Disparities in disease presentation in the four screenable cancers according to health insurance status.

OBJECTIVES: Current guidelines support the use of screening for early detection in breast, prostate, colorectal and cervical cancer. The purpose of this study was to evaluate whether insurance status predicts for more advanced disease in these four currently screened cancers. STUDY DESIGN: The Surveillance, Epidemiology, and End Results (SEER) database was queried for breast, prostate, colorectal and cervix in patients aged 18-64 years. The database was queried from 2007 to 2011, with 425,614 patients with known insurance status included. METHODS: Multinomial logistic regression was used to evaluate insurance status and cancer presentation. RESULTS: Under multivariate analysis for breast cancer, uninsured patients more often had invasive disease (odds ratio [OR]: 1.55), T- (OR: 2.00), N- (OR: 1.59) stage, and metastatic disease (OR: 3.48), and were more often high-grade (OR: 1.21). For prostate cancer, uninsured patients again presented more commonly with higher T-stage (OR: 1.45), nodal (OR: 2.90) and metastatic (OR: 4.98) disease, in addition to higher prostate-specific antigen (OR: 2.85) and Gleason score (OR: 1.65). Colorectal cancer had similar findings with uninsured individuals presenting with more invasive disease (OR: 1.78), higher T (OR: 1.86), N (OR: 1.22), and M (OR: 1.58) stage, in addition to higher carcinoembryonic antigen levels (OR: 1.66). Similar results were seen for cervical cancer with uninsured having higher T (OR: 2.03), N (OR: 1.21), and M (OR: 1.45) stage. CONCLUSION: In the four cancers detected by screening exams, those without health insurance present with more advanced disease, with higher stage and grade, and more elevated tumour markers.

Microscopic and macroscopic tumor and parenchymal effects of liver stereotactic body radiotherapy.

PURPOSE: To describe the histologic and volumetric changes in normal liver tissue after stereotactic body radiotherapy (SBRT) for liver metastases. METHODS AND MATERIALS: Pre- and post-SBRT imaging studies were analyzed to evaluate the effect of SBRT on normal liver volume (NLV) in 15 patients treated in a prospective clinical trial. Two other patients underwent exploratory surgery after SBRT and histologic analyses of the irradiated liver were performed to characterize the pathologic effects of SBRT. RESULTS: In the 15 patients studied quantitatively, the total NLV had decreased transiently at 2-3 months after SBRT and then began to regenerate at 3-8 months after SBRT. The median NLV reduction at the maximal observed effect was 315 cm(3) (range, 125-600) or 19% (range, 13-33%). Among the several dosimetric parameters evaluated, the strongest linear correlation was noted for the NLV percentage receiving 30 Gy as a predictor of maximal NLV reduction (r(2) = 0.72). The histologic changes observed 2 and 8 months after SBRT demonstrated distinct zones of tissue injury consistent with localized veno-occlusive disease. CONCLUSION: The well-demarcated focal parenchymal changes after liver SBRT (demonstrated both radiographically and histologically) within the high-dose zone are consistent with a threshold dose-induced set of phenomena. In contrast, the more global effect of NLV reduction, which is roughly proportional to whole organ dose parameters, resembles more closely an effect determined from radiobiologically parallel architecture. These observations suggest that modeling of normal tissue effects after liver SBRT might require different governing equations for different classes of effects.

How should we describe the radioblologic effect of extracranial stereotactic radlosurgery: equivalent uniform dose or tumor control probability?

Extracranial stereotactic radiosurgery (ESR) is now undergoing clinical investigation at numerous institutions as a treatment for solitary malignant lesions. Because there is no standard ESR technique, the same minimum dose might be applied through widely variable target dose-volume histograms. For multicenter trials of ESR or interinstitutional comparisons, a reliable index of radiobiological dose equivalency might facilitate the evaluation of dose-response relationships. Equivalent uniform dose (EUD) and tumor control probability (TCP) were considered for this application. While EUD appears more robust for the prospective description of ESR, TCP is expected to remain more valuable for a post hoc estimation of radiosensitivity parameters.

The effect of setup uncertainty on normal tissue sparing with IMRT for head-and-neck cancer.

PURPOSE: Intensity-modulated radiotherapy (IMRT) is being evaluated in the management of head-and-neck cancers at several institutions, and a Radiation Therapy Oncology Group study of its utility in parotid sparing is under development. There is an inherent risk that the sharper dose gradients generated by IMRT amplify the potentially detrimental impact of setup uncertainty. The International Commission on Radiation Units and Measurements Report 62 (ICRU-62) defined planning organ-at-risk volume (PRV) to account for positional uncertainties for normal tissues. The purpose of this study is to quantify the dosimetric effect of employing PRV for the parotid gland and to evaluate the use of PRV on normal-tissue sparing in the setting of small clinical setup errors. METHODS AND MATERIALS: The optimized nine-beam IMRT plans for three head-and-neck cancer patients participating in an institutional review board approved parotid-sparing protocol were used as reference plans. A second optimized plan was generated for each patient by adding a PRV of 5 mm for the contralateral parotid gland. The effect of these additions on the quality of the plans was quantified, in terms of both target coverage and normal-tissue sparing. To test the value of PRV in a worst-case scenario, systematic translational setup uncertainties were simulated by shifting the treatment isocenter 5 mm superiorly, inferiorly, left, right, anteriorly, and posteriorly, without altering optimized beam profiles. At each shifted isocenter, dose distributions were recalculated, producing a total of six shifted plans without PRV and six shifted plans with PRV for each patient. The effect of setup uncertainty on parotid sparing and the value of PRV in compensating for the uncertainty were evaluated. RESULTS: The addition of the PRV and reoptimization did not significantly affect the dose to gross tumor volume, spinal cord, or brainstem. In contrast, without any shift, the PRV did increase parotid sparing and reduce coverage of the nodal region adjacent to the parotid gland. As expected, when the plans were shifted, the greatest increase in contralateral parotid irradiation was noted with shifts toward the contralateral parotid gland. With these shifts, the average volume of contralateral parotid receiving greater than 30 Gy was reduced from 22% to 4% when a PRV was used. This correlated with a reduction in the average normal-tissue complication probability (NTCP) from 22% to 7%. CONCLUSIONS: The use of PRV may limit the volume of normal tissue structures, such as the parotid gland, exceeding tolerance dose as a result of setup errors. Consequently, it will be important to incorporate the nomenclature of ICRU-62 into the design of future IMRT studies, if the clinical gains of increased normal-tissue sparing are to be realized.

Cost analysis of erythropoietin versus blood transfusions for cervical cancer patients receiving chemoradiotherapy.

PURPOSE: Red blood cell (RBC) transfusions or erythropoietin (EPO) can be used to evade the detrimental effects of anemia during radiotherapy, but the economic consequences of selecting either intervention are not well defined. The RBC transfusion needs during chemoradiotherapy for cervix cancer were quantified to allow comparison of RBC transfusion costs with the projected cost of EPO in this setting. METHODS AND MATERIALS: For patients receiving pelvic radiotherapy, weekly cisplatin, and brachytherapy, the RBC units transfused during treatment were tallied. RBC transfusion costs per unit included the blood itself, laboratory fees, and expected value (risk multiplied by cost) of transfusion-related viral illness. EPO costs included the drug itself and supplemental RBC transfusions when hemoglobin was not adequately maintained. An EPO dosage based on reported usage in cervix cancer patients was applied. RESULTS: Transfusions were given for hemoglobin <10 g/dL. Among 12 consecutive patients, 10 needed at least 1 U of RBC before or during treatment, most commonly after the fifth week. A total of 37 U was given during treatment, for an average of 3.1 U/patient. The sum total of the projected average transfusion-related costs was $990, compared with the total projected EPO-related costs of $3869. CONCLUSIONS: Because no proven clinical advantage has been documented for EPO compared with RBC transfusions to maintain hemoglobin during cervix cancer treatment, for most patients, transfusions are an appropriate and appealingly less expensive option.

Long-term local control and survival after concomitant boost accelerated radiotherapy for locally advanced cervix cancer.

Between 1989 and 1994, a prospective clinical trial tested the safety and efficacy of concomitant boost accelerated superfractionated (CBASF) radiotherapy for patients with locally advanced cervix cancer. CBASF radiotherapy included 45 Gy/25 fractions to the pelvis and a 14.4 Gy/9 fraction concomitant boost to the primary tumor, followed by brachytherapy for a total point A dose of 85 Gy to 90 Gy. The 22 patients of International Federation of Gynecology and Obstetrics stages IIIA-IVA who received CBASF radiotherapy now have a median follow-up time of more than 8 years. The 7-year actuarial rates of local control and overall survival are 81% and 36%, respectively. Serious late toxicity included bowel injury requiring colostomy in eight patients within 2.5 years after treatment, but no other severe toxicity was observed after longer follow-up intervals. The local control and survival rates achieved with CBASF radiotherapy were higher than those observed within a matched contemporaneous cohort of patients treated with standard radiotherapy alone at the same institution (p = 0.1 for local control, 0.09 for survival). The encouraging trend toward improved tumor control, tempered by the complication rate, suggests an opportunity to apply more sophisticated radiotherapy techniques that might sustain the favorable effects of dose intensification while mitigating the normal tissue toxicity.

A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics.

PURPOSE: Preclinical studies indicate that RSR13 oxygenates and radiosensitizes hypoxic solid tumors by decreasing the oxygen (O(2))-binding affinity of hemoglobin (Hb). A Phase I open-label, multicenter dose and frequency escalation study was conducted to assess the safety, tolerance, pharmacokinetics, and pharmacodynamic effect of daily RSR13 administration to cancer patients receiving concurrent palliative radiotherapy (RT). METHODS AND MATERIALS: Eligibility criteria included the following: ECOG performance status < or =2; resting and exercise arterial oxygen saturation (SaO(2)) > or =90%; an indication for palliative RT, 20-40 Gy in 10-15 fractions. RSR13 was administered i.v. via central vein over 60 min immediately before RT. Patients received supplemental O(2) via nasal cannula at 4 L/min during RSR13 infusion and RT. Plasma, red blood cell (RBC), and urine RSR13 concentrations were assayed. The pharmacodynamic effect of RSR13 on Hb-O(2) binding affinity was quantified by multipoint tonometry and expressed as an increase in p50, defined as the partial pressure of O(2) that results in 50% SaO(2). The RSR13 dose in the first cohort was 75 mg/kg once a week for two doses; successive cohorts received higher, more frequent doses up to 100 mg/kg/day for 10 days during RT. RESULTS: Twenty patients were enrolled in the study. Repeated daily doses of RSR13 were generally well tolerated. Two adverse events of note occurred: (1) A patient with pre-existing restrictive lung disease had transient persistent hypoxemia after the sixth RSR13 dose; (2) a patient with a recurrent glioma receiving high-dose corticosteroids had edema after the seventh RSR13 dose, likely due to the daily high-volume fluid infusions. Both patients recovered to baseline status with conservative management. Maximum pharmacodynamic effect occurred at the end of RSR13 infusion and was proportional to the RBC RSR13 concentration. After an RSR13 dose of 100 mg/kg, the peak increase in p50 averaged 8.1 mm Hg, consistent with the targeted physiologic effect, and then diminished with a half-life of approximately 5 h. CONCLUSIONS: RSR13 was well tolerated in daily doses up to 100 mg/kg administered for 10 days during RT. The combined administration of RSR13 with 4 L/min supplemental O(2) yielded pharmacodynamic conditions in which hypoxic tumor radiosensitization can occur. Ongoing Phase II and Phase III studies are evaluating the combination of RT and RSR13 for selected indications, including primary brain tumors, brain metastases, and non-small-cell lung cancer.

Extracorporeal irradiation of tumorous calvaria. Case report.

This patient with recurrent meningioma grossly involving the frontal bone underwent craniotomy and tumor resection. During the procedure a bone flap was irradiated extracorporeally at a very high dose (120 Gy) sufficient to sterilize residual tumor cells, and the bone was then successfully replaced orthotopically for reconstruction. The use of autologous irradiated bone in this setting offers advantages over cadaveric transplantation and prosthetic implants. Radiation might cause less disruption of the bone's architecture than other techniques of tumor cell eradication.

Gynecologic brachytherapy: digital fluoroscopy for placement verification and treatment planning.

The authors evaluated the feasibility of using digital fluoroscopic images for device placement verification and dosimetric planning for gynecologic brachytherapy. Adequate images were obtained rapidly, and the limited pincushion distortion on digital fluoroscopic images produced negligible variations in brachytherapy dose calculations compared with those calculated with standard radiographs. Intraoperative digital fluoroscopy can facilitate both placement verification and dosimetric planning for gynecologic brachytherapy.

Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases.

PURPOSE: Modeling studies have demonstrated a potential biologic advantage of fractionated stereotactic radiotherapy for malignant brain tumors as compared to radiosurgery (SRS), even when only a few fractions are utilized. We prospectively evaluated the feasibility, toxicity, efficacy and cost of hypofractionated stereotactic radiotherapy (HSRT) in the treatment of selected radiosurgery-eligible patients with brain metastases. METHODS AND MATERIALS: Patients with a limited number of brain metastases not involving the brainstem or optic chiasm underwent linac-based HSRT delivered in 3 fractions using a relocatable stereotactic frame. Depth-helmet and reference point measurements were recorded to address treatment accuracy. All patients underwent whole brain radiotherapy to a dose of 30 Gy. Toxicity, response, and survival duration were recorded for each patient. Prognostic factors were assessed by Cox regression analysis. Cost comparisons with a cohort of SRS treated patients were performed. RESULTS: Thirty-two patients with 57 brain metastases were treated with HSRT. Twenty-three and 9 patients underwent HSRT for upfront and salvage treatment, respectively. The median dose delivered was 27 Gy, given in 3 fractions of 9 Gy. From 3328 depth-helmet measurements, the absolute median setup deviation in AP, lateral, and vertical orientations was approximately 1.0 mm. No significant acute toxicity was seen. Late toxicities included seizures in four patients, and radionecrosis in two patients. The median survival duration from treatment was 12 months. KPS (p = 0.039) and RTOG-RPA class (p = 0.039) were identified as significant prognostic factors for survival. HSRT was $4119 less costly than SRS. CONCLUSION: HSRT, as delivered in this study, is more comfortable for patients and less costly than SRS in the treatment of selected patients with brain metastases. Proper dose selection and radiobiologic/toxicity trade-offs with SRS await further study.

Conformal radiotherapy: what is it and why does it matter?

Three-dimensional conformal radiotherapy is quickly becoming a standard radiation oncology practice at many academic and community-based departments. Three-dimensional conformal radiotherapy allows clinicians to deliver safer and more accurate treatments to patients. It is also being used to increase tumor doses for situations in which traditional radiation techniques have been unsuccessful. Current and future clinical trials of dose-escalated three-dimensional conformal radiotherapy will examine its ultimate clinical effectiveness.

Desmoplastic malignant melanoma of the palatal alveolar mucosa: sustained disease-free survival after surgery and postoperative radiotherapy.

Aggressive surgical and radiotherapeutic management of a patient with desmoplastic malignant melanoma arising from the mucosa of the oral cavity has resulted in disease-free survival of more than 2(1/2) years after diagnosis. This case represents only the tenth reported instance of desmoplastic malignant melanoma arising from the oral cavity and only the third for which survival has exceeded 2 years. Details of the clinical, histopathologic, and therapeutic features of the case are provided to augment the paucity of literature available to clinicians managing this rare disease.

Recurrent cervical carcinoma: typical and atypical manifestations.

After treatment of cervical carcinoma, recurrent disease may be observed in multiple sites at imaging. Both typical and atypical manifestations of recurrent disease occur. Typical manifestations of recurrent cervical carcinoma involve the pelvis and lymph nodes. Pelvic recurrences may be observed as masses involving the cervix and uterus, vagina or vaginal cuff, parametria, bladder, ureters, rectum, or ovaries and may result in fistula formation or hydronephrosis. Nodal recurrence may be identified as enlarged pelvic and retroperitoneal nodes. Atypical manifestations of recurrent cervical carcinoma are being recognized with greater frequency due to the use of intensive pelvic radiation therapy, the evolution of improved imaging techniques, and the more frequent use of imaging as a means of surveillance. These atypical manifestations may involve the solid organs of the abdomen (focal masses) as well as the peritoneum, mesentery, and omentum (implants); gastrointestinal tract (obstruction, fistula formation, ischemia); chest (metastases to the lung parenchyma, pleura, and pericardium); bones (destructive lesions); and other sites. Familiarity with the imaging features of recurrent cervical carcinoma in these anatomic locations will facilitate prompt, accurate diagnosis and treatment.

Determining the optimal block margin on the planning target volume for extracranial stereotactic radiotherapy.

PURPOSE: To determine the block margin that minimizes normal tissue irradiation outside of the planning target volume (PTV) for body stereotactic radiotherapy (Body-SRT) of lung and liver tumors. METHODS AND MATERIALS: Representative patient cases of lung and liver tumors were chosen for analysis. A PTV was constructed for each case and plans were generated which employed an array of block margins ranging from -2.5 mm to 10 mm at isocenter. Plans were generated for cerrobend blocks and for a multileaf collimator. The prescription isodose coverage was renormalized for each case and dose-volume histograms (DVH) and normal tissue complication probabilities (NTCP) were determined for each plan. RESULTS AND CONCLUSION: For the cases studied, the optimal block margin was in the 0.0 mm range. The ranking of plans was identical for both dose-volume based and biological based criteria. The method of blocking had no significant effect on treatment plans. The use of narrow margins for Body-SRT results in normal tissue sparing and creates significant target dose inhomogeneity which may be beneficial for tumor control.

Optimization of planar high-dose-rate implants.

PURPOSE: Brachytherapy has long been used to deliver localized radiation to the breast and other cancer sites. For interstitial implants, proper source positioning is critical in obtaining satisfactory dose distributions. The present work examines techniques for optimizing source guide placement in high-dose-rate (HDR) biplanar implants, and examines the effects of suboptimal catheter placement. METHODS AND MATERIALS: Control of individual dwell times in HDR implants allows a high degree of dose uniformity in planes parallel to the implant planes. Biplanar HDR implants can be considered optimized when the dose at the implant center is equal to the dose at the symmetric target boundaries. It is shown that this optimal dose uniformity is achieved when the interplanar separation is related to the target thickness T through the direct proportionality, s = T/square root2. To quantify the significance of source positioning, the average dose and a related quantity, equivalent uniform dose (EUD), were calculated inside the treatment volume for two conditions of suboptimal catheter geometry. In one case, the interplanar spacing was varied from 1 cm up to the target thickness T, while a second study examined the effects of off-center placement of the implant planes. RESULTS: Both the average dose and EUD were minimized when the interplanar spacing satisfied the relationship s = T/square root2. EUD, however, was significantly smaller than the average dose, indicating a reduced relative cell killing in the high dose regions near the dwell points. It was also noted that in contrast to the average dose, the EUD is a relatively weak function of catheter misplacement, suggesting that the biological consequences of suboptimal implant geometry may be less significant than is indicated by the increase in average dose. CONCLUSION: A concise formula can be used to determine the interplanar separation needed for optimal dose uniformity in Manchester-type implants. Deviations from optimal source geometry result in an increase in the average dose inside the treatment volume, but the weaker dependence of the EUD suggests that the surviving fraction of cells may not be not strongly affected by suboptimal source geometry.

RSR13, an allosteric effector of haemoglobin, and carbogen radiosensitize FSAII and SCCVII tumours in C3H mice.

Pre-clinical evaluation has demonstrated that 2-[4-(((3,5-dimethylanilino)carbonyl)methyl)phenoxy]-2-methylpropi onic acid (RSR13) acts as an allosteric effector of haemoglobin (Hb). RSR13 binding to Hb results in decreased haemoglobin-oxygen (Hb-O2) affinity, improved tumour oxygenation, and enhanced radiation-induced cell killing in several experimental tumour systems. In the present work, ex vivo clonogenic survival analyses are applied in two murine tumour systems to characterize the relationship between the magnitude of decrease in Hb-O2 affinity and radiosensitization, the influence of inspired pO2 upon this effect, and the efficacy of combining RSR13 and radiation during a course of repeated radiation exposures. For FSaII tumours in C3H mice breathing air, 100 mg kg(-1) RSR13 administered intraperitoneally produced an enhancement ratio (ER) of 1.3, but there was marked desensitization at a RSR13 dose of 300 mg kg(-1) (ER 0.6). The most likely reason for the increased radioresistance was insufficient oxygen loading of Hb in the pulmonary circulation due to reduced haemoglobin-oxygen affinity because carbogen breathing combined with 300 mg kg(-1) RSR13 reversed the effect and produced an ER of 1.8. In SCCVII tumours in C3H mice irradiated with eight fractions of 2.5 Gy over 4 days, the surviving fraction was reduced to 58-67% of control values when RSR13 was combined with radiation on days 1 and 2, days 3 and 4, or days 1-4. These results confirm that combining RSR13 and irradiation within a fractionated course of clinically relevant low-dose exposures provides significant radiosensitization. Additional preclinical experimentation is needed to define better the optimum dose-scheduling conditions for clinical applications.

Calcium-dependent stimulation of mitogen-activated protein kinase activity in A431 cells by low doses of ionizing radiation.

Ionizing radiation at 2 Gy activates the epidermal growth factor receptor (EGFR) kinase activity in A431 squamous carcinoma cells and as a consequence transiently activates a downstream effector, mitogen-activated protein kinase (MAPK). A dose-response analysis shows fourfold activation 3-5 min after irradiation at 0.5 Gy with no additional activation after doses up to 4 Gy. Activation is independent of protein kinase C as defined by marginal effects of protein kinase C down-regulation and the protein kinase C inhibitor, chelerythrine. In contrast, an intracellular Ca2+ chelator (BAPTA/AM), a Ca2+ antagonist (TMB-8) and a phospholipase C inhibitor (U73223), which inhibits radiation-induced Ca2+ oscillations, all block MAPK stimulation. The upstream component, Raf-1, is also activated through a mechanism that is dependent on EGFR and Ca2+. Activation of Raf-1, monitored by tyrosine phosphorylation and co-immunoprecipitation with Ras, was inhibited by BAPTA/AM and TMB-8, indicating that the Ca2+-dependent step occurs at or before the interaction of Ras and Raf-1. Neither the Ras guanosine triphosphate exchange protein, SOS, nor Ca2+-activated tyrosine kinases linked to the MAPK pathway, focal adhesion kinase and PYK2, were stimulated by radiation. In contrast, EGF activated SOS as shown by the enhanced association of SOS with EGFR in co-immunoprecipitation experiments. These results suggest that activation of EGFR-dependent downstream signaling induced by radiation differs from that induced by the natural ligands of EGFR.