abstract: Purpose: To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). Methods and Materials: Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m2/day)/carboplatinum (70 mg/m2) on days 1–5 and 29–33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 μg, days 15–19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1–3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). Results: This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: ± G-CSF, p = 0.0072). Conclusion: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.

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

Abstract: Purpose: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT). Methods and Materials: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose–volume histograms. The recurrences were classified as 1) "in-field," in which 95% or more of the recurrence volume (V recur ) was within the 95% isodose; 2) "marginal," in which 20% to 95% of V recur was within the 95% isodose; or 3) "outside," in which less than 20% of V recur was within the 95% isodose. Results: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68–90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared. Conclusions: The majority of local-regional recurrences after conformal and segmental IMRT were "in-field," in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.

Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients

Abstract: Purpose: To better predict permanent complications from arteriovenous malformation (AVM) radiosurgery. Methods and Materials: Data from 85 AVM patients who developed symptomatic complications following gamma knife radiosurgery and 337 control patients with no complications were evaluated as part of a multi-institutional study. Of the 85 patients with complications, 38 patients were classified as having permanent symptomatic sequelae (necrosis). AVM marginal doses varied from 10–35 Gy and treatment volumes from 0.26–47.9 cc. Median follow-up for patients without complications was 45 months (range: 24–92). Results: Multivariate analysis of the effects of AVM location and the volume of tissue receiving 12 Gy or more (12-Gy-Volume) allowed construction of a significant postradiosurgery injury expression (SPIE) score. AVM locations in order of increasing risk and SPIE score (from 0–10) were: frontal, temporal, intraventricular, parietal, cerebellar, corpus callosum, occipital, medulla, thalamus, basal ganglia, and pons/midbrain. The final statistical model predicts risks of permanent symptomatic sequelae from SPIE scores and 12-Gy-Volumes. Prior hemorrhage, marginal dose, and Marginal-12-Gy-Volume (target volume excluded) did not significantly improve the risk-prediction model for permanent sequelae (p ≥ 0.39). Conclusion: The risks of developing permanent symptomatic sequelae from AVM radiosurgery vary dramatically with location and, to a lesser extent, volume. These risks can be predicted according to the SPIE location-risk score and the 12-Gy-Volume.

Enhancement of radiosensitivity by proteasome inhibition: Implications for a role of NF-κB

Abstract: Purpose: NF-κB is activated by tumor necrosis factor, certain chemotherapeutic agents, and ionizing radiation, leading to inhibition of apoptosis. NF-κB activation is regulated by phosphorylation of IκB inhibitor molecules that are subsequently targeted for degradation by the ubiquitin-proteasome pathway. PS-341 is a specific and selective inhibitor of the proteasome that inhibits NF-κB activation and enhances cytotoxic effects of chemotherapy in vitro and in vivo . The objective of this study was to determine if proteasome inhibition leads to enhanced radiation sensitivity. Methods and Materials: Inhibition of NF-κB activation in colorectal cancer cells was performed by treatment of LOVO cells with PS-341 or infection with an adenovirus encoding IκB super-repressor, a selective NF-κB inhibitor. Cells were irradiated at 0, 2, 4, 6, 8, and 10 Gy with or without inhibition of NF-κB. NF-κB activation was determined by electrophoretic mobility gel shift assay, and apoptosis was evaluated using the TUNEL assay. Growth and clonogenic survival data were obtained to assess effects of treatment on radiosensitization. In vitro results were tested in vivo using a LOVO xenograft model. Results: NF-κB activation was induced by radiation and inhibited by pretreatment with either PS-341 or IκBα super-repressor in all cell lines. Inhibition of radiation-induced NF-κB activation resulted in increased apoptosis and decreased cell growth and clonogenic survival. A 7–41% increase in radiosensitivity was observed for cells treated with PS-341 or IκBα. An 84% reduction in initial tumor volume was obtained in LOVO xenografts receiving radiation and PS-341. Conclusions: Inhibition of NF-κB activation increases radiation-induced apoptosis and enhances radiosensitivity in colorectal cancer cells in vitro and in vivo . Results are encouraging for the use of PS-341 as a radiosensitizing agent in the treatment of colorectal cancer.

Toxicity in head and neck cancer: a review of trends and issues.

Abstract: The quest for improved fractionation and combined modality regimens in head and neck cancer has also yielded progressively higher rates of toxicity. Time compression of dose delivery in accelerated fractionation has produced high rates of severe mucositis including the early stoppage of two randomized trials. The addition of chemotherapy has introduced systemic toxicity and can exacerbate local tissue reactions when used concurrent with radiotherapy. Mucositis is recognized as the principal impediment to efforts at further treatment intensification. The development and utilization of standardized toxicity grading criteria and accepted reporting standards has lagged toxicity production, impeding a full appreciation of the true extent of both acute and late toxicity. Objective data regarding acute and chronic effects on organ function are also sorely lacking. A better characterization of the frequency, severity, and duration of the various toxicities encountered in head and neck cancer will also allow the rational development of toxicity interventions. New methods are needed to summarize the global or aggregate toxicity of a treatment program. Further research into the assessment and analysis of toxicity is not only crucial to improvements in quality of life (QOL), but perhaps, improved rates of disease control as well.

Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response.

Abstract: 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 p p max ( p p 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 .

Technical aspects of the deep inspiration breath-hold technique in the treatment of thoracic cancer

Abstract: Purpose: The goal of this paper is to describe our initial experience with the deep inspiration breath-hold (DIBH) technique in conformal treatment of non–small-cell lung cancer with particular emphasis on the technical aspects required for implementation. Methods and Materials: In the DIBH technique, the patient is verbally coached through a modified slow vital capacity maneuver and brought to a reproducible deep inspiration breath-hold level. The goal is to immobilize the tumor and to expand normal lung out of the high-dose region. A physicist or therapist monitors and records patient breathing during simulation, verification, and treatment using a spirometer with a custom computer interface. Examination of internal anatomy during fluoroscopy over multiple breath holds establishes the reproducibility of the DIBH maneuver for each patient. A reference free-breathing CT scan and DIBH planning scan are obtained. To provide an estimate of tumor motion during normal tidal breathing, additional scan sets are obtained at end inspiration and end expiration. These are also used to set the spirometer action levels for treatment. Patient lung inflation is independently verified over the course of treatment by comparing the distance from the isocenter to the diaphragm measured from the DIBH digitally reconstructed radiographs to the distance measured on the portal films. Patient breathing traces obtained during treatment were examined retrospectively to assess the reproducibility of the technique. Results: Data from the first 7 patients, encompassing over 250 treatments, were analyzed. The inferred displacement of the centroid of gross tumor volume from its position in the planning scan, as calculated from the spirometer records in over 350 breath holds was 0.02 ± 0.14 cm (mean and standard deviation). These data are consistent with the displacements of the diaphragm (−0.1 ± 0.4 cm; range, from −1.2 to 1.1 cm) relative to the isocenter, as measured on the (92) portal films. The latter measurements include the patient setup error. The patient averaged displacement of the tumor during free breathing, determined from the tumor displacement between end inspiration and end expiration, was 0.8 ± 0.5 cm in both the superior-inferior and anterior-posterior directions and 0.1 cm (± 0.1 cm) medial-laterally. Conclusion: Treatment of patients with the DIBH technique is feasible in a clinical setting. With this technique, consistent lung inflation levels are achieved in patients, as judged by both spirometry and verification films. Breathing-induced tumor motion is significantly reduced using DIBH compared to free breathing, enabling better target coverage.

Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers.

Abstract: Purpose: The dose distributions of intensity-modulated radiotherapy (IMRT) treatment plans can be shown to be significantly superior in terms of higher conformality if designed to simultaneously deliver high dose to the primary disease and lower dose to the subclinical disease or electively treated regions. We use the term “simultaneous integrated boost” (SIB) to define such a treatment. The purpose of this paper is to develop suitable fractionation strategies based on radiobiological principles for clinical trials and routine use of IMRT of head and neck (HN) cancers. The fractionation strategies are intended to allow escalation of tumor dose while adequately sparing normal tissues outside the target volume and considering the tolerances of normal tissues embedded within the primary target volume. Methods and Materials: IMRT fractionation regimens are specified in terms of “normalized total dose” (NTD), i.e., the biologically equivalent dose given in 2 Gy/fx. A linear-quadratic isoeffect formula is applied to convert NTDs into “nominal” prescription doses. Nominal prescription doses for a high dose to the primary disease, an intermediate dose to regional microscopic disease, and lower dose to electively treated nodes are used for optimizing IMRT plans. The resulting nominal dose distributions are converted back into NTD distributions for the evaluation of treatment plans. Similar calculations for critical normal tissues are also performed. Methods developed were applied for the intercomparison of several HN treatment regimens, including conventional regimens used currently and in the past, as well as SIB strategies. This was accomplished by comparing the biologically equivalent NTD values for the gross tumor and regional disease, and bone, muscle, and mucosa embedded in the gross tumor volume. Results: (1) A schematic HN example was used to demonstrate that dose distributions for SIB IMRT are more conformal compared to dose distributions when IMRT is divided into a large-field phase and a boost phase. Both were shown to be significantly superior compared to dose distributions obtained using conventional beams for the large-field phase followed by IMRT for the boost phase. (2) The relationship between NTD and nominal dose for HN tumors was found to be quite sensitive to the choice of tumor clonogen doubling time but relatively insensitive to other parameters. (3) For late effect normal tissues embedded in the tumor volume and assumed to receive the same dose as the tumor, the biologically equivalent NTD for the SIB IMRT may be significantly higher. (4) Normal tissues outside the target volume receive lower dose due to the higher conformality of the IMRT plans. The biologically equivalent NTDs are even lower due to the lower dose per fraction in the SIB strategy. Conclusions: IMRT dose distributions are most conformal when designed to be delivered as SIB. Using isoeffect radiobiological relationships and published HN data, fractionation strategies can be designed in which the nominal dose levels to the primary, regional disease and electively treated volumes are appropriately adjusted, each receiving different dose/fx. Normal tissues outside the treated volumes are at reduced risk in such strategies since they receive lower total dose as well as lower dose/fx. However, the late effect toxicities of tissues embedded within the primary target volume and assumed to receive the same dose as the primary may pose a problem. The efficacy and safety of the proposed fractionation strategies will need to be evaluated with careful clinical trials.

An off-line strategy for constructing a patient-specific planning target volume in adaptive treatment process for prostate cancer.

Abstract: Purpose: To improve the efficacy of dose delivery and dose escalation for external beam radiotherapy of prostate cancer, an off-line strategy for constructing a patient-specific planning target volume is developed in the adaptive radiotherapy process using image feedback of target location and patient setup position. Materials and Methods: We hypothesize that a patient-specific confidence-limited planning target volume (cl-PTV), constructed using an initial sequence of daily measurements of internal target motion and patient setup error, exists and ensures that the clinical target volume (CTV) in the prostate cancer patient receives the prescribed dose within a predefined dose tolerance. A patient-specific bounding volume to correct for target location and compensate for target random motion was first constructed using the convex hull of the first k days of CT measurements. The bounding volume and the initial days of CT measurements were minimized based on a predefined dosimetric criterion. The hypothesis was tested using multiple daily CT images by mimicking the actual treatment of both conventional 4-field-box and intensity-modulated radiotherapy (IMRT) on each of 30 patients with prostate cancer. For each patient, a patient-specific setup margin was also applied to the bounding volume to form the final cl-PTV. This margin was determined using the random setup error predicted from the initial days of portal imaging measurements and the residuals after correcting for the systematic setup error. Results: The bounding volume constructed using daily CT measurements in the first week of treatment are adequate for the conventional beam delivery to achieve maximum dose reduction in the CTV of 2% or less of the prescription dose, for at least 80% of patients ( p = 0.08), and 4.5% or less for 95% of patients ( p = 0.1). However, for IMRT delivery, 2 weeks of daily CT measurements are required to achieve a similar level of the dosimetric criterion, otherwise the maximum dose reduction of 7%, on average, in the CTV is expected. Furthermore, the patient-specific setup margin required for the IMRT treatment is at least twice larger than that for the conventional treatment, to maintain the same dosimetric criterion. As compared to the conventional PTV, the volume of cl-PTV is significantly reduced, while maintaining the same dosimetric criterion. Conclusion: The cl-PTV for prostate treatment can be constructed within the first week of treatment using the feedback of imaging measurements. The cl-PTV has the capability to exclude the systematic variation and compensate for the patient-specific random variation on target location and patient setup position. This implies that in the current off-line image feedback adaptive treatment process, a single plan modification can be performed within the second week of treatment to improve the efficacy of dose delivery and dose escalation for external beam therapy of prostate cancer.

Intensity modulation to improve dose uniformity with tangential breast radiotherapy: initial clinical experience.

Abstract: Purpose: We present a new technique to improve dose uniformity and potentially reduce acute toxicity with tangential whole-breast radiotherapy (RT) using intensity-modulated radiation therapy (IMRT). The technique of multiple static multileaf collimator ( s MLC) segments was used to facilitate IMRT. Methods and Materials: Ten patients with early-stage breast cancer underwent treatment planning for whole-breast RT using a new method of IMRT. The three-dimensional (3D) dose distribution was first calculated for equally weighted, open tangential fields (i.e., no blocks, no wedges). Dose calculation was corrected for density effects with the pencil-beam superposition algorithm. Separate MLC segments were constructed to conform to the beam's-eye-view projections of the 3D isodose surfaces in 5% increments, ranging from the 120% to 100% isodose surface. Medial and lateral MLC segments that conformed to the lung tissue in the fields were added to reduce transmission. Using the beam-weight optimization utility of the 3D treatment planning system, the s MLC segment weights were then determined to deliver the most uniform dose to 100 reference points that were uniformly distributed throughout the breast. The accuracy of the dose calculation and resultant IMRT delivery was verified with film dosimetry performed on an anthropomorphic phantom. For each patient, the dosimetric uniformity within the breast tissue was evaluated for IMRT and two other treatment techniques. The first technique modeled conventional practice where wedges were derived manually without consideration of inhomogeneity effects (or density correction). A recalculation was performed with density correction to represent the actual dose delivered. In the second technique, the wedges were optimized using the same beam-weight optimization utility as the IMRT plan and included density correction. All dose calculations were based on the pencil-beam superposition algorithm. Results: For the s MLC technique, treatment planning required approximately 60 min. Treatment delivery (including patient setup) required approximately 8–10 min. Film dosimetry measurements performed on an anthropomorphic phantom generally agreed with calculations to within ± 3%. Compared to the wedge techniques, IMRT with s MLC segments resulted in smaller "hot spots" and a lower maximum dose, while maintaining similar coverage of the treatment volume. A median of only 0.1% of the treatment volume received ≥ 110% of the prescribed dose when using IMRT versus 10% with standard wedges. A total of 6–8 segments were required with the majority of the dose delivered via the open segments. The addition of the lung-block segments to IMRT was of significant benefit for patients with a greater proportion of lung parenchyma within the irradiated volume. Since August 1999, 32 patients have been treated in the clinic with the IMRT technique. No patient experienced RTOG grade III or greater acute skin toxicity. Conclusion: The use of intensity modulation with an s MLC technique for tangential breast RT is an efficient and effective method for achieving uniform dose throughout the breast. It is dosimetrically superior to the treatment techniques that employ only wedges. Preliminary findings reveal minimal or no acute skin reactions for patients with various breast sizes.

The reproducibility of organ position using active breathing control (ABC) during liver radiotherapy.

Abstract: Purpose: To evaluate the intrafraction and interfraction reproducibility of liver immobilization using active breathing control (ABC). Methods and Materials: Patients with unresectable intrahepatic tumors who could comfortably hold their breath for at least 20 s were treated with focal liver radiation using ABC for liver immobilization. Fluoroscopy was used to measure any potential motion during ABC breath holds. Preceding each radiotherapy fraction, with the patient setup in the nominal treatment position using ABC, orthogonal radiographs were taken using room-mounted diagnostic X-ray tubes and a digital imager. The radiographs were compared to reference images using a 2D alignment tool. The treatment table was moved to produce acceptable setup, and repeat orthogonal verification images were obtained. The positions of the diaphragm and the liver (assessed by localization of implanted radiopaque intra-arterial microcoils) relative to the skeleton were subsequently analyzed. The intrafraction reproducibility (from repeat radiographs obtained within the time period of one fraction before treatment) and interfraction reproducibility (from comparisons of the first radiograph for each treatment with a reference radiograph) of the diaphragm and the hepatic microcoil positions relative to the skeleton with repeat breath holds using ABC were then measured. Caudal-cranial (CC), anterior-posterior (AP), and medial-lateral (ML) reproducibility of the hepatic microcoils relative to the skeleton were also determined from three-dimensional alignment of repeat CT scans obtained in the treatment position. Results: A total of 262 fractions of radiation were delivered using ABC breath holds in 8 patients. No motion of the diaphragm or hepatic microcoils was observed on fluoroscopy during ABC breath holds. From analyses of 158 sets of positioning radiographs, the average intrafraction CC reproducibility (σ) of the diaphragm and hepatic microcoil position relative to the skeleton using ABC repeat breath holds was 2.5 mm (range 1.8–3.7 mm) and 2.3 mm (range 1.2–3.7 mm) respectively. However, based on 262 sets of positioning radiographs, the average interfraction CC reproducibility (σ) of the diaphragm and hepatic microcoils was 4.4 mm (range 3.0–6.1 mm) and 4.3 mm (range 3.1–5.7 mm), indicating a change of diaphragm and microcoil position relative to the skeleton over the course of treatment with repeat breath holds at the same phase of the respiratory cycle. The average population absolute intrafraction CC offset in diaphragm and microcoil position relative to skeleton was 2.4 mm and 2.1 mm respectively; the average absolute interfraction CC offset was 5.2 mm. Analyses of repeat CT scans demonstrated that the average intrafraction excursion of the hepatic microcoils relative to the skeleton in the CC, AP, and ML directions was 1.9 mm, 0.6 mm, and 0.6 mm respectively and the average interfraction CC, AP, and ML excursion of the hepatic microcoils was 6.6 mm, 3.2 mm, and 3.3 mm respectively. Conclusion: Radiotherapy using ABC for patients with intrahepatic cancer is feasible, with good intrafraction reproducibility of liver position using ABC. However, the interfraction reproducibility of organ position with ABC suggests the need for daily on-line imaging and repositioning if treatment margins smaller than those required for free breathing are a goal.

High rate of detection of unsuspected distant metastases by pet in apparent stage III non-small-cell lung cancer: implications for radical radiation therapy.

Abstract: Purpose: Most radical radiotherapy (RT) candidates with non–small-cell lung cancer (NSCLC) have Stage III disease and ultimately die with distant metastases. We tested the hypothesis that positron emission tomography (PET) using 18-F fluorodeoxyglucose (FDG) would detect more unsuspected metastases in apparent Stage III disease than in Stages I–II. Methods and Materials: Staging FDG-PET was performed for 167 NSCLC patients, with Stage I–III by conventional workup, who were candidates for curative therapy with surgery ( n = 8), radical chemo/RT or RT ( n = 156), or preoperative chemo/RT ( n = 3). Each patient was allocated a conventional "pre-PET stage" and a "post-PET stage" that relied on PET when discordance with conventional staging occurred. Results: Stage distribution pre-PET was n = 39 (Stage I), n = 28 (Stage II), and n = 100 (Stage III). In 32 patients (19%), PET detected distant metastasis, most commonly abdominal with 17 cases (adrenal, n = 7; liver, n = 4; other, n = 6). Other sites included lung ( n = 10) and bone ( n = 6). PET-detected metastasis increased with increasing pre-PET stage from I (7.5%) through II (18%) to III (24%, p = 0.016), and, in particular, was significantly higher in Stage III ( p = 0.039). Biopsy confirmation was not routine, but progression occurred at PET-detected metastatic sites or other metastatic sites in all but 3 of the 32 patients by last review. Conclusion: PET staging is recommended for radical RT candidates with NSCLC. The highest yield of unexpected distant metastases is observed in Stage III.

The potential for sparing of parotids and escalation of biologically effective dose with intensity-modulated radiation treatments of head and neck cancers: a treatment design study.

Abstract: Purpose: Conventional radiotherapy for cancers of the head and neck (HN) can yield acceptable locoregional tumor control rates, but toxicity of many normal tissues limits our ability to escalate dose. Xerostomia represents one of the most common complications. The purpose of this study is to investigate the potential of intensity-modulated radiotherapy (IMRT) to achieve adequate sparing of parotids and to escalate nominal and/or biologically-effective dose to achieve higher tumor control without exceeding normal tissue tolerances. Methods and Materials: An IMRT optimization system, developed at our institution for research and clinical purposes, and coupled to a commercial radiation treatment planning system, has been applied to a number of cases of HN carcinomas. IMRT plans were designed using dose- and dose-volume-based criteria for 4 and 6 MV coplanar but non-collinear beams ranging in number from 5 to 15 placed at equi-angular steps. Detailed analysis of one of the cases is presented, while the results of the other cases are summarized. For the first case, the IMRT plans are compared with the standard 3D conformal radiation treatment (3DCRT) plan actually used to treat the patient, and with each other. The aim of the 3DCRT plan for this particular case was to deliver 73 Gy to the tumor volume in 5 fractions of 2 Gy and 28 fractions of 2.25 Gy/fx; and 46 Gy to the nodes in 2 Gy/fx while maintaining critical normal tissues to below specified tolerances. The IMRT plans were designed to be delivered as a "simultaneous integrated boost" (SIB) using the "sweeping window" technique with a dynamic MLC. The simultaneous integrated boost strategy was chosen, partly for reasons of efficiency in planning and delivery of IMRT treatments, and partly with the assumption that dose distributions in such treatments are more conformal and spare normal tissues to a greater extent than those with sequential boost strategy. Biologically equivalent dose normalized to 2 Gy/fx, termed here as normalized total dose (NTD), for this strategy was calculated using published head and neck fractionation data. Results: IMRT plans were more conformal than the 3DCRT plans. For equivalent coverage of the tumor and the nodes, and for the dose to the spinal cord and the brainstem maintained within tolerance limits, the dose to parotids was greatly reduced. For the detailed example presented, it was shown that the tumor and the nodes in the 3DCRT plan receive NTDs of 78 and 46 Gy, respectively. For the IMRT plan, a nominal dose of 70 Gy could be delivered to the tumor in 28 fractions of 2.5 Gy each, simultaneously with 50.4 Gy to nodes with 1.8 Gy/fx. The two are biologically equivalent to 82 and 46 Gy, respectively, if delivered in 2 Gy/fx. Similar computations were carried out for other cases as well. The quality of IMRT plans was found to improve with increasing number of beams, up to 9 beams. Dose-volume-based criteria led to a modest improvement in IMRT plans and required less trial and error. Conclusion: IMRT has the potential to significantly improve radiotherapy of HN cancers by reducing normal tissue dose and simultaneously allowing escalation of dose. SIB strategy is not only more efficient and yields better dose distributions, but may also be biologically more effective. Dose-volume-based criteria is better than purely dose-based criteria. The quality of plans improves with number of beams, reaching a saturation level for a certain number of beams, which for the plans studied was found to be 9.