Assessing four-dimensional radiotherapy planning and respiratory motion-induced dose difference based on biologically effective uniform dose.

Four-dimensional (4D) radiotherapy is considered as a feasible and ideal solution to accommodate intra-fractional respiratory motion during conformal radiation therapy. With explicit inclusion of the temporal changes in anatomy during the imaging, planning, and delivery of radiotherapy, 4D treatment planning in principle provides better dose conformity. However, the clinical benefits of developing 4D treatment plans in terms of tumor control rate and normal tissue complication probability as compared to other treatment plans based on CT images of a fixed respiratory phase remains mostly unproven. The aim of our study is to comprehensively evaluate 4D treatment planning for nine lung tumor cases with both physical and biological measures using biologically effective uniform dose (D =) together with complication-free tumor control probability, P+. Based on the examined lung cancer patients and PTV margin applied, we found similar but not identical curves of DVH, and slightly different mean doses in tumor (up to 1.5%) and normal tissue in all cases when comparing 4D, P0%, and P50% plans. When it comes to biological evaluations, we did not observe definitively PTV size dependence in P+ among these nine lung cancer patients with various sizes of PTV. Moreover, it is not necessary that 4D plans would have better target coverage or higher P+ as compared to a fixed phase IMRT plan. However, on the contrary to significant deviations in P+ (up to 14.7%) observed if delivering the IMRT plan made at end-inhalation incorrectly at end-exhalation phase, we estimated the overall P+, PB, and PI for 4D composite plans that have accounted for intra-fractional respiratory motion.

Dosimetric quantification of dose fall-off in liver SBRT planning using dual photon energy IMRT.

INTRODUCTION: The purpose of this study was to dosimetrically compare 6 MV, 10 MV and a hybrid of 6 and 10 MV photon beam energies in liver stereotactic body radiotherapy (SBRT) patients using a fixed-field IMRT technique. The objectives of the study were to evaluate dosimetric differences in the target volume and investigate if dose fall-off could be improved with 10MV beam energy. METHODS AND MATERIALS: Sixteen (n=16) liver SBRT patients previously treated using a non-coplanar, fixed-field IMRT technique with 6 MV were replanned using 10 MV and dual photon energy (DE). Plans were generated in Pinnacle3 using a Novalis Tx with HD120 MLC. For each patient, three plans with the same beam geometry were created using 6 MV, 10 MV and DE. For DE plans, the central axis effective depth from each beam was calculated and the values averaged. Beams with an effective depth greater than the average were assigned to 10 MV. All patients were optimized with the same planning objectives and normalized such that 98% of the target received 100% of prescription dose. Metrics used for comparison were the homogeneity index, conformity indices, and dose fall-off parameters at various isodose levels. RESULTS: The three techniques showed comparable PTV conformity and inhomogeneity for all patients-differences in the median values 「0.6%. With regard to dose fall-off, no statistically significant differences were noted among the techniques for R80, R60 and R50; however, 10 MV showed statistical significance in the lowest median values of R40, R30, and R20. Ten MV and DE plans also demonstrated a statistically significant reduction in the total number of monitor units (MU) of 14.9% (p 「0.01) and 12.0% (p 「0.01) as compared to 6 MV, respectively. CONCLUSION: Both dual energy and 10 MV photon beams had similar PTV dosimetric characteristics to 6 MV for liver SBRT but findings show faster dose fall-off for 10 MV and DE plans at the 40%, 30%, and 20% prescription isodose levels.

Potency following high-dose three-dimensional conformal radiotherapy and the impact of prior major urologic surgical procedures in patients treated for prostate cancer.

PURPOSE: To assess the impact of high-dose three-dimensional conformal radiotherapy (3DCRT) on potency in patients treated for clinically localized prostate cancer and to identify factors that might predict the outcome of sexual function following treatment. METHODS AND MATERIALS: One hundred twenty-four consecutive patients treated with 3DCRT for localized prostate cancer at UCSF between 1991-1993 were included in this retrospective analysis. Patient responses were obtained from a mailed questionnaire, telephone interviews, or departmental records. Medial follow-up was 21 months. RESULTS: Sixty patients reported having sexual function prior to 3DCRT, including 47 who were fully potent and 13 who were marginally potent. Of the remaining 64 patients, 45 were impotent, 7 were on hormones, 1 was status-postorchiectomy, and 11 were not evaluable. Following 3DCRT, 37 of 60 patients (62%) retained sexual function sufficient for intercourse. Of those with sexual function before irradiation, 33 of 47 (70%) of patients fully potent and 4 of 13 (31%) of patients marginally potent maintained function sufficient for intercourse (p < 0.01). Potency was retained in 6 of 15 (40%) patients with a history of a major urologic surgical procedure (MUSP) and in 31 of 45 (69%) with no history of a MUSP (p < 0.04). Transurethral resection of the prostate was the MUSP in eight of these patients, with four (50%) maintaining sexual function. CONCLUSIONS: Patients who receive definitive 3DCRT for localized prostate cancer appear to maintain potency similar to patients treated with conventional radiotherapy. However, patients who are marginally potent at presentation or who have a history of a MUSP appear to be at increased risk of impotence following 3DCRT.

Flutamide-induced liver toxicity including fatal hepatic necrosis.

PURPOSE: To describe hepatic injuries in three patients who received flutamide prior to and during radiation treatment to make radiation oncologists aware of the need for careful monitoring of liver function during use of this drug. METHODS AND MATERIALS: The records of three patients who developed abnormal liver function tests while undergoing total androgen suppression (TAS), as well as the literature concerning flutamide toxicity were reviewed and summarized. RESULTS: Three of 34 patients treated with a TAS regimen incorporating flutamide developed significant hepatic abnormalities: elevated transaminases [2] and fatal hepatic necrosis [1]. Following the discontinuation of flutamide, two patients recovered fully. Unfortunately, the third patient's hepatic function continued to deteriorate, which culminated in his death. Transient elevations in serum transaminases, which do not exceed four times the upper limits of normal, are common and apparently without clinical significance. Unfortunately, idiosyncratic serious and/or fatal liver damage can occur. Significant liver toxicity may be obviated by monitoring of liver function tests (LFT) early in the course of flutamide therapy. CONCLUSION: The incidence of hepatic toxicity associated with flutamide may be higher than previously suggested. To prevent the development of serious hepatic dysfunction, all patients receiving flutamide should be monitored clinically for signs and symptoms referable to hepatic injury and with serial LFT. We recommend baseline LFT followed by serial LFT at weeks 2, 4, 6, and 8 from the start of treatment with flutamide. Flutamide should be stopped promptly if significant liver abnormalities are detected.

Adjuvant brachytherapy in the treatment of soft-tissue sarcomas.

For many patients with STS, administering adjuvant radiation treatments in the form of interstitial brachytherapy provides an excellent alternative to a protracted course of EBRT. Ideal patients are those with intermediate- or high-grade tumors amenable to en bloc resection. Attractive features of this approach include an untainted pathologic specimen, expeditious completion of treatment, reduction in wound complications, and improved functional outcome. Brachytherapy can permit definitive reirradiation by tightly localizing the high dose radiation exposure. It is also useful in patients who are known to have or be at high risk of metastatic disease, for whom the rapid completion of local treatment allows systemic therapy to begin quickly. Introduction of HDR techniques has shifted the delivery of brachytherapy from inpatient solitary confinement to an outpatient setting. Early reports using HDR brachytherapy for treatment of adult and pediatric STS are quite encouraging. The clinical equivalence between hyperfractionated HDR schedules and traditional LDR techniques is gaining acceptance.

The radiobiology and physics of brachytherapy.

The principles of radiobiology are the same for both EBRT and brachytherapy. Strict spatial limitation of the delivered dose, a function of the inverse square law, is one reason that brachytherapy is attractive. The biologic rationale of LDR implants is maximization of normal tissue repair to enhance the therapeutic ratio. Fractionated HDR treatment schedules have been formulated that provide good biologic approximation of the well-established LDR practices. The HDR approach improves both patient comfort and radiation safety; also, the brief treatment times can permit geometric improvements by transiently displacing sensitive structures.

Subunity coordinate translation with Fourier transform to achieve efficient and quality three-dimensional medical image interpolation.

A new approach to the interpolation of three-dimensional (3D) medical images is presented. Instead of going through the conventional interpolation scheme where the continuous function is first reconstructed from the discrete data set and then resampled, the interpolation is achieved with a subunity coordinate translation technique. The original image is first transformed into the spatial-frequency domain. The phase of the transform is then modified with n-1 linear phase terms in the axial direction to achieve n-1 subunity coordinate translations with a distance 1/n, where n is an interpolation ratio, following the phase shift theorem of Fourier transformation. All the translated images after inverse Fourier transformation are then interspersed in turn into the original image. Since windowing plays an important role in the process, different window functions have been studied and a proper recommendation is provided. The interpolation quality produced with the present method is as good as that with the sampling (sinc) function, while the efficiency, thanks to the fast Fourier transformation, is very much improved. The approach has been validated with both computed tomography (CT) and magnetic resonance (MR) images. The interpolations of 3D CT and MR images are demonstrated.

Reducing scatter radiation to the contralateral breast with a mobile, conformal shield during breast cancer radiotherapy.

During a standard course of breast radiotherapy, the contralateral breast generally receives approximately 2.5 to 6.0 Gy of scattered radiation. Although most studies have not found an overall increase in metachronous contralateral breast cancers in patients undergoing radiotherapy, a cohort of younger women may be genetically more susceptible to radiation-induced breast cancers and may thus be adversely affected by the scattered radiation. We are attempting to develop a simple, convenient, effective mechanism for minimizing the scattered radiation to the contralateral breast during the process of clinical breast radiotherapy. We therefore designed a conformal, platform-based breast shield consisting of 2.5 cm of molded lead in a mobile counterweighted polystyrene casing. This shield was intended to serve as a physical barrier to prevent both low and high energy scattered photons from the medial and lateral tangential fields. We conducted a prospective trial of 20 women, each woman serving as her own control. Each woman received breast radiotherapy with and without shield, and an array of thermoluminescent dosimeters was positioned across the contralateral breast to evaluate the in vivo dosimetry and the impact of the breast shield on surface absorption of scattered radiation. We found that the use of the breast shield reduced the median dose of scattered radiation by approximately 60% (p < 0.0001). This represented a median dose reduction of approximately 300 cGy at the nipple. The shield was easily positioned and added < 1 min to daily setup time. We conclude that the use of this sort of surface barrier shielding technique was feasible, effective, and practical for clinical use. The degree of scatter reduction accomplished through the use of this breast shield may be biologically significant, especially for those patients with biologic or epidemiologic risk factors that may predispose them to the development of radiogenic breast cancers.

Treatment of prognosis of primary breast lymphoma: a review of 13 cases.

Primary non-Hodgkin's lymphoma (NHL) of the breast is a rare entity that does not have a well-defined treatment strategy. At presentation, most patients are clinically thought to have a primary breast carcinoma, and the diagnosis of lymphoma is made at biopsy. Once the diagnosis of lymphoma is made, patients are treated with some combination of chemotherapy, radiation therapy, and surgery. We review The Cleveland Clinic Foundation experience with primary breast lymphoma. Between 1980 and 1996, 17 patients with primary breast lymphoma were seen at The Cleveland Clinic Foundation, and 13 had follow-up information available. All patients underwent a staging workup including computed tomography (CT) scan of the chest, abdomen, and pelvis, as well as bilateral bone marrow biopsies; all patients staged IE (breast involvement only) or IIE (limited to the breast and ipsilateral axilla) were included. We did not include patients with more extensive supradiaphragmatic nodal involvement who were stage IIE. Patients received some combination of surgery, radiation, and chemotherapy. The median follow-up was 34 months, with a range of 7 to 138 months. There was an equal incidence of right- versus left-sided lesions. Five patients survived at least 5 years from the time of diagnosis. Long-term survival in patients with primary NHL of the breast is possible. We recommend treating patients with aggressive NHL of the breast with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, followed by involved field radiation and treating those patients with indolent lymphoma with involved field radiation alone.

Recent advances in the treatment of skull base tumors using radiation.

The evolution of technology has led to dramatic advances in the ability to treat tumors of the skull base, and the future of these devices seems bright. Only with time, however, will we be certain of their true role in the management of tumors of the skull base.

Characteristics of natural scenes related to the fractal dimension.

Many objects in images of natural scenes are so complex and erratic, that describing them by the familiar models of classical geometry is inadequate. In this paper, we exploit the power of fractal geometry to generate global characteristics of natural scenes. In particular we are concerned with the following two questions: 1) Can we develop a measure which can distinguish between different global backgrounds (e.g., mountains and trees)? and 2) Can we develop a measure that is sensitive to change in distance (or scale)? We present a model based on fractional Brownian motion which will allow us to recover two characteristics related to the fractal dimension from silhouettes. The first characteristic is an estimate of the fractal dimension based on a least squares linear fit. We show that this feature is stable under a variety of real image conditions and use it to distinguish silhouettes of trees from silhouettes of mountains. Next we introduce a new theoretical concept called the average Holder constant and relate it mathematically to the fractal dimension. It is shown that this measurement is sensitive to scale in a predictable manner, and hence, provides the potential for use as a range indicator. Corroborating experimental results are presented.

Tradeoffs for assuming rigid target motion in Mlc-based real time target tracking radiotherapy: a dosimetric and radiobiological analysis.

We report on our assessment of two types of real time target tracking modalities for lung cancer radiotherapy namely (1) single phase propagation (SPP) where motion compensation assumes a rigid target and (2) multi-phase propagation (MPP) where motion compensation considers a deformable target. In a retrospective study involving 4DCT volumes from six (n=6) previously treated lung cancer patients, four-dimensional treatment plans representative of the delivery scenarios were generated per modality and the corresponding dose distributions were derived. The modalities were then evaluated (a) Dosimetrically for target coverage adequacy and normal tissue sparing by computing the mean GTV dose, relative conformity gradient index (CGI), mean lung dose (MLD) and lung V(2)0; (b) Radiobiologically by calculating the biological effective uniform dose (D) for the target and organs at risk (OAR) and the complication free tumor control probability (P(+)). As a reference for the comparative study, we included a 4D Static modality, which was a conventional approach to account for organ motion and involved the use of individualized motion margins. With reference to the 4D Static modality, the average percent decrease in lung V(20) and MLD were respectively (13.1-/+6.9) % and (11.4-/+ 5.6)% for the MPP modality, whereas for the SPP modality they were (9.4-/+6.2) % and (7.2-/+4.7) %. On the other hand, the CGI was observed to improve by 15.3-/+13.2 and 9.6-/+10.0 points for the MPP and SPP modalities, respectively while the mean GTV dose agreed to better than 3% difference across all the modalities. A similar trend was observed in the radiobiological analysis where the P(+) improved on average by (6.7-/+4.9) % and (4.1-/+3.6) % for the MPP and SPP modalities, respectively while the D computed for the OAR decreased on average by (6.2-/+3.6) % and (3.8-/+3.5) % for the MPP and SPP tracking modalities, respectively. The D calculated for the GTV for all the modalities was in agreement to better than 2% difference. In general, respiratory motion induces target displacement and deformation and therefore the complex MPP real time target tracking modality is the preferred. On the other hand, the SPP approach affords simplicity in implementation at the expense of failing to account for target deformation. Radiobiological and dosimetric analyses enabled us to investigate the consequences of failing to compensate for deformation and assess the impact if any on the clinical outcome. While it is not possible to draw any general conclusions on a small patient cohort, our study suggests that the two tracking modalities can lead to comparable clinical outcomes and as expected are advantageous when compared with the static conventional modality.

Hypercalcemia caused by metastatic adamantinoma: response to radiotherapy.

Purpose. To describe successful palliation of a patient with metastatic adamantinoma presenting with lung metastases and hypercalcemia resulting from a parathormone-like substance released from the tumor.Methods and materials. The records of a patient with a history of a tibial adamantinoma who presented with symptoms of hypercalcemia 20 years after the original surgery, as well as the literature concerning hypercalcemia and adamantinoma were reviewed and summarized.Results. After thorough review of the literature we found no prior reports of radiation being used for palliation of hypercalcemia associated with metastatic adamantinoma.We report rapid improvement in symptoms and normalization of serum calcium levels following a course of radiation therapy. The patient remains asymptomatic 15 months following radiotherapy despite a gradual return of elevated serum calcium levels.Discussion. Radiation therapy should be considered as a palliative option for patients who are not surgical candidates presenting with medically refractory hypercalcemia.

Phase II trial of liposomal doxorubicin (Doxil) in advanced soft tissue sarcomas.

PURPOSE: To assess the objective response rate, toxicity experienced, progression-free survival, and overall survival of patients with previously untreated advanced soft tissue sarcomas treated with a liposomal doxorubicin formulation (Doxil). METHODS: Patients with metastatic or recurrent soft tissue sarcoma who had received no prior chemotherapy for advanced disease were treated with liposomal doxorubicin (Doxil) according to a two stage accrual design. Doxil was administered at 50 mg/m2 every 4 weeks. A total of 15 patients were treated and are evaluable for response and toxicity. RESULTS: The male/female ratio was 7/8, the median age was 60 years (34-75) and the ECOG performance status was 0-1 in >90% of patients. Leiomyosarcoma (7/15) and malignant fibrous histiocytoma (2/15) were the most common histologic diagnoses. No objective responses were observed in the 15 evaluable patients. No lethal toxicity occurred. Grade 3-4 leukopenia or neutropenia were reported in 3/15 (20%) patients. Grade 3 mucositis or hand-foot syndrome occurred in 2/15 (13%) and 1/15 (7%) patients respectively and seemed more severe in older patients. The median time to progression was 1.9 months (range 0.9-6.2). Twelve patients have now died. The Kaplan-Meier estimate of median overall survival is 12.3 months. As called for in the study design, accrual was terminated because no responses were obtained in the first 15 patients. CONCLUSION: Though well-tolerated, Doxil given according to this dose and schedule to patients with advanced soft tissue sarcoma had no significant therapeutic activity. A correlation between older age and skin/mucosal toxicity of Doxil is suggested in this study but needs confirmation. Future investigations of Doxil in soft tissue sarcomas should use a different schedule and dose.

Successful conversion from a linear accelerator-based program to a Gamma Knife radiosurgery program: the Cleveland Clinic experience.

From August 1989 to January 1997, 307 treatments in 293 patients were performed with a linear accelerator-based (LINAC) stereotactic radiosurgery system. Because of the program s success, the need for a dedicated radiosurgery unit in Ohio and the desire to treat functional disorders, the Cleveland Clinic Health System (CCHS) obtained the first Gamma Knife in the state of Ohio. Based on the previous volume of patients for radiosurgery, it was estimated that 75-100 patients would be treated during the first year of operation. However, during the first calendar year, 214 treatments were performed on 205 patients, which far exceeded expectations. The success of the CCHS Gamma Knife Center can be attributed to an increase in a number of factors. These included marketing efforts, patient awareness, increased use for functional disorders, physician understanding of radiosurgery, use by qualified nonaffiliated radiation oncologists and neurosurgeons, and outpatient delivery (95% with the Gamma Knife vs <5% with the LINAC). With proper planning, education, and awareness, the opening of a Gamma Knife Center can greatly increase the volume of radiosurgery performed when compared with a LINAC-based program.