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Purpose To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). Methods and Materials We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS. Results Irradiation with doses higher than approximately 10 Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated. Conclusions In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcomes. However, current practice when delivering intrapleural PDT uses a point source to deliver light that is monitored by seven isotropic detectors placed within the pleural cavity to assess its uniformity. We have developed a real-time infrared (IR) tracking camera to follow the movement of the light point source and the surface contour of the treatment area. The calculated light fluence rates were matched with isotropic detectors using a two-correction factor method and an empirical model that includes both direct and scattered light components. Our clinical trial demonstrated that we can successfully implement the IR navigation system in 75% (15/20) of the patients. Data were successfully analyzed in 80% (12/15) patients because detector locations were not available for three patients. We conclude that it is feasible to use an IR camera-based system to track the motion of the light source during PDT and demonstrate its use to quantify the uniformity of light distribution, which deviated by a standard deviation of 18% from the prescribed light dose. The navigation system will fail when insufficient percentage of light source positions is obtained (

Background/objectives Oligometastatic sarcoma pulmonary metastases (PM's) are traditionally treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) is an effective, safe alternative to surgery that can achieve excellent local control (LC) with a favorable toxicity profile. Methods Patients treated with SBRT for sarcoma PM's from 2011 to 2016 at Massachusetts General Hospital and the University of Pennsylvania were included. Median dose was 50 Gy. Patients underwent computed tomography (CT) or positron emission tomography/CT Q3 months post-SBRT. Results 44 patients with 56 separate PM's were treated with SBRT. Median age was 59 (range 19-82). 82% received prior chemotherapy, 66% had prior pulmonary resections (range, 1-5 resections), and 32% received prior thoracic radiotherapy. Median lesion size was 2.0 cm (range, 0.5-8.1 cm). Median follow-up was 16 months and 25 months for patients alive at last follow-up. Overall survival at 12 and 24 months was 74% (95% confidence interval [CI], 67%-81%) and 46% (95% CI, 38%-55%). LC at 12 and 24 months was 96% (95% CI, 93%-98%) and 90% (95% CI, 84%-96%). LC and overall survival did not differ based on age, gender, histology, fractionation, lesion location, or size (P > .05). Three developed Common Terminology Criteria for Adverse Events version 4 grade-2 chest-wall toxicities; one had grade-2 pneumonitis. Conclusions In the first multi-institutional series on SBRT for sarcoma PM's, SBRT has excellent LC and is well-tolerated. SBRT should be considered as an alternative/complement to resection.

Pleural photodynamic therapy (PDT) is performed intraoperatively for the treatment of microscopic disease in patients with malignant pleural mesothelioma. Accurate delivery of light dose is critical to PDT efficiency. As a standard of care, light fluence is delivered to the prescribed fluence using eight isotropic detectors in pre-determined discrete locations inside the pleural cavity that is filled with a dilute Intralipid solution. An optical infrared (IR) navigation system was used to monitor reflective passive markers on a modified and improved treatment delivery wand to track the position of the light source within the treatment cavity during light delivery. This information was used to calculate the light dose, incorporating a constant scattered light dose and using a dual correction method. Calculation methods were extensively compared for eight detector locations and seven patient case studies. The light fluence uniformity was also quantified by representing the unraveled three-dimensional geometry on a two-dimensional plane. Calculated light fluence at the end of treatment delivery was compared to measured values from isotropic detectors. Using a constant scattered dose for all detector locations along with a dual correction method, the difference between calculated and measured values for each detector was within 15%. Primary light dose alone does not fully account for the light delivered inside the cavity. This is useful in determining the light dose delivered to areas of the pleural cavity between detector locations, and can serve to improve treatment delivery with implementation in real-time in the surgical setting. We concluded that the standard deviation of light fluence uniformity for this method of pleural PDT is 10%.

Purpose The purpose of this study was to evaluate dose prescription and recording compliance to international standard (International Commission on Radiation Units & Measurements [ICRU]-83) in patients treated with intensity modulated radiation therapy (IMRT) among academic institutions. Methods and materials Ten institutions participated in this study to collect IMRT data to evaluate compliance to ICRU-83. Under institutional review board clearance, data from 5094 patients—including treatment site, technique, planner, physician, prescribed dose, target volume, monitor units, planning system, and dose calculation algorithm—were collected anonymously. The dose-volume histogram of each patient, as well as dose points, doses delivered to 100% (D100), 98% (D98), 95% (D95), 50% (D50), and 2% (D2), of sites was collected and sent to a central location for analysis. Homogeneity index (HI) as a measure of the steepness of target and is a measure of the shape of the dose-volume histogram was calculated for every patient and analyzed. Results In general, ICRU recommendations for naming the target, reporting dose prescription, and achieving desired levels of dose to target were relatively poor. The nomenclature for the target in the dose prescription had large variations, having every permutation of name and number contrary to ICRU recommendations. There was statistically significant variability in D95, D50, and HI among institutions, tumor site, and technique with P values Conclusions Nearly 95% of patient treatments deviated from the ICRU-83 recommended D50 prescription dose delivery. This variability is significant (P

In this rapidly evolving time of precision medicine and scientifically based cancer care, how radiation oncology became a strong research-based scientific discipline in the United States after its separation from diagnostic radiology might be lost. The importance of generational mentorship, “family trees,” and interpersonal relationships can be difficult or impossible to trace absent personal narrative recollections of those involved. Henry S. Kaplan is a central figure and the focal point for 3 generations of research-based academic department chairs. This report establishes a first draft of a living record of the radiation oncology history of the Kaplan legacy to serve as an example of how knowledge networks grow and flourish and as an impetus for others to trace the legacy of other radiation oncology academic “trees.”

Background/Objectives Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) can be an alternative to surgery that can achieve high rates of local control (LC) with limited toxicity. Methods Thirty consecutive sarcoma patients received SBRT to 39 PM's from 2011 to 2015 at two university hospitals to a median dose of 50 Gy in 4–5 fractions with CyberKnife or linear accelerator. Patients underwent CT or PET/CT scans q3 months after SBRT. Results 77% received prior chemotherapy, 70% had 1–3 prior pulmonary resections, and 26% received prior thoracic radiotherapy. Median lesion size was 2.4 cm (range 0.5–8.1 cm). Median follow-up was 16 and 23 months for patients alive at last follow-up. At 12 and 24 months, LC was 94% and 86%, and OS was 76% and 43%. LC and OS did not differ by SBRT technique, fractionation regimen, lesion location, histology, or size (all P > 0.05). Three developed grade 2 chest-wall toxicity with no other grade ≥2 toxicities. Conclusions This is the largest series on SBRT for sarcoma PM's and demonstrates that SBRT is well-tolerated with excellent LC across tumor locations and sizes. SBRT should be considered in these patients, and prospective studies are warranted. J. Surg. Oncol. 2016;114:65–69. © 2016 Wiley Periodicals, Inc.

Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that arises in the mediastinum from B-cells of thymic origin. Optimal management of patients with PMBL remains controversial. The present study evaluates outcomes of 27 PMBL patients treated with R-CHOP with or without radiation therapy (RT). It investigates the role of both interim and posttreatment fluorodeoxyglucose-positron emission tomography (FDG-PET) as prognostic markers of outcome. Additionally, it assesses postprogression therapies in the six patients who had progressive disease. At a median follow-up of 41.5 months (range: 6.1–147.2 months), OS was 95.5% (95% CI = 71.9–99.4) and progression-free survival (PFS) was 70.4% (95% CI = 49.4–83.9) for the entire cohort. The negative predictive values of interim and posttreatment FDG-PET scans were both 100%. Patients who failed initial therapy and were treated with salvage regimens and autologous stem cell transplantation (ASCT) all achieved and maintained CR. PMBL patients can achieve excellent outcomes with minimal toxicities when treated with R-CHOP with or without RT. Negative interim and negative posttreatment FDG-PET results identified PMBL patients who achieve long-term remission. However, the significance of both positive interim and positive posttreatment FDG-PET results needs to be better defined. Those who failed initial therapy were successfully treated with salvage regimens and ASCT.

We evaluated whether staging with positron emission tomography (PET) or treatment with rituximab after involved-field radiation therapy (IFRT) results in an improved progression-free survival (PFS) for early-stage indolent non-Hodgkin lymphoma (NHL).We identified 42 patients with stage I/II low-grade NHL treated with initial IFRT at our institution between 1992 and 2009, who had been staged with computed tomography (CT) or PET. A retrospective analysis was performed to evaluate PFS according to staging by CT or PET, and by receipt of rituximab after IFRT.Overall PFS was 68% and 61% at 5 and 10 years, respectively. There was no significant difference in PFS whether patients were staged by CT (n=17) or by PET (n=25), with 5-year PFS rates of 76% and 60%, respectively. Eleven patients received 4 weekly doses of rituximab after IFRT, with no improvement in 5-year PFS: 46% for rituximab-treated patients versus 72% for patients who were not given rituximab. However, more patients who were given rituximab were stage II.Patients with limited stage indolent NHL staged with either CT or PET and treated with IFRT have favorable PFS compared with historical controls. The administration of 4 weekly doses of rituximab after IFRT did not improve PFS in these patients. The use of rituximab in this setting should be evaluated in a randomized prospective study.

Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), are rapidly becoming accepted practice for the radiotherapy of certain tumors. Typically SRS and SBRT involve the delivery of one or a few large dose fractions of 8 to 30 Gy per fraction: a major paradigm shift from radiotherapy practice over the past 90 years when, with relatively large amounts of normal tissues receiving high doses, the goal was to maximize tumor response for an acceptable level of normal tissue injury. The development of SRS and SBRT have come about because of technological advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumors with reduced margins and high gradients outside of the target, thereby minimizing doses to surrounding normal tissues. Because the results obtained with SRS and SBRT have been impressive they have raised the question of whether classic radiobiological modeling, and the linear-quadratic (LQ) model, are appropriate for large doses per fraction. In addition to objections to the LQ model, the possibility of additional biological effects resulting from endothelial cell damage and/or enhanced tumor immunity, have been raised to account for the success of SRS and SBRT. In this review, we conclude that the available preclinical and clinical data do not support a need to change the LQ model nor invoke phenomena over and above the classic 5 R’s of radiobiology/radiotherapy with the likely exception that for some tumors high doses of irradiation may produce enhanced antitumor immunity. Thus, we suggest that for most tumors the standard radiobiology concepts of the 5 R’s are sufficient to explain the clinical data, and the excellent results obtained from clinical studies are the result of the much larger biologically effective doses (BEDs) that are delivered with SRS and SBRT.

Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) and computed tomography (CT) has essentially replaced CT alone for staging of lymphomas. FDG-PET has been incorporated into the revised response criteria, but response adapted strategies are still being evaluated. The role of FDG-PET/CT in radiation treatment planning is still being developed. It is unclear how to use FDG-PET/CT to determine whether to give consolidative radiation, where to radiate, and what dose. Ongoing efforts are underway to use early interim FDG-PET/CT to limit therapy in good prognosis patients. A multidisciplinary team is important in the management of patients with lymphoma, leading to individualized treatment plans and better outcomes.

Despite descriptions of light-mediated therapy in ancient texts and the discovery of photodynamic therapy (PDT) in the early 1900s, the landmark article in 1978 in Cancer Research by Dougherty and his colleagues at the Roswell Park Cancer Institute remains rightly viewed as the starting point for clinical PDT in modern medicine. As a large clinical series that explored many of the factors now viewed as critical determinates of PDT dose, efficacy, and toxicity, that study showed remarkable foresight, yet it also served to raise as many questions as it answered. Since its publication, PDT has been increasingly utilized in clinical practice for the treatment of both benign and malignant conditions, and many of their questions have yielded new technologies and areas of investigation, thus remaining highly relevant nearly 40 years after their initial asking. Moreover, continuing advances in our ability to measure physical properties such as absorbed light dose, photosensitizer concentration, tissue oxygen concentration, and singlet oxygen production in real-time may allow for adaptive modification of light delivery during PDT on a fine scale to optimize treatment response. Finally, combining molecularly targeted drugs and novel photosensitizers has the potential to improve further the therapeutic index and extend the spectrum of clinical PDT far beyond what was imagined when that sentinel manuscript was written. Cancer Res; 76(9); 2497–9. ©2016 AACR. See related article by Dougherty et al., Cancer Res 1978;38:2628–35. Visit the Cancer Research 75th Anniversary timeline.

Results of the Hodgkin's Disease.6 trial are critically examined in light of the advances in radiation therapy techniques that have occurred since it was initiated. The ultimate findings of the HD.6 trial do not close the case for combined-modality treatment of limited-stage Hodgkin's disease.

Background Radical pleurectomy (RP) for mesothelioma is often considered either technically unfeasible or an operation limited to patients who would not tolerate a pneumonectomy. The purpose of this study was to review our experience using RP and intraoperative photodynamic therapy (PDT) for mesothelioma. Methods Thirty-eight patients (42–81 years) underwent RP-PDT. Thirty five of 38 (92%) patients also received systemic therapy. Standard statistical techniques were used for analysis. Results Thirty seven of 38 (97%) patients had stage III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual 7 th Edition, 2010]) and 7/38 (18%) patients had nonepithelial subtypes. Macroscopic complete resection was achieved in 37/38 (97%) patients. There was 1 postoperative mortality (stroke). At a median follow-up of 34.4 months, the median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18%) patients with nonepithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1, and 4.8 months, respectively. The median survival and PFS for the 20/31 (64%) patients with N2 epithelial disease were 31.7 and 15.1 months, respectively. Conclusions It was possible to achieve a macroscopic complete resection using lung-sparing surgery in 97% of these patients with stage III/IV disease. The survival we observed with this approach was unusually long for the patients with the epithelial subtype but, interestingly, the PFS was not. The reason for this prolonged survival despite recurrence is not clear but is potentially related to preservation of the lung or some PDT-induced effect, or both. We conclude that the results of this lung-sparing approach are safe, encouraging, and warrant further investigation.

Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) can be an alternative to surgery that can achieve high rates of local control (LC) with limited toxicity.Thirty consecutive sarcoma patients received SBRT to 39 PM's from 2011 to 2015 at two university hospitals to a median dose of 50 Gy in 4-5 fractions with CyberKnife or linear accelerator. Patients underwent CT or PET/CT scans q3 months after SBRT.77% received prior chemotherapy, 70% had 1-3 prior pulmonary resections, and 26% received prior thoracic radiotherapy. Median lesion size was 2.4 cm (range 0.5-8.1 cm). Median follow-up was 16 and 23 months for patients alive at last follow-up. At 12 and 24 months, LC was 94% and 86%, and OS was 76% and 43%. LC and OS did not differ by SBRT technique, fractionation regimen, lesion location, histology, or size (all P 0.05). Three developed grade 2 chest-wall toxicity with no other grade ≥2 toxicities.This is the largest series on SBRT for sarcoma PM's and demonstrates that SBRT is well-tolerated with excellent LC across tumor locations and sizes. SBRT should be considered in these patients, and prospective studies are warranted. J. Surg. Oncol. 2016;114:65-69. © 2016 Wiley Periodicals, Inc.

Background Photodynamic therapy (PDT) is a light-based cancer treatment that acts to a depth of several millimeters into tissue. This study reviewed the results of patients who underwent a macroscopic complete resection, by two different surgical techniques, and intraoperative PDT as a treatment for malignant pleural mesothelioma. Methods From 2004 to 2008, 28 patients with malignant pleural mesothelioma underwent macroscopic complete resection, 14 by modified extrapleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intraoperative PDT. The surgical technique evolved over this period such that 13 of the last 16 patients underwent lung-sparing procedures, even in the setting of large-bulk tumors. Results Demographics in the MEPP and RP cohorts were similar in age, sex, stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was present in 12 of 14 patients (86%), with 50% or more with +N2 disease. The median overall survival for the MEPP group was 8.4 months, but has not yet been reached for the RP group at a median follow-up of 2.1 years. Conclusions In addition to the inherent advantages of sparing the lung, RP plus PDT yielded a superior overall survival than MEPP plus PDT in this series. The overall survival for the RP plus PDT group was, for unclear reasons, superior to results reported in many surgical series, especially for a cohort with such advanced disease. Given these results, we believe RP plus PDT is a reasonable option for appropriate patients pursuing a surgical treatment for malignant pleural mesothelioma and that this procedure can serve as the backbone of surgically based multimodal treatments.

TBI has been used widely in the setting of BMT over the past 3 decades. Early research demonstrated feasibility and efficacy in the myeloablative setting, in preparation first for allogenic BMT and later for autologous stem cell rescue. As experience with TBI increased, its dual roles of myeloablation and immunosuppression came to be recognized. Toxicity associated with myeloablative TBI remains significant, and this treatment is generally reserved for younger patients with excellent performance status. Reduced intensity conditioning regimens may be useful to provide immunosuppression for patients who are not candidates for myeloablative treatment. Efforts to reduce toxicity through protection of normal tissue using methods of normal tissue blocking and use of TLI, rather than TBI, continue. In the future, modalities such as helical tomotherapy, proton radiotherapy and radioimmunotherapy, may have roles in delivery of radiation to the BM and lymphoid structures with reduced normal tissue toxicity. With further investigation, these efforts may expand the therapeutic ratio associated with TBI, allowing safer delivery to a broader range of patients.

Background Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT. Methods We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy. Results Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT. Conclusions Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients.

The authors look back at the five decades of radiation oncology and consider how one's choices and decisions influence how a career is pursued and how a professional life is lived., Accomplishments and contributions in a career in radiation oncology, and in medicine in general, involve individual choices that impact the direction of a specialty, decisions in patient care, consequences of treatment outcome, and personal satisfaction. Issues in radiation oncology include: the development and implementation of new radiation treatment technology; the use of multimodality and biologically based therapies; the role of nonradiation “energy” technologies, often by other medical specialties, including the need for quality assurance in treatment and data reporting; and the type of evidence, including appropriate study design, analysis, and rigorous long-term follow-up, that is sought before widespread implementation of a new treatment. Personal choices must weigh: the pressure from institutions—practices, departments, universities, and hospitals; the need to serve society and the underserved; the balance between individual reward and a greater mission; and the critical role of personal values and integrity, often requiring difficult and “life-defining” decisions. The impact that each of us makes in a career is perhaps more a result of character than of the specific details enumerated on one's curriculum vitae. The individual tapestry weaved by choosing the more or less traveled paths during a career results in many pathways that would be called success; however, the one path for which there is no good alternative is that of living and acting with integrity.

Results Of the 803 patients, 12% were treated for brain cancer, 26% for head and neck cancer, and 62% for prostate cancer. The recorded dose variability from prescription was widespread for the minimum, maximum, and isocenter doses. A total of 46% of the patients received a maximum dose that was more than 10% higher than the prescribed dose, and 63% of the patients received a dose that was more than 10% lower than the prescribed dose. At all five institutions, the prostate cancer cases had the smallest dosimetric variation and the head and neck cancer cases had the largest variation. The median dose to the target varied from the prescribed dose by ±2% in 68% of the patients, by ±5% in 88% of the patients, and by ±10% in 96% of the patients. The recorded isocenter dose varied from prescription for all disease sites and treatment planning systems. Conclusions Substantial variation in the prescribed and delivered doses exists among medical institutions, raising concerns about the validity of comparing clinical outcomes for IMRT. The isocenter dose in IMRT is simply a point dose and often does not reflect the prescription dose that is specified by a selected isodose line encompassing the target volume. This study suggests the need for national and/or international guidelines for dose prescription, planning, and reporting for a meaningful clinical trial in IMRT. J Natl Cancer Inst 2008;100: 300 – 307 An improvement in radiation therapy outcomes could be achieved by periodic comparisons of clinical practices through outcome evaluations from clinical trials and studies. For a multicenter study, a meaningful comparison of clinical outcomes in response to radiation treatment requires a standardized process for dose specifi cation. Treatment outcome can be interpreted meaningfully only with accurate knowledge of the reference dose and the dose distribution. National guidelines for clinical reference dosimetry, such as those put forth by Task Groups 21 and 51 of the Radiation Therapy Committee of the American Association of Physicists in Medicine ( 1 , 2 ), recommend that the reference dose (machine output) should not vary by more than ±2% among centers. For patient treatment, the combined dosimetric uncertainty in the target volume (which includes differences in patient setup and

The optical properties (absorption [mu(a)], transport scattering [mu('s)] and effective attenuation [mu(eff)] coefficients) of normal canine prostate were measured in vivo using interstitial isotropic detectors. Measurements were made at 732 nm before, during and after motexafin lutetium (MLu)-mediated photodynamic therapy (PDT). They were derived by applying the diffusion theory to the in vivo peak fluence rates measured at several distances (3, 6, 9, 12 and 15 mm) from the central axis of a 2.5 cm cylindrical diffusing fiber (CDF). Mu(a) and mu('s) varied between 0.03-0.58 and 1.0-20 cm(-1), respectively. Mu(a) was proportional to the concentration of MLu.Mu(eff) varied between 0.33 and 4.9 cm(-1) (mean 1.3 +/- 1.1 cm(-1)), corresponding to an optical penetration depth (8 = 1/(mu(eff)) of 0.5-3 cm (mean 1.3 +/- 0.8 cm). The mean light fluence rate at 0.5 cm from the CDF was 126 +/- 48 mW/cm2 (N = 22) when the total power from the fiber was 375 mW (150 mW/cm). This study showed significant inter- and intraprostatic differences in the optical properties, suggesting that a real-time dosimetry measurement and feedback system for monitoring light fluences during treatment should be advocated for future PDT studies. However, no significant changes were observed before, during and after PDT within a single treatment site.

High-dose melphalan with autologous stem cell support improves survival as part of initial therapy for myeloma. Previous studies of pre-transplant induction regimens have compared paraprotein response rates but not long-term outcomes after transplant. We reviewed the records of all patients with multiple myeloma who received an autologous stem cell transplant at the University of Pennsylvania Medical Center. We compared outcomes for 69 patients who received high-dose melphalan conditioning after January 1, 2003 as part of initial therapy for myeloma, including 41 patients who received anthracycline-based induction (VAD or DVD) and 28 patients who received thalidomide and dexamethasone induction. Baseline characteristics in these two groups were not different, though potentially clinically important differences were apparent in assignment to post-transplant consolidation and maintenance therapy. Despite similar response rates during induction therapy, thalidomide and dexamethasone induction was associated with better progression-free survival (hazard ratio 0.18, P = 0.011) after transplant. This effect persisted in multivariable regression models including baseline characteristics and post-transplant treatment. Overall survival was not different between the two groups. These results suggest that the use of thalidomide during induction therapy may lead to improved long-term outcomes after transplant. Future trials comparing induction therapies should examine progression-free and overall survival after transplant to confirm this benefit.

An isotropic detector-based system was compared with a flat photodiode-based system in patients undergoing pleural photodynamic therapy. Isotropic and flat detectors were placed side by side in the chest cavity, for simultaneous in vivo dosimetry at surface locations for twelve patients. The treatment used 630nm laser to a total light irradiance of 30 J/cm2 (measured with the flat photodiodes) with photofrin® IV as the photosensitizer. Since the flat detectors were calibrated at 532nm, wavelength correction factors (WCF) were used to convert the calibration to 630nm (WCF between 0.542 and 0.703). The mean ratio between isotropic and flat detectors for all sites was linear to the accumulated fluence and was 3.4±0.6 or 2.1±0.4, with or without the wavelength correction for the flat detectors, respectively. The μeff of the tissues was estimated to vary between 0.5 to 4.3 cm−1 for four sites (Apex, Posterior Sulcus, Anterior Chest Wall, and Posterior Mediastinum) assuming μs′ = 7 cm−1. Insufficient information was available to estimate μeff directly for three other sites (Anterior Sulcus, Posterior Chest Wall, and Pericardium) primarily due to limited sample size, although one may assume the optical penetration in all sites to vary in the same range (0.5 to 4.3 cm−1).

Isotropic detectors with spherical scattering tips are commonly used for in-vivo dosimetry of light fluence rate during photodynamic therapy (PDT). These detectors are typically calibrated in-air. It has been well established that the response of an isotropic detector is a function of the refractive index (n) of the surrounding medium when it is surrounded by an infinite medium of uniform n. However, there are few, if any, studies of the isotropic detector response when the detector is placed in a secondary medium, such as air, before it is placed inside the infinite uniform medium. This condition often arises when one places the isotropic detector inside an air-filled catheter which is then inserted into a turbid medium, such as tissue. We have performed theoretical and experimental studies to determine the correction factors in water (n = 1.33), which has a refractive index similar to that of tissue (n = 1.4). We found that the resulting correction factor is almost the same (within 20%) as the correction factor for the outermost medium (the water) rather than the immediate medium surrounding the isotropic detector (air). The detector correction factor is also a function of the index of refraction of the probe material. For a 1-mm diameter probe from CardioFocus, the detector correction factor varied from 1 (in air) to 1.09 (at air-water interface) to 1.49 (completely submerged in water). At the air-water interface the spherical bulb of the isotropic detector is placed half in air and half in water. For a 0.5-mm diameter probe from the same company, it varied from 1 (in air) to 1.32 (at air-water interface) to 1.87 (in water). For a 0.3-mm diameter probe from the same company, it varied from 1 (in air) to 1.32 (at air-water interface) to 1.71 (in water). We have also found that the detector response changes by less than 10% when the detector position is varied from touching the catheter wall closest to the light source, to not touching, to touching the catheter wall farthest from the light source. The calibration factors between individual isotropic detectors of the same type varied within 5% for all detector types. Thus mean correction factor can be used for each individual isotropic detector of the same type.

Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcome. However, common practice uses a point source to deliver light to the pleural cavity with the light uniformity monitored by 7 detectors placed within the pleural cavity. To improve the uniformity of light fluence rate distribution, we have used a real-time infrared (IR) tracking camera to track the movement of the light point source. The same tracking device is used to determine the surface contour of the treatment area. This study examines the light fluence (rate) delivered between the measurement and calculation in phantom studies. Isotropic detectors were used for in-vivo light dosimetry. Light fluence rate in the pleural cavity is calculated and compared with the in-vivo calculation. Phantom studies show that the surface contour can be determined with an accuracy of 2 mm, with maximum deviation of 5 mm. We can successfully match the calculated light fluence rates with the in-vivo measurements. Preliminary results indicate that the light fluence rate can have up to 50% deviation compared to the prescription in phantom experiments. The IR camera has been used successfully in pleural PDT patient treatment to track the motion of light source in real-time. We concluded that it is feasible to develop an IR camera based system to guide the motion of the light source to improve the uniformity of light distribution.

Purpose: A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues. Experimental Design: Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models. Results: Photofrin concentration was measured in 301 samples collected from 58 of 100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P < 0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P = 0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31 ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (≤2.31). Conclusions: Some selectivity is found in Photofrin uptake between tumor and normal tissues of the peritoneal cavity, but absolute differences in drug uptake relative to toxicity-limiting normal tissues (intestine) are small. This narrow differential in drug selectivity likely contributes to a narrow window in therapeutic application, which has been previously reported.

Purpose: A previous phase I trial of i.p. photodynamic therapy established the maximally tolerated dose of Photofrin (Axcan Pharma, Birmingham, AL)-mediated photodynamic therapy and showed encouraging efficacy. The primary objectives of this phase II study were to determine the efficacy and toxicities of i.p. photodynamic therapy in patients with peritoneal carcinomatosis and sarcomatosis. Experimental Design: Patients received Photofrin 2.5 mg/kg i.v. 48 hours before debulking surgery. Intraoperative laser light was delivered to the peritoneal surfaces of the abdomen and pelvis. The outcomes of interest were (a) complete response, (b) failure-free survival time, and (c) overall survival time. Photosensitizer levels in tumor and normal tissues were measured. Results: One hundred patients were enrolled into one of three strata (33 ovarian, 37 gastrointestinal, and 30 sarcoma). Twenty-nine patients did not receive light treatment. All 100 patients had progressed by the time of statistical analysis. The median failure-free survival and overall survival by strata were ovarian, 2.1 and 20.1 months; gastrointestinal cancers, 1.8 and 11.1 months; sarcoma, 3.7 and 21.9 months. Substantial fluid shifts were observed postoperatively, and the major toxicities were related to volume overload. Two patients died in the immediate postoperative period from bleeding, sepsis, adult respiratory distress syndrome, and cardiac ischemia. Conclusions: Intraperitoneal Photofrin-mediated photodynamic therapy is feasible but does not lead to significant objective complete responses or long-term tumor control. Heterogeneity in photosensitizer uptake and tumor oxygenation, lack of tumor specificity for photosensitizer uptake, and the heterogeneity in tissue optical properties may account for the lack of efficacy observed.

Although follicular lymphoma (FL) is generally responsive to conventional-dose chemotherapy, improved survival in patients with this disease has been difficult to demonstrate. High-dose chemo/radiotherapy followed by autologous stem-cell transplantation (ASCT) can improve response rates, although its effects on survival remain controversial. Between 1990 and 2003, we transplanted 49 patients with low-grade FL at our institution. Twenty-two patients (45%) had undergone histologic transformation at the time of ASCT. In all, 44 patients (90%) had relapsed disease and five patients (10%) were resistant to chemotherapy at the time of transplantation. After ASCT, 30 patients (61%) were in complete remission (CR). The median overall survival (OS) has not been reached, while the median event-free survival (EFS) is 2.4 years. At a median follow-up of 5.5 years (longest 12.4 years), a plateau has been reached with 56% of patients remaining alive, and 35% event-free. ASCT was well tolerated except for two (4%) treatment-related deaths. In multivariable analysis, CR after ASCT and age less than 60 years are the best predictors of EFS and OS. ASCT is thus a safe therapeutic approach in FL, resulting in long-term EFS and OS for some patients, even with transformed disease.

As each year ushers in new and innovative survival-enhancing treatments for castration-resistant prostate cancer with bone metastases, patients and their physicians have a sense of empowerment associated with this growing therapeutic arsenal.1–5 Nonetheless, nearly 30,000 men still die from prostate cancer every year, and many have debilitating illness from osseous involvement. For this latter group, Alpharadin in Symptomatic Prostate Cancer Patients, a randomized, placebo-controlled study reported by Parker et al. in this issue of the Journal, focuses on a new weapon in anticancer therapy.6 Radium-223 dichloride (radium-223), the first alpha emitter to undergo phase 3 testing and receive approval . . .

Purpose: Complete alopecia is a universal complication of whole brain radiation therapy which contributes to patient anxiety over treatment. Tempol, a nitroxide radioprotector, has been shown to protect against radiation-induced alopecia in an animal model. This phase Ib study was designed to evaluate the safety and side effect profile of topical Tempol in patients with brain metastases being treated with whole brain radiotherapy. Experimental Design: Twelve patients with metastatic cancer to the brain were enrolled in the study between October 2000 and February 2003. Tempol (70 mg/ml concentration solution) was applied topically to the scalp 15 minutes before and washed off immediately after the completion of each of 10 fractions of whole brain radiation. Pharmacokinetic studies to evaluate the systemic absorption of Tempol were performed. Patients were assessed for toxicity before, during, and after Tempol administration. A secondary end point of the study, hair retention, was also scored. Results: Eleven patients were treated with topical Tempol. Adverse events that were considered possibly, probably, or definitely related to Tempol, included asymptomatic grade 2 (two patients) and grade 1 (one patient) hypoglycemia, grade 1 forehead skin redness (one patient), grade 1 dry scalp (one patient), and grade 1 tingling sensation on the scalp (one patient). Tempol was not detected in blood samples from more than 50% of the patients. Mean maximum Tempol levels for individual patients at any time point varied from 0.4 to 3.1 μmol/L. Hair retention was localized to the base of the scalp where the Tempol solution pooled after application in the first four patients on the study. Subsequently, full scalp hair retention was seen in three of final five evaluable patients after gauze had been wrapped around the head to hold the solution against the scalp. Conclusions: This study demonstrates that topical application of Tempol to the scalp before whole brain radiation is safe and well tolerated. Evidence of protection against radiation-induced alopecia was observed. A phase II study that uses a gel formulation to increase the exposure of scalp to Tempol has been initiated.

Purpose: Response to photodynamic therapy depends on adequate tumor oxygenation as well as sufficient accumulation of photosensitizer in the tumor. The goal of this study was to investigate the presence of hypoxia and retention of the photosensitizer Photofrin in the tumors of patients with intra-abdominal carcinomatosis or sarcomatosis. Experimental Design: Tumor nodules from 10 patients were studied. In nine of these patients, hypoxia was identified in histological sections of biopsied tumor after administration of the hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5). In separate tumor nodules from 10 patients, Photofrin uptake was measured by fluorescence after tissue solubilization. Results: Hypoxia existed in the tumors of five patients, with three of these patients demonstrating at least one severely hypoxic nodule. Physiological levels of oxygen were present in the tumors of four patients. An association between tumor size and hypoxia was not evident because some tumor nodules as small as ∼2 mm in diameter were severely hypoxic. However, even these tumor nodules contained vascular networks. Three patients with severely hypoxic tumor nodules exhibited moderate levels of Photofrin uptake of 3.9 ± 0.4 to 3.9 ± 0.5 ng/mg (mean ± SE). The four patients with tumors of physiological oxygenation did not consistently exhibit high tumor concentrations of Photofrin: mean ± SE drug uptake among these patients ranged from 0.6 ± 0.8 to 5.8 ± 0.5 ng/mg. Conclusions: Carcinomatosis or sarcomatosis of the i.p. cavity may exhibit severe tumor hypoxia. Photofrin accumulation in tumors varied by a factor of ∼10× among all patients, and, on average, those with severe hypoxia in at least one nodule did not demonstrate poor Photofrin uptake in separate tumor samples. These data emphasize the need for reconsideration of the generally accepted paradigm of small tumor size, good oxygenation, and good drug delivery because this may vary on an individual tumor basis.

Purpose Non—small-cell lung cancer (NSCLC) with pleural spread is incurable, with median survival rates ranging from 6 to 9 months. Surgery alone fails to locally control this disease or extend survival beyond the accepted treatment, palliative chemotherapy. Methods We conducted a phase II trial to evaluate the effects on local control and survival of combining surgery with intraoperative photodynamic therapy (PDT), a light-based cancer treatment, in patients with NSCLC with pleural spread. Patients received porfimer sodium (2 mg/kg), 24 hours before surgery, at which time all gross tumor was resected and followed by illumination of the hemithorax with 630 nm light to a measured dose of 30 J/cm2. Photosensitizer levels in tumor and surrounding normal tissue were measured. Results Twenty-two patients with NSCLC were enrolled; 17 underwent complete debulking and PDT, three underwent partial debulking/PDT, and two patients were unresectable. Local control of pleural disease at 6 months was achieved in 11 of 15 (73.3%; 95% CI, 44.9% to 92.2%) assessable patients. Median overall survival for all 22 patients was 21.7 months (95% CI, 17.7 to 25.8 months). Measured levels of porfimer sodium in tumor were greater than those measured in normal tissues, with ratios ranging from 1.19 to 22.42. Conclusion Our results indicate surgery and PDT can be performed safely with very good local control. The median survival of 21.7 months, calculated from the time of surgery and PDT is encouraging. Further evaluation of this therapy is warranted.

Background Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT. Methods A total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy–decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax. Results Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J · cm −2 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications. Conclusions Foscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted.

Intensity-modulated radiation therapy (IMRT) is a refinement of current radiotherapy techniques rather than a major breakthrough. The term IMRT includes several different techniques that all share with classical arc therapy the principle of using multiple fields to reduce the dose to normal tissues, but integrating to a higher dose throughout the tumor volume itself. This paper reviews not only the putative upside but also the downside of the development of IMRT. Theoretical, practical, and cost considerations, both positive and negative, are discussed. There are several issues to be considered, but the most important perversely predict a significant increase in radiation-induced neoplasms, resulting not only from larger volumes of tissue exposed to more modest but still mutagenic doses, but also from a significant increase in total body dose from leakage, because the beam is typically on for a considerably longer period of time than is conventional. A plea is made for radiation oncologists to maintain a strong biologic and cellular orientation as oncology rapidly becomes more molecular in its orientation.

We used Diffuse Optical Spectroscopy to measure the effect of PDT on hemoglobin concentration changes during intra-operative PDT for mesothelioma. Those with less PDT-created hypoxia had better prognosis than those with severe hypoxia.

PURPOSE: Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non–small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT. PATIENTS AND METHODS: A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors. RESULTS: A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P = .06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose ≥ 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%. CONCLUSION: Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.

The Stanford team of Drs. Henry S. Kaplan and Saul A. Rosenberg churned out an extensive amount of clinical research on the evaluation and treatment of Hodgkin's disease and other lymphomas throughout the 1960's, 70's and 80's. After Dr. Kaplan's death in 1983, Dr. Rosenberg continued clinical research in this area. A training experience under these physicians was both exhilarating and productive, as the discipline with which Drs. Kaplan and Rosenberg approached patients actually eclipsed the individual studies which were carried out. The overall product of their efforts, in conjunction with that of other investigators throughout the world, changed the mindset of physicians to approaching these patients with curative intent, rather than traditional palliation which had been the general policy up to the late 1950's. Today the vast majority of Hodgkin's patients who are treated get cured, although there is still some room for further improvement. The strong character traits of Drs. Kaplan and Rosenberg left lasting impressions, not only on other staff, but most especially on the young trainees who learned to accept and appreciate their efforts at excellence. Their method of approach and the gains achieved by it became the paradigm for the study of other malignant diseases.

I have been asked to write a commentary on the developing trends of modern radiation oncology and the present hightech pathway that is being so heavily traveled. At the risk of appearing to be a Socratic gadfly by some (also a curmudgeon and agent provocateur by others), I begin with two quotes: “If you want to cure Hodgkin’s disease, you must learn to think like a Reed-Sternberg cell.” Henry S. Kaplan. “If radiation oncologists treated poliomyelitis, today we would have bigger iron lungs.” Franz Buschke.

Summary Background: High-dose chemotherapy with autologous stemcell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy. Patients and methods: Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients. Results: Overall and disease-free survival rates at 18 months were 83% (± 4%) and 77% (± 4%) respectively. Twenty patients (19.4%) received radiation therapy prior to transplant. Of the remaining 83, 77 received radiation therapy after transplant. Overall, 5 (19.2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%-24.5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation. Conclusion: Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.

Photodynamic therapy (PDT) is a treatment modality using a photosensitising drug and light to kill cells. The clinical use of PDT requires the presence of a photosensitising agent, oxygen and light of a specific wavelength which matches the absorption characteristics of the photosensitiser. When the photosensitiser is activated by the appropriate wavelength of light, it interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. The appeal of PDT in oncology is that the photosensitiser tends to be retained in tumour tissues for a longer period of time as compared with normal tissues resulting in a large therapeutic index. This potential for minimal normal tissue toxicity has prompted an interest in studying PDT as a cancer treatment. Furthermore, the use of PDT is not precluded by prior radiotherapy, chemotherapy or surgery. The development of PDT has been hampered by the limitations of the older photosensitisers, namely limited depth of tissue penetration, and extended skin phototoxicity which limits the number of applications during a course of treatment. However, newer photosensitisers are being developed which allow greater depth of tissue penetration and have minimal skin phototoxicity allowing for multiple fractionated treatments. With such advancements, PDT has great potential to become an integral part of cancer treatment in the future.