Tolerance of Normal Rabbit Facial Bones and Teeth to Synchrotron X-Ray Microbeam Irradiation.

Microbeam radiation therapy, an alternative radiosurgical treatment under preclinical investigation, aims to safely treat muzzle tumors in pet animals. This will require data on the largely unknown radiation toxicity of microbeam arrays for bones and teeth. To this end, the muzzle of six young adult New Zealand rabbits was irradiated by a lateral array of microplanar beamlets with peak entrance doses of 200, 330 or 500 Gy. The muzzles were examined 431 days postirradiation by computed microtomographic imaging (micro-CT) ex vivo, and extensive histopathology. The boundaries of the radiation field were identified histologically by microbeam tracks in cartilage and other tissues. There was no radionecrosis of facial bones in any rabbit. Conversely, normal incisor teeth exposed to peak entrance doses of 330 Gy or 500 Gy developed marked caries-like damage, whereas the incisors of the two rabbits exposed to 200 Gy remained unscathed. A single, unidirectional array of microbeams with a peak entrance dose ≤200 Gy (valley dose14 Gy) did not damage normal bone, teeth and soft tissues of the muzzle of normal rabbits longer than one year after irradiation. Because of that, Microbeam radiation therapy of muzzle tumors in pet animals is unlikely to cause sizeable damage to normal teeth, bone and soft tissues, if a single array as used here delivers a limited entrance dose of 200 Gy and a valley dose of ≤14 Gy.

Radiation therapy planning using MRI-CT fusion in dogs and cats with brain tumors.

INTRODUCTION: Volume definition is a delicate step within the radiation treatment planning process and the precision of defining the volumes to irradiate is important for the success of the radiation treatment. Traditionally, radiation plans are created using computed tomography (CT) studies. Due to its different mechanism of action, magnetic resonance imaging (MRI) is more sensitive for detection of brain lesions. Therefore, using fused images of both imaging modalities should result in a more precise definition of the volumes to irradiate. The feasibility to fuse CT and MRI studies performed at different institutions was tested to subsequently analyse the influence of the fused images on target volume definition. MATERIALS AND METHODS: Fourteen dogs and four cats with brain lesions having MR- and CT-imaging were included. Contrast-enhanced radiotherapy planning CT scans were fused to T1-weighted post-contrast and T2-weighted MRI scans. The gross tumor volume (GTV), the clinical tumor volume (CTV) and the planning target volume (PTV) were delineated on CT- and MRI studies. CT and MRI volumes were compared with regard to volumetric and spatial differences. RESULTS: The mean GTV was larger on MRI than on CT (2.15 vs.1.54 cm3). Also the mean CTV was larger on MRI than on CT (5.34 vs. 4.38 cm3). Consequently, the mean PTV was larger on MRI than on CT (14.20 vs. 10.82 cm3) as well. None of the differences in defined volumes were significant. Fusion images were accepted showing mean errors of 1.32 mm (mean error) and 1.73 mm (maximal error). CONCLUSION: CT-MRI fusion was feasible especially when defined, reliable, and consistent anatomic landmarks were used as registration points. Volumetric differences between CT and MRI were insignificant. In general, GTV and CTV were easier identified on MRI.

Response of the rat spinal cord to X-ray microbeams.

BACKGROUND AND PURPOSE: To quantify the late dose-related responses of the rat cervical spinal cord to X-ray irradiations by an array of microbeams or by a single millimeter beam. MATERIALS AND METHODS: Necks of anesthetized rats were irradiated transversely by an 11 mm wide array of 52 parallel, 35 µm wide, vertical X-ray microbeams, separated by 210 µm intervals between centers. Comparison was made with rats irradiated with a 1.35 mm wide single beam of similar X-rays. Rats were killed when paresis developed, or up to 383 days post irradiation (dpi). RESULTS: Microbeam peak/valley doses of ≈357/12.7 Gy to 715/25.4 Gy to an 11 mm long segment of the spinal cord, or single beam doses of ≈146-454 Gy to a 1.35 mm long segment caused foreleg paresis and histopathologically verified spinal cord damage; rats exposed to peak/valley doses up to 253/9 Gy were paresis-free at 383 dpi. CONCLUSIONS: Whereas microbeam radiation therapy [MRT] for malignant gliomas implanted in rat brains can be safe, palliative or curative, the high tolerance of normal rat spinal cords to similar microbeam exposures justifies testing MRT for autochthonous malignancies in the central nervous system of larger animals with a view to subsequent clinical applications.

Efficacy and toxicity of an accelerated hypofractionated radiation therapy protocol in cats with oral squamous cell carcinoma.

Squamous cell carcinoma (SCC) is the most common feline oral tumor. Standard radiation protocols have been reported to achieve tumor control durations of 1.5-5.5 months (45-165 days). The purpose of this study was to describe the efficacy and toxicity of an accelerated hypofractionated radiation therapy protocol in cats with oral SCC. Twenty-one cats with histologically confirmed oral SCC and T1-3N0M0 were treated with 10 once-daily fractions (Monday-Friday) of 4.8 Gy. Seventeen cats had macroscopic disease and four were microscopic after incomplete excision. Acute toxicity consisted of grade 2 mucositis in all cats and this was effectively managed using esophageal or gastric tube feeding, pain medication, and antibiotics. Late toxicity effects for cats with available follow-up data included alopecia (4 cats), leukotricia (6), tongue ulceration (1), and oronasal fistula (1). Response could be assessed in 17 cats (seven complete response and five partial response). Four cats (19%) developed metastatic disease without evidence of local progression. The median progression-free survival (PFS) was 105 days (1 year PFS of 23%), median local progression-free survival (LPFS) was 219 days (1 year LPFS of 41%), and median overall survival (OS) was 174 days (1 year OS of 29%). Only tumor stage was prognostic, with T1 having a median PFS of 590 days. Findings indicated that this accelerated hypofractionated radiation therapy protocol was well tolerated in cats with oral SCC, with manageable adverse events. Tumor response was observed in most cats and long tumor control durations were achieved in some cats.

Assessment of changes in vascularity and blood volume in canine sarcomas and squamous cell carcinomas during fractionated radiation therapy using quantified contrast-enhanced power Doppler ultrasonography: a preliminary study.

Radiation therapy does not only target tumour cells but also affects tumour vascularity. In the present study, changes in tumour vascularity and blood volume were investigated in five grade 1 oral fibrosarcomas, eight other sarcomas (non-oral soft tissue and bone sarcomas) and 12 squamous cell carcinomas in dogs during fractionated radiation therapy (total dose, 45-56 Gy). Contrast-enhanced power Doppler ultrasound was performed before fraction 1, 3, 6, 8, 10, 12, 14 and 15 or 16 (sarcomas) or 17 (squamous cell carcinomas). Prior to treatment, median vascularity and blood volume were significantly higher in squamous cell carcinomas (P=0.0005 and 0.001), whereas measurements did not differ between oral fibrosarcomas and other sarcomas (P=0.88 and 0.999). During the course of radiation therapy, only small, non-significant changes in vascularity and blood volume were observed in all three tumour histology groups (P=0.08 and P=0.213), whereas median tumour volume significantly decreased until the end of treatment (P=0.04 for fibrosarcomas and other sarcomas, P=0.008 for squamous cell carcinomas). It appeared that there was a proportional decrease in tumour volume, vascularity and blood volume. Doppler measurements did not predict progression free interval or survival in any of the three tumour groups (P=0.06-0.86). However, the number of tumours investigated was small and therefore, the results can only be considered preliminary.

Correlation of quantified contrast-enhanced power Doppler ultrasonography with immunofluorescent analysis of microvessel density in spontaneous canine tumours.

Conventionally, tumour vascularity is assessed invasively by immunofluorescent analysis. Quantified contrast-enhanced power Doppler ultrasound has been used to measure tumour angiogenesis non-invasively in humans and experimental animals. The purpose of this study was to correlate quantified contrast-enhanced power Doppler ultrasound with immunofluorescent results in 45 spontaneous canine tumours. With power Doppler, mean vascularity was high in squamous cell carcinomas, moderate in malignant oral melanomas and low in sarcomas. There was high mean vascularity in squamous cell carcinomas and low mean vascularity in sarcomas and malignant oral melanomas. Although Doppler parameters correlated moderately with microvascular density for all tumours (P=0.004, r=0.4), they did not correlate within histology groups. These analyses show that vascularity differs among canine tumour histology groups. However, dependent on the method used, measurement of tumour vascularity can provide different biological information.

3D conformal radiation therapy for palliative treatment of canine nasal tumors.

We evaluated the response of 38 dogs treated with a coarsely fractionated, palliative radiation protocol based on CT-based 3D treatment planning. Dogs with histologically confirmed malignant nasal tumors were studied. Treatment prescriptions consisted of 3-4 x 8 Gy, 4-5 x 6 Gy, or 10 x 3 Gy fractions. Selected patient and tumor factors were evaluated for an effect on outcome. Resolution of clinical signs was reported after irradiation in all dogs. Acute toxicities were mild and short lived. Thirty-seven of 38 dogs died or were euthanized due to tumor-related disease. Overall median progression-free interval (PFI) was 10 months. Tumor stage affected response, with modified stage 1 patients having a median PFI 21.3 months vs. a median PFI of 8.5 months for modified stage 2 patients (P = 0.0006). Modified stage was the only factor significantly related to outcome. Based on these findings, a palliative radiation prescription based on computerized treatment planning may be justified in some canine nasal tumor patients.

Correlation of pretreatment polarographically measured oxygen pressures with quantified contrast-enhanced power doppler ultrasonography in spontaneous canine tumors and their impact on outcome after radiation therapy.

PURPOSE: To evaluate the use of noninvasive quantified contrast-enhanced power Doppler ultrasonography as a surrogate in the estimation of tumor hypoxia measured by invasive pO(2) histography in canine tumors. MATERIAL AND METHODS: Data of pretreatment tumor oxygenation status, tumor vascularity and blood volume, and tumor response after radiation therapy was collected in 48 spontaneous malignant oral tumors (Table 1). Tumor oxygenation status was correlated to vascularity and blood volume, and influences on outcome after treatment were analyzed. RESULTS: Although vascularity and blood volume correlated moderately with median pO(2) (r = 0.51 and 0.61; p = 0.001 and < 0.0001) and percentage of pO(2) readings < or = 2.5, 5, and 10 mmHg (r = -0.37 to -0.42; p < 0.01-0.03) for all tumors, they did not correlate within the different histology groups (p = 0.06-0.9). For all tumors, pretreatment oxygenation status, vascularity and blood volume were not found to be of prognostic value (Tables 2 and 3). CONCLUSION: These analyses show that quantified contrast-enhanced power Doppler ultrasonography does not represent a noninvasive indirect method to assess tumor hypoxia measured by invasive pO(2) histography. Both technologies were nonprognostic indicators in spontaneous malignant canine oral tumors.

Dynamic computed tomography to measure tissue perfusion in spontaneous canine tumors.

Dynamic computed tomography (CT) is widely used in humans to determine tumor perfusion via time-attenuation curves. Five types of time-attenuation curves have been identified and shown to have prognostic relevance in humans. The goal of our study was to assess the feasibility of this technology in spontaneous canine tumors and to determine time-attenuation curves and perfusion patterns in different tumor types. Thirty-one dogs with tumors accessible for biopsy were evaluated (15 carcinomas, 16 sarcomas). Dynamic CT was performed at the level of the largest tumor cross-section. Time-attenuation curves were calculated and ratios from the tumor to a contralateral artery were derived for wash-in, peak attenuation, time to peak attenuation, wash-out, and perfusion. Median perfusion was significantly higher and median time to peak ratio was significantly shorter in carcinomas and bone sarcomas compared with soft tissue sarcomas (P = 0.03 and 0.01). There was a trend of lower median upslope and wash-out ratio in soft tissue sarcomas in comparison with carcinomas (P = 0.06 and 0.09). Although peak ratio was lowest in soft tissue sarcomas, differences were not significant (P = 0.3). The most common type of time-attenuation curve for all tumors had a slow to moderately rapid wash-in with a low to moderate attenuation peak followed by a plateau phase. In conclusion, dynamic CT is feasible and time-activity curve-derived measurements differed between spontaneous canine tumors. More data has to be collected in a larger number of patients and correlated with response to treatment and outcome.

Proton spot scanning radiotherapy of spontaneous canine tumors.

Thirty dogs with spontaneous tumors were irradiated with proton therapy using a novel spot scanning technique to evaluate the safety and efficacy of the system, and to study the acute and late radiation reactions. Nasal tumors, soft tissue sarcomas, and miscellaneous tumors of the head were treated with a median total dose of 52.5 Gy given in 3.5 Gy fractions. Acute effects, late effects, tumor response, and outcome were analyzed. No unexpected radiation reactions were seen, however two dogs did develop in-field osteosarcoma, and one dog developed in-field bone necrosis. Complete response to therapy was seen in 40% (12/30), partial response in 47% (14/30), and no response in 13% (4/30). Median survival for all dogs was 385 days (range of 14-4583 days). Dogs with nasal cavity tumors had a median survival of 385 days (range of 131-1851 days) and dogs with soft tissue sarcomas had a median survival time of 612 days (range of 65-4588 days). Treatment outcome was similar to historical controls. This new proton spot scanning technique proved to be safe and reliable.

Clinical assessment of repeated propofol-associated anesthesia in cats.

OBJECTIVE: To assess the effects of repeated episodes of propofol-associated anesthesia on quality of recovery from anesthesia, clinical status, and erythrocyte physiology in cats. DESIGN: Original study. ANIMALS: 37 cats undergoing short-duration anesthesia for radiotherapy. PROCEDURES: Twice daily on 5 consecutive days, 13 cats with squamous cell carcinoma of the nasal planum (group 1) underwent anesthesia: first via administration of propofol or a midazolam (0.2 mg/kg [0.09 mg/lb])-propofol combination and then via administration of ketamine and midazolam each day (latter data were not analyzed). During a 19-day period, 24 cats with vaccine associated sarcoma (group 2) were anesthetized 12 times with propofol or a midazolam-propofol combination. Anesthesia was maintained with propofol in both groups. Hematologic analysis was performed before, during, and on completion of radiotherapy; changes in Hct and hemoglobin concentration between groups were compared. RESULTS: Mean duration of anesthesia was 8.1 minutes (range, 5 to 20 minutes); no adverse events were detected during recovery. Total dose of propofol administered did not differ between groups 1 (6.34 mg/kg [2.88 mg/lb]) and 2 (4.71 mg/kg [2.14 mg/lb]). Midazolam administration decreased the propofol dose by 26%. Overall decreases from baseline in Hct and hemoglobin concentration were not significantly different between the 2 groups, nor clinically important; however, compared with baseline, values in group 2 were significantly lower after 6 and 12 anesthetic episodes for both protocols. Heinz bodies were identified in low numbers in both groups during radiotherapy. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that repeated propofol-associated short-duration anesthesia does not lead to clinically relevant hematologic changes in cats undergoing short-duration radiotherapy.

Contrast harmonic imaging of the normal canine spleen.

The purpose of this study was to assess the perfusion pattern and perfusion dynamics in the normal canine spleen using contrast harmonic imaging. Twenty-five dogs without clinical or ultrasonographic evidence of splenic disease were studied. Twenty-three dogs were scanned with only manual restraint; two dogs were sedated with buprenorphin. All dogs received an intravenous bolus of a microbubble contrast medium (SonoVue). The perfusion pattern during the blood pool phase represented a skewed bell-shaped curve. A tissue-specific late phase, similar to humans, was not observed. Time/intensity curves were generated for a selected region. Mean average-derived peak intensity (PI) was 6.6dB, mean time to peak intensity calculated from the initial rise (TTP) was 25.6 s and mean area under the curve (AUC) was 523.6 dBs. If dogs were divided into two body weight groups (< or =15 and >15 kg body weight), average derived peak intensity area, time to peak intensity, and area under the curve were lower for the smaller dogs than for the larger animals. However, differences were not statistically significant (P = 0.2, 0.05, and 0.08, respectively). No significant association was found between hematocrit, hemoglobin concentration, red blood cell count, blood pressure, heart rate, age, gender, and the perfusion variables. In conclusion, these baseline data may prove useful in the evaluation of dogs with diffuse or focal splenic disease.

Potential for intensity-modulated radiation therapy to permit dose escalation for canine nasal cancer.

We evaluated the impact of inverse planned intensity-modulated radiation therapy (IMRT) on the dose-volume histograms (DVHs) and on the normal tissue complication probabilities (NTCPs) of brain and eyes in dogs with nasal tumors. Nine dogs with large, caudally located nasal tumors were planned using conventional techniques and inverse planned IMRT for a total prescribed dose of 52.5 Gy in 3.5 Gy fractions. The equivalent uniform dose for brain and eyes was calculated to estimate the normal tissue complication probability (NTCP) of these organs. The NTCP values as well as the DVHs were used to compare the treatment plans. The dose distribution in IMRT plans was more conformal than in conventional plans. The average dose delivered to one-third of the brain was 10 Gy lower with the IMRT plan compared with conventional planning. The mean partial brain volume receiving 43.6 Gy or more was reduced by 25.6% with IMRT. As a consequence, the NTCPs were also significantly lower in the IMRT plans. The mean NTCP of brain was two times lower and at least one eye could be saved in all patients planed with IMRT. Another possibility with IMRT is dose escalation in the target to improve tumor control while keeping the NTCPs at the same level as for conventional planning. Veterinary

Photodynamic therapy of feline cutaneous squamous cell carcinoma using a newly developed liposomal photosensitizer: preliminary results concerning drug safety and efficacy.

BACKGROUND: Squamous cell carcinomas are common skin tumors in cats. We investigated photodynamic therapy (PDT) using a new liposomal photosensitizer as a minimally invasive, effective treatment that can be easily performed while achieving good cosmetic results. AIM: The goal of this study was to assess and describe possible toxicities using a liposomal formulation of the photosensitizer meta-(Tetrahydroxyphenyl)Chlorin (m-THPC) and investigate if favorable pharmacokinetics translate into favorable tumor response and control. ANIMALS: Eighteen client-owned cats with 20 spontaneous cutaneous squamous cell carcinomas were included in the study. METHODS: PDT was performed using a new, liposomal formulation of the photosensitizer. Toxicity, tumor response, and tumor control were evaluated retrospectively. RESULTS: No general adverse effects were observed in cats treated with the new liposomal formulation. Mild local toxicity such as erythema and edema were seen in 15% of the patients. All cats responded to therapy, with a complete response rate of 100%. The overall 1-year control rate was 75%. The tumor recurrence rate was 20% with a median time to recurrence of 172.25 +/-87.1) days. CONCLUSIONS AND CLINICAL IMPORTANCE: A new liposomal photosensitizer was successfully used for squamous cell carcinoma in cats and was well tolerated. There were no systemic adverse effects observed with the liposomal formulation. The favorable pharmacokinetics of the liposomal drug resulted in a favorable tumor response.

Simultaneous application of the vascular endothelial growth factor (VEGF) receptor inhibitor PTK787/ZK 222584 and ionizing radiation does not further reduce the growth of canine oral melanoma xenografts in nude mice.

PTK787/ZK 222584 is an inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinases. In this study, the effectiveness of PTK787/ZK 222584 and radiation on canine oral melanoma xenografts was assessed. Xenografts were treated with radiotherapy (4x6Gy), or with PTK787/ZK 222584, or with a combination of both. Treatment efficacy was assessed using a tumour growth delay assay, serial power Doppler and pO(2) measurements during and after therapy. There was a significant growth delay for the group treated with radiation alone and for the combined treatment group. However, tumour growth delay was similar in both groups. Tumours were hypoxic before irradiation and no significant re-oxygenation occurred during therapy. In all tumours, vascularity and perfusion were significantly lower at the end of the study but no significant differences in perfusion, vascularity and oxygenation status were observed between and within treatment groups. The combination of PTK787/ZK 222584 and radiotherapy did not perform better than radiotherapy alone in this model.

The impact of dose escalation on secondary cancer risk after radiotherapy of prostate cancer.

PURPOSE: To estimate secondary cancer risk due to dose escalation in patients treated for prostatic carcinoma with three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated RT (IMRT), and spot-scanned proton RT. METHODS AND MATERIALS: The organ equivalent dose (OED) concept with a linear-exponential, a plateau, and a linear dose-response curve was applied to dose distributions of 23 patients who received RT of prostate cancer. Conformal RT was used in 7 patients, 8 patients received IMRT with 6- and 15-MV photons, and 8 patients were treated with spot-scanned protons. We applied target doses ranging from 70 Gy to 100 Gy. Cancer risk was estimated as a function of target dose and tumor control probability. RESULTS: At a 100-Gy target dose the secondary cancer risk relative to the 3D treatment plan at 70 Gy was +18.4% (15.0% for a plateau model, 22.3% for a linear model) for the 6-MV IMRT plan, +25.3% (17.0%, 14.1%) for the 15-MV IMRT plan, and -40.7% (-41.3%, -40.0%) for the spot-scanned protons. The increasing risk of developing a radiation-associated malignancy after RT with increasing dose was balanced by the enhanced cure rates at a larger dose. CONCLUSIONS: Cancer risk after dose escalation for prostate RT is expected to be equal to or lower than for conventional 3D treatment at 70 Gy, independent of treatment modality or dose-response model. Spot-scanned protons are the treatment of choice for dose escalation because this therapy can halve the risk of secondary cancers.

Imaging diagnosis--metastatic hemangiosarcoma causing cerebral hemorrhage in a dog.

A 9-year-old male Appenzeller mountain dog had progressive severe ataxia and central vestibular syndrome that was localized clinically to the brain stem. The cerebrospinal fluid characteristics were suggestive of hemorrhage into the subarachnoid space. On computed tomography (CT), hyperattenuating masses were found in the left lateral ventricle extending into the cerebrum, and another involving the cerebellum and brainstem. The hyperattenuation of the masses in noncontrast images and the absence of contrast enhancement were consistent with hemorrhage. The dog underwent euthanasia. A metastatic hemangiosarcoma in the brain, causing acute bleeding in the left lateral ventricle and the brainstem, was found. A solitary mass in the left myocardium was thought to be the primary site. CT characteristics of intracranial hemorrhage are reviewed.

Reevaluation of the University of Wisconsin 2-year protocol for treating canine lymphosarcoma.

This retrospective study investigated a population of 96 dogs with newly diagnosed malignant lymphosarcoma that were treated with the commonly used University of Wisconsin-Madison (UW-M) chemotherapy protocol. Pretreatment characteristics were analyzed to determine prognostic factors. Dogs with higher World Health Organization (WHO) stages (including stage IV) and dogs with hypercalcemia were at significantly higher risk of relapse (P=0.018 and P=0.016, respectively). Dose reduction, treatment delays, and prior therapy with cortico-steroids were not associated with clinical outcome. First remission duration of 270 days was similar to historically reported data. Overall survival time of 218 days was much shorter than historical data.

Interrelation of directly measured oxygenation levels, erythropoietin and erythropoietin receptor expression in spontaneous canine tumours.

The expression of the hypoxia-inducible protein erythropoietin in tumour cells correlates with levels of tumour hypoxia. Our aim was to look for an interrelation of directly measured oxygenation levels, the presence of tissue erythropoietin and its receptor. Data of tumour oxygenation status, plasma and tissue erythropoietin and its receptor in a group of spontaneously occurring tumours in 15 dogs were collected. Polarographic tumour oxygen partial pressure measurements were obtained and data were correlated. Significant positive correlations were found between tissue erythropoietin and the percentages of pO2 values < or = 10 mmHg. Multivariate analysis revealed no parameters influencing plasma erythropoietin levels. Our results show that a co-expression of erythropoietin receptor and its ligand in spontaneous canine tumours exists, that the level of hypoxia in tumour cells correlates with the level of tissue erythropoietin and suggest the need to be quantitatively and functionally tested as novel prognostic biological parameters in neoplastic tissues.

The impact of IMRT and proton radiotherapy on secondary cancer incidence.

BACKGROUND AND PURPOSE: There is concern about the increase of radiation-induced malignancies with the application of modern radiation treatment techniques such as intensity-modulated radiotherapy (IMRT) and proton radiotherapy. Therefore, X-ray scatter and neutron radiation as well as the impact of the primary dose distribution on secondary cancer incidence are analyzed. MATERIAL AND METHODS: The organ equivalent dose (OED) concept with a linear-exponential and a plateau dose-response curve was applied to dose distributions of 30 patients who received radiation therapy of prostate cancer. Three-dimensional conformal radiotherapy was used in eleven patients, another eleven patients received IMRT with 6-MV photons, and eight patients were treated with spot-scanned protons. The treatment plans were recalculated with 15-MV and 18-MV photons. Secondary cancer risk was estimated based on the OED for the different treatment techniques. RESULTS: A modest increase of 15% radiation-induced cancer results from IMRT using low energies (6 MV), compared to conventional four-field planning with 15-MV photons (plateau dose-response: 1%). The probability to develop a secondary cancer increases with IMRT of higher energies by 20% and 60% for 15 MV and 18 MV, respectively (plateau dose-response: 2% and 30%). The use of spot-scanned protons can reduce secondary cancer incidence as much as 50% (independent of dose-response). CONCLUSION: By including the primary dose distribution into the analysis of radiation-induced cancer incidence, the resulting increase in risk for secondary cancer using modern treatment techniques such as IMRT is not as dramatic as expected from earlier studies. By using 6-MV photons, only a moderate risk increase is expected. Spot-scanned protons are the treatment of choice in regard to secondary cancer incidence.