Biological Effective Radiation Dose for Multiple Myeloma Palliation.

Purpose: Various radiation therapy (RT) dose/fractionation schedules are acceptable for palliation in multiple myeloma. Nine years of single-institution RT experience were reviewed to determine the influence of dose/fractionation and other factors pertinent to individualizing therapy. Methods and Materials: In total, 152 items were identified from Current Procedural Terminology codes for multiple myeloma treatment from 2012 through June 30, 2021. After exclusions, 205 sites of radiation in 94 patients were reviewed. Data were captured from treatment planning and clinical records. To statistically assess the association between biological effective dose (BED10) and variables of interest, BED was first dichotomized to <24 Gy versus ≥24 Gy. Multivariate analysis used SAS software and a generalized estimating equation approach to account for multiple observations per patient. Results: Fractions of 1.8 to 8 Gy were used in 1 to 25 fractions. Most patients had no significant toxicity. Grade 1 toxicity was more likely with greater BED radiation courses, as expected (20% vs 12% for BED <24 Gy). Pain relief was complete or very good for most sites, with <3% reporting no pain relief. Eleven sites in 9 patients required retreatment. All retreatment sites had palliation that was lasting, with a median of 22 months to last follow-up or death after repeat course (range, 0.5-106 months). There was a trend for better pain control and less risk of fracture retreatment with BED ≥24 Gy. Conclusions: Most patients had good palliation without toxicity. BED ≥24 Gy caused 8% greater risk of grade 1 toxicity and trended toward better pain control plus reduced risk of fracture retreatment.

Safety and Outcome Measures of First-in-Human Intraperitoneal α Radioimmunotherapy With 212Pb-TCMC-Trastuzumab.

PURPOSE: One-year monitoring of patients receiving intraperitoneal (IP) Pb-TCMC-trastuzumab to provide long-term safety and outcome data. A secondary objective was to study 7 tumor markers for correlation with outcome. METHODS: Eighteen patients with relapsed intra-abdominal human epidermal growth factor receptor-2 expressing peritoneal metastases were treated with a single IP infusion of Pb-TCMC-trastuzumab, delivered <4 h after 4 mg/kg IV trastuzumab. Seven tumor markers were studied for correlation with outcome. RESULTS: Six dose levels (7.4, 9.6, 12.6, 16.3, 21.1, 27.4 MBq/m) were well tolerated with early possibly agent-related adverse events being mild, transient, and not dose dependent. These included asymptomatic, abnormal laboratory values. No late renal, liver, cardiac, or other toxicity was noted up to 1 year. There were no clinical signs or symptoms of an immune response to Pb-TCMC-trastuzumab, and assays to detect an immune response to this conjugate were negative for all tested. Tumor marker studies in ovarian cancer patients showed a trend of decreasing Cancer antigen 72-4 (CA 72-4) aka tumor-associated glycoprotein 72 (TAG-72) and tumor growth with increasing administered radioactivity. Other tumor markers, including carbohydrate antigen (CA125), human epididymis protein 4 (HE-4), serum amyloid A (SAA), mesothelin, interleukin-6 (IL-6), and carcinoembryonic antigen (CEA) did not correlate with imaging outcome. CONCLUSIONS: IP Pb-TCMC-trastuzumab up to 27 MBq/m seems safe for patients with peritoneal carcinomatosis who have failed standard therapies. Serum TAG-72 levels better correlated to imaging changes in ovarian cancer patients than the more common tumor marker, CA125.

MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT Applied for Dosimetry of Radiopharmaceutical Therapy.

The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on (177)Lu (lutetium) and its application in radiopharmaceutical therapy.

A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases.

PURPOSE: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1 to 4 brain metastases treated with radiosurgery without whole-brain radiation therapy (WBRT). METHODS AND MATERIALS: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase 2 trial of radiosurgery (15-24 Gy) and adjuvant temozolomide. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. RESULTS: Twenty-five patients were enrolled between 2002 and 2005; 3 were not evaluable for determining DBF. Of the remaining 22 patients, tumor types included non-small cell lung cancer (n = 8), melanoma (n = 7), and other (n = 7). Extracranial disease was present in 10 (45%) patients. The median number of tumors at the time of radiosurgery was 3 (range, 1-6). The median overall survival was 31 weeks. The median radiographic follow-up for patients who did not develop DBF was 33 weeks. Six patients developed DBF. The 1-year actuarial risk of DBF was 37%. CONCLUSIONS: In this study, there was a relatively low risk of distant brain failure observed in the nonmelanoma subgroup receiving temozolamide. However, patient selection factors rather than chemotherapy treatment efficacy are more likely the reason for the relatively low risk of distant brain failure observed in this study. Future trial design should account for these risk factors.

Pazopanib combined with radiation: in vivo model of interaction.

OBJECTIVE: Assess interaction of pazopanib, an oral antivascular endothelial growth factor inhibitor, with radiation in tumor xenograft models. METHODS: Flank xenografts in female athymic nude mice of human lung cancer cell line, A549, and head and neck cancer cell line, UM-SCC-6, were allowed to grow to ∼5×5 mm. Groups were then treated with pazopanib and/or escalating doses of radiation and tumor measurements over time compared with untreated tumor-bearing controls. Pazopanib (100 mg/kg) began 7 days before radiation and continued for 28 days. Daily radiation was 0.5, 1, 2, or 3 Gy ×5 days. RESULTS: Tumors in the A549 control group reached >4× the original size by day 36 postradiation. All treatment groups had less robust tumor growth (p<0.05) and the group receiving pazopanib+3 Gy radiation/day had tumor regression to less than baseline. In the UM-SCC-6-tumor-bearing animals, tumors in all treatment groups had less robust growth than untreated controls after day 23 post-treatment. CONCLUSION: The combination of pazopanib and radiation resulted in a trend of superior tumor growth inhibition compared with either agent alone. All treatment groups had impaired tumor progression compared with untreated controls.

Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients.

PURPOSE: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy. EXPERIMENTAL DESIGN: IP 212Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters. RESULTS: Imaging studies after 0.2 mCi/m2 (7.4 MBq/m2) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity. CONCLUSIONS: Pharmacokinetics and imaging after 0.2 mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance.

MIRD pamphlet No. 24: Guidelines for quantitative 131I SPECT in dosimetry applications.

The reliability of radiation dose estimates in internal radionuclide therapy is directly related to the accuracy of activity estimates obtained at each imaging time point. The recently published MIRD pamphlet no. 23 provided a general overview of quantitative SPECT imaging for dosimetry. The present document is the first in a series of isotope-specific guidelines that will follow MIRD 23 and focuses on one of the most commonly used therapeutic radionuclides, (131)I. The purpose of this document is to provide guidance on the development of protocols for quantitative (131)I SPECT in radionuclide therapy applications that require regional (normal organs, lesions) and 3-dimensional dosimetry.

Phase I study of a modified regimen of 9°Yttrium-ibritumomab tiuxetan for relapsed or refractory follicular or transformed CD20+ non-Hodgkin lymphoma.

Radioimmunotherapy capitalizes on the radiosensitivity of non-Hodgkin lymphoma (NHL) and the targeted nature of monoclonal antibodies. In an attempt to reverse bone marrow infiltration with B-cells and optimize the biodistribution of Yttrium-90 (9°Y)-ibritumomab tiuxetan, we conducted a phase I study combining a single course of 9°Y-ibritumomab tiuxetan after a 4-weekly course of rituximab in relapsed or refractory low-grade or transformed CD20+ B-cell NHLs with <25% marrow involvement. The 0.4 mCi/kg dose was associated with 80% grade-4 cytopenias. Dose escalation was held, and 6 patients were enrolled at a 0.3 mCi/kg cohort. As the 0.3 mCi/kg dose was well tolerated, the 0.4 mCi/kg cohort was expanded to 6 additional patients. In the expansion cohort, grade-4 cytopenia developed in 33%. Further dose escalation was held, and the maximum tolerated dose was determined at 0.4 mCi/kg. With this regimen, marrow involvement decreased in all patients with complete clearance in 50%. The overall response rate was 82%. With a median follow-up of 31.7 months, the median progression-free survival and time to next treatment were 12.3 and 10.9 months, respectively. Although this regimen was associated with a high response rate, the hematologic toxicity was higher than with the standard 9°Y-ibritumomab tiuxetan regimen.

Biodistribution and dosimetry of In-111/Y-90-HuCC49ΔCh2 (IDEC-159) in patients with metastatic colorectal adenocarcinoma.

BACKGROUND: CC49, an antibody (mAb) reactive to tumor-associated glycoprotein (TAG-72), has been extensively studied for radioimmunotherapy for colon cancer. Myelotoxicity has been dose-limiting because of prolonged circulation time in the plasma, and human anti-mouse antibody responses were observed in the majority of patients. A CH2 domain deleted and humanized CC49 (HuCC49ΔCh2) was developed to ameliorate these problems. This study reports biodistribution and dosimetry of (111)In/(90)Y-HuCC49ΔCh2 (IDEC-159). MATERIALS AND METHODS: Five (5) patients with colon cancer were enrolled. Each patient received intravenous administration of 185 MBq (111)In-HuCC49ΔCh2, followed by sequential gamma camera imaging, and blood counting. Uptakes and clearance half-lives for organs and tumors were quantified from images. Absorbed doses for (90)Y-HuCC49ΔCh2 were derived from (111)In-HuCC49ΔCh2 kinetic data. RESULTS: Compared to reported (111)In/(90)Y-CC49 data in the literature, median blood circulation T(1/2ß) was less at 38 (31-43) hours for (90)Y-HuCC49ΔCh2, than 50 hours for (90)Y-CC49. Median tumor-to-marrow absorbed dose ratio was 18 for (90)Y-HuCC49ΔCh2, and 9.53 for (90)Y-CC49. Median tumor-to-liver absorbed dose ratio was 3.14 for (90)Y-HuCC49ΔCh2, and 1.0 for (90)Y-CC49. Median tumor-to-spleen absorbed dose was 3.19 for (90)Y-HuCC49ΔCh2, and 1.07 for (90)Y-CC49. CONCLUSIONS: A humanized and CH2 domain-deleted CC49 antibody radiolabeled with (111)In/(90)Y showed improved tumor-to-normal dose ratios over those reported from studies with intact CC49.

Pilot trial of preoperative (neoadjuvant) letrozole in combination with bevacizumab in postmenopausal women with newly diagnosed estrogen receptor- or progesterone receptor-positive breast cancer.

INTRODUCTION: Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of antiestrogen adjuvant therapy. We designed a pilot study to assess the feasibility and short-term efficacy of neoadjuvant letrozole and bevacizumab (anti-VEGF) in postmenopausal women with stage II and III estrogen receptor/progesterone receptor-positive breast cancer. PATIENTS AND METHODS: Patients were treated with a neoadjuvant regimen of letrozole orally 2.5 mg/day and bevacizumab intravenously 15 mg/kg every 3 weeks for a total of 24 weeks before the surgical treatment of their breast cancer. Patients were followed for toxicity at 3-week intervals, and tumor assessment (a physical examination and ultrasound) was performed at 6-week intervals. Positron emission tomography (PET) scans were performed before therapy and 6 weeks after the initiation of therapy. RESULTS: Twenty-five evaluable patients were treated. The regimen was well-tolerated, except in 2 patients who were taken off the study for difficulties controlling their hypertension. An objective clinical response occurred in 17 of 25 patients (68%), including 16% complete responses (CRs) and 52% partial responses. The 4 patients with clinical CRs manifested pathologic CRs in their breasts (16%), although 1 patient had residual tumor cells in her axillary nodes. Eight of 25 patients (32%) attained stage 0 or 1 status. The PET scan response at 6 weeks correlated with clinical CRs and breast pathologic CRs at 24 weeks (P < .0036). CONCLUSION: Combination neoadjuvant therapy with letrozole and bevacizumab was well-tolerated and resulted in impressive clinical and pathologic responses. The Translational Breast Cancer Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.

MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy.

The potential of alpha-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of alpha-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with alpha-particle emitters. Although alpha-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted alpha-particle emitter therapy and to provide guidance and recommendations for human alpha-particle emitter dosimetry.

Impact of rituximab treatment on (90)Y-ibritumomab dosimetry for patients with non-Hodgkin lymphoma.

UNLABELLED: To determine whether the therapeutic effect of (90)Y-ibritumomab might be enhanced by a full course of rituximab followed by single dose of (90)Y-ibritumomab, the trial included pre- and post-rituximab treatment imaging with (111)In-ibritumomab and blood pharmacokinetics. Comparison of the pre- and post-rituximab imaging and blood data allowed for the assessment of impact of rituximab on (90)Y-ibritumomab dosimetry. METHODS: Seventeen patients with relapsed B cell non-Hodgkin lymphoma first received 250 mg/m(2) of rituximab plus 185 MBq of (111)In-ibritumomab for initial dosimetry evaluation. In weeks 2-4, patients received 3 weekly 375 mg/m(2) doses of rituximab. In week 6, patients received a 250 mg/m(2) dose of rituximab plus 185 MBq of (111)In-ibritumomab for a second dosimetry evaluation. Five sequential, whole-body gamma-camera images were acquired after the (111)In-ibritumomab injection. Calculated radiation doses were based on patient-specific organ masses. For each patient, paired comparison of radiation doses before and after rituximab treatment was performed. Paired comparison of residence times for spleen and tumor was also performed. RESULTS: Before rituximab treatment, the median radiation dose (mGy/MBq) was 0.48 (range, 0.24-0.86) for total body, 3.7 (range, 2.1-11.6) for liver, 6.1 (range, 1.8-17.8) for spleen, 3.3 (range, 2.0-4.7) for kidneys, 2.4 (range, 1.3-3.7) for heart wall, 1.1 (range, 0.4-2.3) for lungs, 0.79 (range, 0.32-1.22) for marrow from blood, and 18.1 (range, 4.7-98.9) for tumor. Paired comparisons were performed in 16 patients only because human antimurine antibody developed in 1 patient. The median change was 0.007 mGy/MBq for body, -0.14 mGy/MBq for liver, -0.31 mGy/MBq for kidneys, 0.38 mGy/MBq for heart wall, -0.17 mGy/MBq for lungs, and 0.046 mGy/MBq for marrow from blood. The median change in residence time was -0.92 h for spleen and -0.24 h for tumor. The changes were statistically insignificant for total body, liver, kidneys, lungs, and marrow from blood. The median residence times, or mGy/MBq if there were no volume changes, decreased 24% for spleen (P = 0.0005) and 28% for tumor (P = 0.005). The median radiation dose to heart wall increased 16%, which was statistically significant (P = 0.002). CONCLUSION: Changes in (90)Y-ibritumomab dosimetry after 4 wk of rituximab treatment were not significant for most organs, except for the heart wall. The reduction of spleen and tumor residence times is more likely to be due to the therapeutic effects of rituximab.

Dosimetric factors associated with long-term dysphagia after definitive radiotherapy for squamous cell carcinoma of the head and neck.

PURPOSE: Intensification of radiotherapy and chemotherapy for head-and-neck cancer may lead to increased rates of dysphagia. Dosimetric predictors of objective findings of long-term dysphagia were sought. METHODS AND MATERIALS: From an institutional database, 83 patients were identified who underwent definitive intensity-modulated radiotherapy for squamous cell carcinoma of the head and neck, after exclusion of those who were treated for a second or recurrent head-and-neck primary lesion, had locoregional recurrence at any time, had less than 12 months of follow-up, or had postoperative radiotherapy. Dosimetric parameters were analyzed relative to three objective endpoints as a surrogate for severe long-term dysphagia: percutaneous endoscopic gastrostomy (PEG) tube dependence at 12 months, aspiration on modified barium swallow, or pharyngoesophageal stricture requiring dilation. RESULTS: Mean dose greater than 41 Gy and volume receiving 60 Gy (V(60)) greater than 24% to the larynx were significantly associated with PEG tube dependence and aspiration. V(60) greater than 12% to the inferior pharyngeal constrictor was also significantly associated with increased PEG tube dependence and aspiration. V(65) greater than 33% to the superior pharyngeal constrictor or greater than 75% to the middle pharyngeal constrictor was associated with pharyngoesophageal stricture requiring dilation. CONCLUSIONS: Doses to the larynx and pharyngeal constrictors predicted long-term swallowing complications, even when controlled for other clinical factors. The addition of these structures to intensity-modulated radiotherapy optimization may reduce the incidence of dysphagia, although cautious clinical validation is necessary.

Margin on gross tumor volume and risk of local recurrence in head-and-neck cancer.

PURPOSE: To determine whether the method or extent of construction of the high-dose clinical target volume (CTV) and high-dose planning target volume (PTV) in intensity-modulated radiation therapy (IMRT) for head-and-neck cancer are associated with an increased risk of locoregional failure. MATERIALS AND METHODS: Patients with nasopharyngeal, oropharyngeal, oral cavity, hypopharyngeal, or laryngeal squamous cell carcinomas treated definitively with IMRT were included. All patients without local relapse had a minimum follow-up of 12 months. Median follow-up for all patients was 24 months. Treatment plans of 85 available patients were reviewed, and the gross tumor volume (GTV) to PTV expansion method was estimated. RESULTS: The GTVs were expanded volumetrically in 71 of 85 patients, by a median of 15 mm (range, 4-25 mm). An anatomic component to the expansion of GTV was used in 14 of 85 patients. Eighteen patients failed locoregionally, for an actuarial locoregional control rate of 77.2% at 2 years. There was no significant difference in locoregional control between patients with GTVs expanded volumetrically vs. those with a component of anatomic expansion. In patients with GTVs expanded volumetrically, no increase in risk of local failure was seen in patients with a total GTV expansion of < or =15 mm. CONCLUSION: In this retrospective study, there was not an increased risk of local failure using smaller margins or expanding GTVs volumetrically when treating head-and-neck cancer patients definitively with IMRT.

Mucositis-related morbidity and resource utilization in head and neck cancer patients receiving radiation therapy with or without chemotherapy.

The objective of this study was to estimate health care-resource utilization in head and neck cancer (HNC) patients. This was a prospective, longitudinal, multicenter, noninterventional study of mucositis in patients receiving radiation with or without chemotherapy for HNC. Mouth and throat soreness and functional impairment were measured using the Oral Mucositis Weekly Questionnaire-HNC. Resource utilization data were obtained from patient interviews and recorded from the patient's medical chart. Seventy-five patients were enrolled from six centers. Fifty (67%) patients received concurrent chemoradiation therapy; 34 (45%) received intensity-modulated radiation therapy. Over the course of treatment, 57 (76%) patients reported severe mouth and throat soreness. Pain and functional impairment because of mouth and throat soreness increased during the course of therapy despite the use of opioid analgesics in 64 (85%) of the patients. Complications of radiation therapy resulted in increased patient visits to physicians, nurses, and nutritionists. Thirty-eight (51%) patients had a feeding tube placed. Twenty-eight patients (37%) were hospitalized, five of whom were hospitalized twice; of the 33 admissions, 10 (30%) were designated as secondary to mucositis by their treating physician. Mean length of hospitalization was 4.9 days (range: 1-16). This study demonstrates that mucositis-related pain and functional impairment is associated with increased use of costly health resources. Effective treatments to reduce the pain and functional impairment of oral mucositis are needed in this patient population.

MIRD dose estimate report No. 20: radiation absorbed-dose estimates for 111In- and 90Y-ibritumomab tiuxetan.

UNLABELLED: Absorbed-dose calculations provide a scientific basis for evaluating the biologic effects associated with administered radiopharmaceuticals. In cancer therapy, radiation dosimetry supports treatment planning, dose-response analyses, predictions of therapy effectiveness, and completeness of patient medical records. In this study, we evaluated the organ radiation absorbed doses from intravenously administered (111)In- and (90)Y-ibritumomab tiuxetan. METHODS: Ten patients (6 men and 4 women) with non-Hodgkin lymphoma, cared for at 3 different medical centers, were administered the tracer (111)In-ibritumomab tiuxetan and assessed using planar scintillation camera imaging at 5 time points and CT-organ volumetrics to determine patient-specific organ biokinetics and dosimetry. Explicit attenuation correction based on the transmission scan or transmission measurements provided the fraction of (111)In-administered activity in 7 major organs, the whole body, and remainder tissues over time through complete decay. Time-activity curves were constructed, and radiation doses were calculated using MIRD methods and implementing software. RESULTS: Mean radiation absorbed doses for (111)In- and for (90)Y-ibritumomab tiuxetan administered to 10 cancer patients are reported for 24 organs and the whole body. Biologic uptake and retention data are given for 7 major source organs, remainder tissues, and the whole body. Median absorbed dose values calculated by this method were compared with previously published dosimetry for ibritumomab tiuxetan and the product package insert. CONCLUSION: In high-dose radioimmunotherapy, the importance of patient-specific dosimetry becomes obvious when the objective of treatment planning is to achieve disease cures, safely, by limiting radiation dose to any critical normal organ to its maximum tolerable value. Compared with the current package insert, we found differences in median absorbed dose by multiples of 24 in the kidneys, 1.8 in the red marrow, 0.65 in the liver, 0.077 in the intestinal wall, 0.30 in the lungs, 0.46 in the spleen, and 0.34 in the heart wall.

Factors associated with long-term dysphagia after definitive radiotherapy for locally advanced head-and-neck cancer.

PURPOSE: The use of altered fractionation radiotherapy (RT) regimens, as well as concomitant chemotherapy and RT, to intensify therapy for locally advanced head-and-neck cancer can lead to increased rates of long-term dysphagia. METHODS AND MATERIALS: We identified 122 patients who had undergone definitive RT for locally advanced head-and-neck cancer, after excluding those who had been treated for a second or recurrent head-and-neck primary, had Stage I-II disease, developed locoregional recurrence, had <12 months of follow-up, or had undergone postoperative RT. The patient, tumor, and treatment factors were correlated with a composite of 3 objective endpoints as a surrogate for severe long-term dysphagia: percutaneous endoscopic gastrostomy tube dependence at the last follow-up visit; aspiration on a modified barium swallow study or a clinical diagnosis of aspiration pneumonia; or the presence of a pharyngoesophageal stricture. RESULTS: A composite dysphagia outcome occurred in 38.5% of patients. On univariate analysis, the primary site (p = 0.01), use of concurrent chemotherapy (p = 0.01), RT schedule (p = 0.02), and increasing age (p = 0.04) were significantly associated with development of composite long-term dysphagia. The use of concurrent chemotherapy (p = 0.01), primary site (p = 0.02), and increasing age (p = 0.02) remained significant on multivariate analysis. CONCLUSION: The addition of concurrent chemotherapy to RT for locally advanced head-and-neck cancer resulted in increased long-term dysphagia. Early intervention using swallowing exercises, avoidance of nothing-by-mouth periods, and the use of intensity-modulated RT to reduce the dose to the uninvolved swallowing structures should be explored further in populations at greater risk of long-term dysphagia.

MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response--implications for radionuclide therapy.

UNLABELLED: Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose-response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. METHODS: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. RESULTS: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and (166)Ho-phosphonate clinical investigations. CONCLUSION: Radionuclide therapy dose-response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.