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Purpose: Adaptive planning to accommodate anatomic changes during treatment requires repeat segmentation. This study uses dosimetric endpoints to assess automatically deformed contours., Methods and Materials: Sixteen patients with head-and-neck cancer had adaptive plans because of anatomic change during radiotherapy. Contours from the initial planning computed tomography (CT) were deformed to the mid-treatment CT using an intensity-based free-form registration algorithm then compared with the manually drawn contours for the same CT using the Dice similarity coefficient and an overlap index. The automatic contours were used to create new adaptive plans. The original and automatic adaptive plans were compared based on dosimetric outcomes of the manual contours and on plan conformality., Results: Volumes from the manual and automatic segmentation were similar; only the gross tumor volume (GTV) was significantly different. Automatic plans achieved lower mean coverage for the GTV: V95: 98.6 +/- 1.9% vs. 89.9 +/- 10.1% (p = 0.004) and clinical target volume: V95: 98.4 +/- 0.8% vs. 89.8 +/- 6.2% (p < 0.001) and a higher mean maximum dose to 1 cm(3) of the spinal cord 39.9 +/- 3.7 Gy vs. 42.8 +/- 5.4 Gy (p = 0.034), but no difference for the remaining structures., Conclusions: Automatic segmentation is not robust enough to substitute for physician-drawn volumes, particularly for the GTV. However, it generates normal structure contours of sufficient accuracy when assessed by dosimetric end points., ((c) 2010 Elsevier Inc. All rights reserved.)

The optimal management of resectable oropharyngeal squamous cell carcinomas is controversial with many treatment options, both surgical and nonsurgical approaches, supported by published experiences with no randomized trials comparing commonly accepted treatments. The treatment decisions are further complicated by the need for local-regional disease control and competing goals to preserve salivary and swallow function. Treatment decisions may also be affected by tumor and patient related factors and a history of environmental exposure to tobacco and evidence of human papilloma virus. We summarize the published literature and provide treatment consensus derived from the modified Delphi methodology., (Copyright 2010 American College of Radiology. Published by Mosby, Inc. All rights reserved.)

Purpose: To determine the patterns of regional recurrence in patients treated with definitive radiotherapy (RT) for cervical cancer., Methods and Materials: The records of 198 patients treated with definitive RT for cervical cancer between 1980 and 2000 who experienced a regional recurrence without a central or distal vaginal recurrence were reviewed. All patients received a combination of external-beam RT and intracavitary brachytherapy. In the 180 patients with a documented location of regional recurrence, the relationship between the recurrence and the radiation fields was determined., Results: The median time to regional recurrence was 13 months (range, 2-85 months). Of the 180 patients who had an evaluable regional recurrence, 119 (66%) had a component of marginal failure; 71 patients recurred above-the-field, 2 patients occurred in the inguinal nodes, and 2 patients recurred above-the-field and in the inguinal nodes. In addition, 105 patients (58%) had a component of in-field failure; 59 patients recurred in-field only, 39 patients recurred in-field and above-the-field, 2 patients recurred in-field, above-the-field, and in the inguinal nodes, and 5 patients recurred in-field and in the inguinal nodes. The median survival after regional recurrence was 8 months (range, 0-194 months)., Conclusions: Most regional recurrences after definitive RT for cervical cancer include a component of marginal failure, usually immediately superior to the radiation field. These recurrences suggest a deficiency in target volume. Recurrences also occur in-field, suggesting a deficiency in dose. Developments in pretreatment staging, field delineation, dose escalation, and posttreatment surveillance may help to improve outcome in these patients.

Purpose: To use an imaging beam line (IBL) to obtain the first megavoltage cone-beam computed tomography (MV CBCT) images of patients with a low atomic number (Z) target, and to compare these images to those taken of the same patients with the 6 MV flattened beam from the treatment beam line (TBL)., Methods: The IBL, which produces a 4.2 MV unflattened beam from a carbon target, was installed on a linear accelerator in use for radiotherapy. Provision was made for switching between the IBL and TBL for imaging the same patient with beams from the low-Z and high-Z targets. Dose was quoted as monitor units times the dose per monitor unit for the standard calibration geometry. Images were acquired with institutional approval and patient consent with both the IBL and TBL on a series of 23 patients undergoing radiotherapy. Patients were imaged daily to weekly and aligned to the planning CT using the images. Doses were reduced over the course of treatment to determine the minimum doses required for alignment. Images were assessed offline., Results: IBL MV CBCT images of prostate, head and neck, lung, and abdomen showed improvement in soft tissue contrast for the same dose as the TBL images. Bony anatomy, air cavities, and fiducial markers were sharper. CBCT with a dose of 1 cGy was sufficient for alignment of prostate and head and neck patients based on bony anatomy or implanted gold seeds, 2-4 cGy for lung, abdomen, and pelvis. Photon scatter in the patient had minimal effect on image quality. The metallic hip prosthesis in one patient showed reduced artifacts compared to diagnostic CT., Conclusions: The IBL has the advantage of improved image quality at the same dose, or reduced dose for the same image quality, over the TBL.

The development of novel technologies for the safe and effective delivery of radiation is critical to advancing the field of radiation oncology. The Emerging Technology Committee of the American Society for Therapeutic Radiology and Oncology appointed a Task Group within its Evaluation Subcommittee to evaluate new electronic brachytherapy methods that are being developed for, or are already in, clinical use. The Task Group evaluated two devices, the Axxent Electronic Brachytherapy System by Xoft, Inc. (Fremont, CA), and the Intrabeam Photon Radiosurgery Device by Carl Zeiss Surgical (Oberkochen, Germany). These devices are designed to deliver electronically generated radiation, and because of their relatively low energy output, they do not fall under existing regulatory scrutiny of radioactive sources that are used for conventional radioisotope brachytherapy. This report provides a descriptive overview of the technologies, current and future projected applications, comparison of competing technologies, potential impact, and potential safety issues. The full Emerging Technology Committee report is available on the American Society for Therapeutic Radiology and Oncology Web site., (Copyright 2010. Published by Elsevier Inc.)

Purpose: To determine the properties of a megavoltage cone-beam CT system using the unflattened beam from a sintered diamond target at 4 and 6 MV., Methods: A sintered diamond target was used in place of a graphite target as part of an imaging beam line (an unflattened beam from a graphite target) installed on a linear accelerator. The diamond target, with a greater density than the graphite target, permitted imaging at the lower beam energy (4 MV) required with the graphite target and the higher beam energy (6 MV) conventionally used with the tungsten/stainless steel target and stainless steel flattening filter. Images of phantoms and patients were acquired using the different beam lines and compared. The beam spectra and dose distributions were determined using Monte Carlo simulation., Results: The diamond target allowed use of the same beam energy as for treatment, simplifying commissioning and quality assurance. Images acquired with the diamond target at 4 MV were similar to those obtained with the graphite target at 4 MV. The slight reduction in low energy photons due to the higher-Z sintering material in the diamond target had minimal effect on image quality. Images acquired at 6 MV with the diamond target showed a small decrease in contrast-to-noise ratio, resulting from a decrease in the fraction of photons in the beam in the energy range to which the detector is most sensitive., Conclusions: The diamond target provides images of a similar quality to the graphite target. Diamond allows use of the higher beam energy conventionally used for treatment, provides a higher dose rate for the same beam current, and potentially simplifies installation and maintenance of the beam line.

Objectives. To determine the utility of routine surveillance MRI in detecting locoregional recurrence following definitive chemoradiation in advanced-stage oropharynx carcinoma. Methods. We identified patients with Stage III-IV oropharynx carcinoma who were treated with chemoradiation between April 2000 and September 2004 and underwent longitudinal followup care at our institution. Patient charts were retrospectively reviewed for findings on MRI surveillance imaging, clinical signs and symptoms, and recurrence. Results. Forty patients received a total of 229 surveillance MRI scans with a minimum follow-up of three years (mean of 5.6 scans per patient). Six patients experienced false-positive surveillance studies that resulted in intervention. Four patients experienced recurrent disease, two of whom had new symptoms or exam findings that preceded radiographic identification of disease. Surveillance MRI scans identified recurrent disease in two asymptomatic patients who were salvaged, one of whom remains free of disease at follow-up. The overall sensitivity and specificity of the MRI surveillance program were 50 and 83 percent, respectively. The mean charge to each patient for the surveillance program was approximately $10,000 annually. Conclusion. In oropharyngeal cancer patients who have been treated with chemoradiation, an imaging surveillance program utilizing MRI produces limited opportunity for successful salvage.

Purpose: To identify clinical risk factors and dose-volume thresholds for treatment-related pneumonitis (TRP) in patients with non-small cell lung cancer (NSCLC)., Methods and Materials: Data were retrospectively collected from patients with inoperable NSCLC treated with radiotherapy with or without chemotherapy. TRP was graded according to Common Terminology Criteria for Adverse Events, version 3.0, with time to grade > or = 3 TRP calculated from start of radiotherapy. Clinical factors and dose-volume parameters were analyzed for their association with risk of TRP., Results: Data from 576 patients (75% with stage III NSCLC) were included in this study. The Kaplan-Meier estimate of the incidence of grade > or = 3 TRP at 12 months was 22%. An analysis of dose-volume parameters identified a threshold dose-volume histogram (DVH) curve defined by V(20) < or = 25%, V(25) < or = 20%, V(35) < or = 15%, and V(50) < or = 10%. Patients with lung DVHs satisfying these constraints had only 2% incidence of grade > or = 3 TRP. Smoking status was the only clinical factor that affected the risk of TRP independent of dosimetric factors., Conclusions: The risk of TRP varied significantly, depending on radiation dose-volume parameters and patient smoking status. Further studies are needed to identify biological basis of smoking effect and methods to reduce the incidence of TRP.

Purpose: At the University of California San Francisco, daily or weekly three-dimensional images of patients in treatment position are acquired for image-guided radiation therapy. These images can be used for calculating the actual dose delivered to the patient during treatment. In this article, we present the process of performing dose recalculation on megavoltage cone-beam computed tomography images and discuss possible strategies for dose-guided radiation therapy (DGRT)., Materials and Methods: A dedicated workstation has been developed to incorporate the necessary elements of DGRT. Patient image correction (cupping, missing data artifacts), calibration, completion, recontouring, and dose recalculation are all implemented in the workstation. Tools for dose comparison are also included. Examples of image correction and dose analysis using 6 head-and-neck and 2 prostate patient datasets are presented to show possible tracking of interfraction dosimetric endpoint variation over the course of treatment., Results: Analysis of the head-and-neck datasets shows that interfraction treatment doses vary compared with the planning dose for the organs at risk, with the mean parotid dose and spinal cord D(1) increasing by as much as 52% and 10%, respectively. Variation of the coverage to the target volumes was small, with an average D(5) dose difference of 1%. The prostate patient datasets revealed accurate dose coverage to the targeted prostate and varying interfraction dose distributions to the organs at risk., Conclusions: An effective workflow for the clinical implementation of DGRT has been established. With these techniques in place, future clinical developments in adaptive radiation therapy through daily or weekly dosimetric measurements of treatment day images are possible.

Purpose: To quantify the uncertainties associated with incorporating diagnostic positron emission tomography/CT (PET/CT) and PET into the radiotherapy treatment-planning process using different image registration tools, including automated and manual rigid body registration methods, as well as deformable image registration., Methods and Materials: The PET/CTs and treatment-planning CTs from 12 patients were used to evaluate image registration accuracy. The PET/CTs also were used without the contemporaneously acquired CTs to evaluate the registration accuracy of stand-alone PET. Registration accuracy for relevant normal structures was quantified using an overlap index and differences in the center of mass (COM) positions. For tumor volumes, the registration accuracy was measured using COM positions only., Results: Registration accuracy was better with PET/CT than with PET alone. The COM displacements ranged from 3.2 +/- 0.6 mm (mean +/- 95% confidence interval, for brain) to 8.4 +/- 2.6 mm (spinal cord) for registration with PET/CT data, compared with 4.8 +/- 1.7 mm (brain) and 9.9 +/- 3.1 mm (spinal cord) with PET alone. Deformable registration improved accuracy, with minimum and maximum errors of 1.1 +/- 0.8 mm (brain) and 5.4 +/- 1.4 mm (mandible), respectively., Conclusions: It is possible to incorporate PET and/or PET/CT acquired in diagnostic positions into the treatment-planning process through the use of advanced image registration algorithms, but precautions must be taken, particularly when delineating tumor volumes in the neck. Acquisition of PET/CT in the treatment-planning position would be the ideal method to minimize registration errors.

Purpose: To determine the radiation dose to the carotid artery in nasopharyngeal cancer patients treated with intensity-modulated radiotherapy (IMRT) and to compare it to the dose delivered by a conventional three-field (3F) technique., Materials and Methods: Sixteen patients with nasopharyngeal cancer who were treated at UCSF with IMRT were selected for this analysis. 3F plans were reconstructed for comparison. The carotid arteries were retrospectively contoured, and the dose received by each of the 32 carotid arteries was determined for both IMRT and 3F plans. A subset of 8 patients with N0/N1 nodal disease was selected for IMRT replanning using additional constraints to reduce the dose to the arteries., Results: Using the standard prescription doses for IMRT and 3F plans, the dose delivered to 95% of the tumor volume was significantly higher in the IMRT plans, reflecting the greater conformality of this technique. The median mean dose to the carotid arteries was 65.7Gy with IMRT vs. 58.4Gy with 3F (p<0.001). After the application of dose constraints to the carotid arteries, it was possible to reduce the mean carotid dose to 54Gy in the IMRT replans., Conclusions: IMRT achieves a higher tumoricidal dose and superior clinical target volume coverage, but results in an increase in the carotid artery dose as compared to conventional 3F technique. With careful IMRT planning, it is possible to constrain the carotid dose for a subset of patients with low-risk neck disease. Further study is necessary to quantify the long-term clinical impact of this intervention.

Background: Treatment outcomes for stage III and IV oropharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy without prior surgical resection were reviewed., Methods: Between April 2000 and September 2004, 71 patients underwent IMRT concurrent with chemotherapy without prior surgical resection for stage III and IV oropharyngeal carcinoma. Chemotherapy was platinum based. The gross tumor volume (GTV) received 70 Gy in 2.12 Gy per fraction. The high-risk clinical tumor volume (CTV) received 59.4 Gy in 1.80 Gy per fraction, and the low-risk CTV received 54 Gy in 1.64 Gy per fraction., Results: With a median follow-up of 33 months, the 3-year local, regional, and locoregional progression-free probabilities were 94%, 94%, and 90%, respectively. The 3-year overall survival estimate was 83%. Locoregional failures occurred in the GTV in 7 patients. Acute grade 3 or 4 toxicity developed in 35 patients. A feeding gastrostomy was placed in 25 patients. Late xerostomia was grade 0 in 16 patients, grade 1 in 31 patients, and grade 2 in 24 patients at last follow-up. No patients experienced grade 3 or 4 late toxicity, except for 1 who developed osteoradionecrosis of the mandible., Conclusions: Excellent local and regional control was achieved with IMRT and concurrent chemotherapy without prior surgical resection in the treatment of stage III and IV oropharyngeal carcinoma. Significant sparing of the parotid glands and other critical normal tissues was possible using IMRT with moderate acute toxicities and minimal severe late effects., ((c) 2008 American Cancer Society)

Purpose: To plan craniospinal irradiation with "field-in-field" (FIF) homogenization in combination with daily, intrafractional modulation of the field junctions, to minimize the possibility of spinal cord overdose., Methods and Materials: Lateral cranial fields and posterior spinal fields were planned using a forward-planned, step-and-shoot FIF technique. Field junctions were automatically modulated and custom-weighted for maximal homogeneity within each treatment fraction. Dose-volume histogram analyses and film dosimetry were used to assess results., Results: Plan inhomogeneity improved with FIF. Planning with daily modulated junction shifts provided consistent dose delivery during each fraction of treatment across the junctions. Modulation minimized the impact of a 5-mm setup error at the junction. Film dosimetry confirmed that no point in the junction exceeded the anticipated dose., Conclusions: Field-in-field planning and modulated junction shifts improve the homogeneity and consistency of daily dose delivery, simplify treatment, and reduce the impact of setup errors.

Purpose: To investigate the rate of high-grade treatment-related pneumonitis (TRP) in patients with advanced non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT)., Methods and Materials: From August 2002 to August 2005, 151 NSCLC patients were treated with IMRT. We excluded patients who did not receive concurrent chemotherapy or who had early-stage cancers, a history of major lung surgery, prior chest RT, a dose <50 Gy, or IMRT combined with three-dimensional conformal RT (3D-CRT). Toxicities were graded by Common Terminology Criteria for Adverse Events version 3.0. Grade > or = 3 TRP for 68 eligible IMRT patients was compared with TRP among 222 similar patients treated with 3D-CRT., Results: The median follow-up durations for the IMRT and 3D-CRT patients were 8 months (range, 0-27 months) and 9 months (range, 0-56 months), respectively. The median IMRT and 3D-CRT doses were 63 Gy. The median gross tumor volume was 194 mL (range, 21-911 mL) for IMRT, compared with 142 mL (range, 1.5-1,186 mL) for 3D-CRT (p = 0.002). Despite the IMRT group's larger gross tumor volume, the rate of Grade > or = 3 TRP at 12 months was 8% (95% confidence interval 4%-19%), compared with 32% (95% confidence interval 26%-40%) for 3D-CRT (p = 0.002)., Conclusions: In advanced NSCLC patients treated with chemoradiation, IMRT resulted in significantly lower levels of Grade > or = 3 TRP compared with 3D-CRT. Clinical, dosimetric, and patient selection factors that may have influenced rates of TRP require continuing investigation. A randomized trial comparing IMRT with 3D-CRT has been initiated.

Purpose: We have increasingly used a two-field noncoplanar "caudal tilt" technique (CTT) for irradiating postlaryngectomy and pharyngectomy patients to avoid matchline problems that can be encountered with the classic three-field head-and-neck radiation technique (3FT). This report compares the clinical outcomes of patients treated with postoperative radiation (PORT) using either 3FT or CTT., Methods and Materials: We conducted a retrospective review of the medical records of all patients with laryngeal or hypopharyngeal cancers consecutively treated with PORT between 1997 and 2002. Three-dimensional dosimetric planning was carried out for all patients., Results: Of 91 patients, 39 were treated with 3FT and 52 with CTT. The median follow-up was 34 months. Estimated rates of 2-year locoregional control, disease-free survival, and overall survival for patients treated with 3FT and CTT were, respectively, 92% and 85% (p=0.241), 62% and 55% (p=0.497), and 77% and 72% (p=0.616). There were no significant differences in the incidence of acute or late side effects in the two groups., Conclusions: "Caudal tilt" technique is often used as an alternative to 3FT for postoperative radiotherapy in cases of greater medical and technical complexity. Despite its use in more challenging cases, CTT provides similar long-term clinical outcomes compared with standard 3FT, when computerized three-dimensional dosimetry is used to assure adequate dosimetry throughout the treated volume.

Merkel cell carcinoma (MCC) is an uncommon primarily dermal malignancy of relatively aggressive biologic course. Several presentations in the mucosa of the head and neck region have been reported in the literature, and 3 such patients have recently been seen at our institution. We review this recent experience and present the first reported primary lingual MCC in a 57-year-old caucasian man. We provide a review of oral mucosal MCC and guidelines for histopathologic and immunohistochemical diagnosis. Merkel cell carcinoma should be included in the differential diagnosis of head and neck mucosal lesions, especially if the tumor is submucosal, and MCC may involve the tongue. Mucosal MCC is aggressive, and there is a high risk for local recurrence and regional and distant metastasis. Fulminating courses are often seen. We discuss our treatment policies based on the current literature.

Objectives: Patients who have received definitive radiation therapy (RT) for a nonlaryngeal T3/4 head and neck squamous cell carcinoma have a limited opportunity for post-RT surgical salvage. The authors reviewed the practice of planned post-RT restaging to determine its impact on the success of early surgical salvage., Methods: A retrospective review was performed for patients with resectable T3/4 cancers of the oropharynx and hypopharynx treated with RT +/- chemotherapy who underwent planned restaging clinically, radiographically (CT or MRI), and by direct laryngoscopy with biopsy at 4 to 8 weeks post-RT. Chemotherapy was given as induction, concurrently, or both. Neck dissection was performed at time of restaging in patients with primary tumor control and initial N2/N3 neck disease or persistent lymphadenopathy., Results: A total of 54 patients had a median follow-up of 34.7 months (range, 7.6-97.8 months). Forty-two patients (78.8%) achieved a complete response (CR) at the primary site immediately after RT. Six developed late local failure at 9 to 61 months, of whom 2 were successfully salvaged. The ultimate 2-year local control among patients with initial CR was 94.8%. The 2-year organ preservation, disease-free survival, and overall survival (OS) rates were was 92.5%, 87%, and 90%, respectively. Twelve patients did not achieve initial CR. Two patients with bulky stage IV disease had unresectable cancers. Ten underwent immediate surgical salvage and 7 achieved local control (1 of whom developed distant metastases) whereas 3 had continued local failure. For patients without initial CR, the 2-year ultimate local control rate was 46.7% and OS was 46.8%. For all patients, overall 2-year local control, organ preservation, and OS rates were 85.6%, 75.6%, and 81.8% respectively. The rate of local failure-free organ preservation was 71.5%., Conclusion: For patients with T3/4 resectable nonlaryngeal head and neck cancers, planned clinical, radiographic, and pathologic restaging at 1 to 2 months after definitive RT provides the opportunity for early surgical salvage in those who fail at the primary site. This practice produces improved overall local control and survival rates compared with the literature reports for delayed attempted salvage with timing based on the findings of routine postradiation clinical surveillance. Future efforts may focus on the improved selection of patients who would be most likely to require early surgical intervention.

Sinonasal adenocarcinomas, a relatively rare entity, are composed of distinctly different morphologic subtypes with variable biological behavior. To investigate the genetic events associated with their development and clinicopathologic features, we analyzed the alterations in K-ras, APC, beta-catenin, hMLH1 and hMSH2 and p53 genes expression in a cohort of 15 primary tumors comprising the two main sinonasal adenocarcinoma subtypes (enteric and seromucinous). The patients consisted of 13 men and two women, who ranged in age from 50 to 87 years. Tumors were predominantly located in the ethmoid sinus. Eight tumors were Enteric-type, and seven were seromucinous type. Nine patients were smokers and four were nonsmokers; and no information was available on two patients. Two of the eight enteric-type, had K-ras mutation at codons 12A and 12B, and one showed microsatellite instability at BAT-25. Two patients with enteric-type tumors had a history of wood-dust exposure, and one had a K-ras mutation at 12A codon as well as p53 overexpression. No patients with the seromucinous type had any genetic abnormalities, except for overexpression of p53 in two tumors. Our results show that (1) a subset of enteric-type sinonasal adenocarcinoma shares certain genetic alterations with colonic adenocarcinomas, (2) the seromucinous-type sinonasal adenocarcinoma lacks alterations and may develop through a different pathway, (3) high p53 expression is associated with aggressive tumor features in both subtypes and (4) the enteric-type runs a more malignant course than the seromucinous counterpart.

Background and Purpose: We retrospectively analyzed results for lymph node negative transitional cell carcinoma of the bladder treated with brachytherapy., Patients and Methods: From 1975-2002, 58 patients received preoperative external irradiation, partial cystectomy (in 69%), iliac node dissection, and iridium-192. Pathologic stage was: 10 pT1, 41 pT2, and 7 pT3. A median total brachytherapy dose of 60 Gy was delivered to the tumor bed., Results: Mean follow-up was 76 months (range, 0.5-296). Tumor stage significantly impacted cause-specific and disease-free survival (P=0.02). Eight pT1 patients were free of disease and 2 died of other cause. For pT2 patients, 5-year cause-specific and overall survival rates were, respectively, 70% (CI 95%: 53-87) and 60% (CI 95%: 43-77). Three pT3 patients died of cancer. For the pT2 patients, the probability of 5-year local control was 65% (CI 95%: 47-83) and being alive without disease with a functional bladder, 50% (CI 95%: 33-67). Previous transurethral resection (TUR) increased the bladder relapse risk among pT2 patients (P=0.03). Twelve patients had severe acute complications and 5 had severe late effects. A high dose of external irradiation increased risk of late complications (P=0.01). Most complications occurred in patients treated before 1985., Conclusions: Highly select patients presenting with pT2 tumors less than 5 cm with no history of previous TUR may be successfully treated with low-dose external irradiation, limited partial cystectomy, and interstitial brachytherapy. High-risk pT1 patients may also benefit. Postoperative complications and late side effects are minimized with modern management. We recommend lifelong cystoscopic surveillance, with prompt surgical salvage for recurrence.

Patients treated on a Phase-I clinical trial of photodynamic therapy (PDT) developed a systemic capillary leak syndrome that constituted the dose-limiting toxicity. We examined serum samples from patients treated at the maximally tolerated dose level for evidence of a systemic, cytokine-mediated inflammatory response. Patients underwent pleurectomy or extrapleural pneumonectomy (EPP) followed by intraoperative PDT of the thorax using Foscan at a dose of 0.1 mg/kg 6 days before surgery and 652 nm red light at a dose of 10 J/cm2. Levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-12 were assayed before Foscan administration; after anesthetic induction, surgical resection and light delivery; in postoperative recovery and the day after the surgery. Of the analyzed patients, eight underwent a pleurectomy and one an EPP followed by PDT. IFN-gamma, TNF-alpha and IL-12 showed no elevation, but IL-1beta, IL-6, IL-8 and IL-10 levels were elevated after surgery and PDT. IL-1beta showed a statistically significant variation from baseline after surgery and IL-6, after PDT. The results suggest a systemically mediated inflammatory response resulting from thoracic surgery followed by PDT. Further investigation of specific mechanisms is warranted.

Background: Liposomal cisplatin preparations have two potential advantages over the free drug when combined with radiation therapy (RT): 1) selective tumor localization, improving the therapeutic ratio, and 2) prolonged half-life, allowing more radiosensitization. We performed a Phase I study of Stealth liposomal cisplatin (SPI-077) concurrent with RT for head and neck squamous cell carcinoma (HNSCC)., Methods: Patients with Stage IVa/b HNSCC were treated with SPI-077, given intravenously twice two weeks apart, concurrent with RT (60-72 Gy in 6-7 weeks). The SPI-077 dose was escalated in standard phase I design., Results: Twenty patients received 38 doses of SPI-077, escalated from 20-200 mg/m2 in six dose levels. Two of these patients received one dose because of reversible Grade 3 liver toxicity or rash. Three patients had a Grade 1, and one had a Grade 2 infusion reaction. Four patients had transiently elevated transaminases: Grade I (n = 1), Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3 neutropenia occurred in one patient. There was no ototoxicity, neurotoxicity, or nephrotoxicity. In-field radiation skin and mucosal toxicities did not appear to be intensified. Ten of 17 patients (59%) finishing treatment achieved initial complete response., Conclusions: Systemic and in-field radiation toxicities of SPI-077 were minimal. Infusion reactions were minimized with a slower and more dilute initial infusion. Further dose escalation was stopped in the absence of dose-limiting toxicity to address the reformulation of the liposomally bound cisplatin. Nonetheless, this study shows that high doses of SPI-077 can be given safely. The potentially beneficial therapeutic ratio suggests that liposomal radiosensitizer preparations warrant further investigation.