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Background and Purpose: Stereotactic body radiotherapy (SBRT) for tumours ≥5 cm is poorly studied and its utility and feasibility is uncertain. We here report the Karolinska experience of SBRT in this setting., Material and Methods: All patients had a gross tumour volume (GTV) ≥70 cc, a prescribed physical dose of at least 40 Gy and received treatment between 1995-2012., Results: We included 164 patients with 175 tumours located in the thorax ( n  = 86), the liver ( n  = 27) and the abdomen ( n  = 62) and treated with a median prescribed dose (BED α/β 10Gy ) of 80 Gy (71.4-113). One- and 2- year local control rates were 82% and 61%. In multivariate analyses, minimum dose to the GTV and histological subtype were associated with local control. Renal cell carcinoma (RCC) histology showed the most favourable local control - 94% at 2 years for all histologies. Thirty-seven patients experienced grade 3-5 toxicity most likely related to SBRT. Seven of the ten patients with grade 5 toxicity, had a centrally located tumour in the thorax., Conclusion: SBRT of tumours >5 cm in diameter may be an option for peripherally located lung and abdominal tumours. Histological origin and tumour location should be considered before treatment.

Purpose : To evaluate the rate and dose response of brachial plexus toxicity post stereotactic body radiation therapy (SBRT) of apically situated lung lesions. Material/methods: We retrospectively identified all patients with apically located tumors, defined by the epicenter of the tumor being located superiorly to the aortic arch, and treated with SBRT between 2008 and 2013. Patients with a shorter follow-up than 6 months were excluded. Primary aim was to evaluate radiation-induced brachial plexopathy (RIBP). Dose to the plexus was assessed by a retrospective delineation of the brachial plexus on the CT used for treatment planning. Then, D max , D 0.1cc , D 1cc and D 3.0cc of the brachial plexus were collected from the dose-volume histograms (DVH) and recalculated to the biologically effective dose (BED) using α/β = 3 Gy. A normal tissue complication probability (NTCP) model, based on four different dose-volume parameters (BED 3,max , BED 3,0.1cc, BED 3,1.0cc, BED 3,3.0cc ) was fitted to the data. Results: Fifty-two patients with 56 apically located tumors were identified. Median prescription dose per fraction was 15 Gy (range 6-17) and median number of fractions was 3 (3-10). With a median follow-up of 30 months (6.1-72) seven patients experienced maximum grade 2 (scored 3 times) or 3 (scored 4 times) RIBP after a median of 8.7 months (range 4.0-31). Three patients had combined symptoms with pain, sensory and motor affection and four patients had isolated pain. Median BED 3,max for the patients experiencing RIBP was 381 Gy (range 30-524) versus BED 3,max of 34 Gy (range 0.10-483) for the patients without RIBP. The NTCP models showed a very high predictive ability (area under the receiver operating characteristic curve (AUC) 0.80-0.88). Conclusion: SBRT of apically located lung lesions may cause severe neurological symptoms; for a three-fraction treatment, we suggest that the maximum dose to the plexus should be kept ≤30 Gy (130 Gy BED 3 ).

Background: Tumour hypoxia is associated with increased radioresistance and poor response to radiotherapy. Pre-treatment assessment of tumour oxygenation could therefore give the possibility to tailor the treatment by calculating the required boost dose needed to overcome the increased radioresistance in hypoxic tumours. This study concerned the derivation of a non-linear conversion function between the uptake of the hypoxia-PET tracer 18 F-HX4 and oxygen partial pressure (pO 2 )., Material and Methods: Building on previous experience with FMISO including experimental data on tracer uptake and pO 2 , tracer-specific model parameters were derived for converting the normalised HX4-uptake at the optimal imaging time point to pO 2 . The conversion function was implemented in a Python-based computational platform utilising the scripting and the registration modules of the treatment planning system RayStation. Subsequently, the conversion function was applied to determine the pO 2 in eight non-small-cell lung cancer (NSCLC) patients imaged with HX4-PET before the start of radiotherapy. Automatic segmentation of hypoxic target volumes (HTVs) was then performed using thresholds around 10 mmHg. The HTVs were compared to sub-volumes segmented based on a tumour-to-blood ratio (TBR) of 1.4 using the aortic arch as the reference oxygenated region. The boost dose required to achieve 95% local control was then calculated based on the calibrated levels of hypoxia, assuming inter-fraction reoxygenation due to changes in acute hypoxia but no overall improvement of the oxygenation status., Results: Using the developed conversion tool, HTVs could be obtained using pO 2 a threshold of 10 mmHg which were in agreement with the TBR segmentation. The dose levels required to the HTVs to achieve local control were feasible, being around 70-80 Gy in 24 fractions., Conclusions: Non-linear conversion of tracer uptake to pO 2 in NSCLC imaged with HX4-PET allows a quantitative determination of the dose-boost needed to achieve a high probability of local control.

Background: Hypoxia imaged by positron emission tomography (PET) is a potential target for optimization in radiotherapy. However, the implementation of this approach with respect to the conversion of intensities in the images into oxygenation and radiosensitivity maps is not straightforward. This study investigated the feasibility of applying two conversion approaches previously derived for 18 F-labeled fluoromisonidazole ( 18 F-FMISO)-PET images for the hypoxia tracer 18 F-flortanidazole ( 18 F-HX4)., Material and Methods: Ten non-small-cell lung cancer patients imaged with 18 F-HX4 before the start of radiotherapy were considered in this study. PET image uptake was normalized to a well-oxygenated reference region and subsequently linear and non-linear conversions were used to determine tissue oxygenations maps. These were subsequently used to delineate hypoxic volumes based partial oxygen pressure (pO 2 ) thresholds. The results were compared to hypoxic volumes segmented using a tissue-to-background ratio of 1.4 for 18 F-HX4 uptake., Results: While the linear conversion function was not found to result in realistic oxygenation maps, the non-linear function resulted in reasonably sized sub-volumes in good agreement with uptake-based segmented volumes for a limited range of pO 2 thresholds. However, the pO 2 values corresponding to this range were significantly higher than what is normally considered as hypoxia. The similarity in size, shape, and relative location between uptake-based sub-volumes and volumes based on the conversion to pO 2 suggests that the relationship between uptake and pO 2 is similar for 18 F-FMISO and 18 F-HX4, but that the model parameters need to be adjusted for the latter., Conclusions: A non-linear conversion function between uptake and oxygen partial pressure for 18 F-FMISO-PET could be applied to 18 F-HX4 images to delineate hypoxic sub-volumes of similar size, shape, and relative location as based directly on the uptake. In order to apply the model for e.g., dose-painting, new parameters need to be derived for the accurate calculation of dose-modifying factors for this tracer.

Background: Presentation of long term results of a phase II multicenter Nordic trial of medically inoperable stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT)., Material and Methods: We report the extended outcome, focusing on long-term effects, of a prospective cohort of 57 evaluable patients with peripherally located T1N0M0 (72%) and T2N0M0 (28%) NSCLC, treated with SBRT 15 Gy × 3, prescribed to the 67% isodose line encompassing the PTV. The patients were inoperable due to chronic obstructive pulmonary disease (65%), cardiovascular disease (25%) or other illnesses (3%) or refused surgery (7%). Median Karnofsky score pre-treatment was 80% (70-100%). Late effects were defined as occurring > 36 months., Results: Thirty-eight patients (67%) were relapse free during their entire follow-up. Local control rate at four and five years were 79% (CI 95% 64-95%) and local relapses occurred at 10-76 months post-treatment. Seven local failures were noted, four occurring ≤ 36 months (all T2a-tumors; two isolated and two in combination with out-of-field relapses) and three occurring > 36 months (T1b-tumors n = 3). Thirteen patients had out-of-field failure only as first presentation of recurrence. Overall survival rate and lung cancer-specific survival rate at five years were 30% and 74%, respectively. Toxicity throughout the entire observation period was acceptable without any grade 5 toxicities. Seventeen grade 3-4 toxicities were noted, three presenting > 36 months (rib fracture, dyspnea and ventricle tachycardia). Median follow-up was 41.5 months (3.4-113.0) for the entire cohort and 59.3 months (36.4-113.0) for the 34 patients (60%) with a follow-up of > 36 months., Conclusion: Throughout the observation period local control was excellent and toxicity limited with no increase in late presenting local relapses or late treatment-related morbidity. This further supports SBRT as an efficient local treatment modality even in a medically impaired patient cohort.

Background: About 2% of patients with a carcinoma in one kidney develop either metastases or a new primary tumor in the contralateral kidney. Often, renal cancers progress rapidly at peripheral sites and a metastasis to the second kidney may not be the patient's main problem. However, when an initial renal cancer is more indolent yet spreads to the formerly unaffected kidney or a new primary tumor forms there, local treatment may be needed. Stereotactic body radiotherapy (SBRT) has been demonstrated as a valuable treatment option for tumors that cause local symptoms. Presented here is a retrospective analysis of patients in whom SBRT was used to control primary or metastatic renal disease., Patients and Methods: Seven patients with a mean age of 64 (44-76) were treated for metastases from a malignant kidney to its contralateral counterpart. Dose/fractionation schedules varied between 10 Gy x 3 and 10 Gy x 4 depending on target location and size, given within one week. Follow-up times for patients who remained alive were 12, 52 and 66 months and for those who subsequently died were 10, 16, 49 and 70 months., Results: Local control, defined as radiologically stable disease or partial/complete response, was obtained in six of these seven patients and regained after retreatment in the one patient whose lesion progressed. Side effects were generally mild, and in five of the seven patients, kidney function remained unaffected after treatment. In two patients, the creatinine levels remained moderately elevated at approximately 160 micromol/L post treatment. At no time was dialysis required., Conclusion: These results indicate that SBRT is a valuable alternative to surgery and other options for patients with metastases from a cancer-bearing kidney to the remaining kidney and provides local tumor control with satisfactory kidney function.

A retrospective study has indicated that stereotactic radiotherapy (SRT) has a value in treating both primary tumors and singular metastatic lesions that cause local symptoms. Here we present the results of a prospective study evaluating the safety and local efficacy of SRT in metastatic or inoperable primary renal cancer. Thirty patients with metastatic renal cell carcinoma (RCC) or inoperable primary RCC received high-dose fraction SRT. In total, 82 lesions were treated. Dose/fractionation schedules varied depending on target location and size. The most frequently used fractionations were 8 Gy x 4, 10 Gy x 4, 15 Gy x 2 or 15 Gy x 3 prescribed to the periphery of the PTV. Local control, defined as radiologically stable disease (SD) or partial/complete response (PR/CR) was obtained in 98% of treated lesions but 19% of lesions were in patients with a follow time of less than 6 months. CR was observed in 21% of the patients and 58% of the patients had a partial volume reduction or local stable disease after a median follow-up of 52 months (range 11-66) for patients alive and 18 months (range 4-57) for deceased patients. Local progression was seen in two lesions. Side effects were grade I-II in 90% of cases. The overall survival was 32 months. SRT for patients with primary and metastatic RCC resulted in high local control rate with generally low toxicity. The method can thus be considered a therapeutic option to surgery in patients with a limited number of metastases, as local treatment in RCC with an indolent presentation or as a method of reducing tumor burden prior to medical treatment.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for skeletal metastases is based on data from 16 randomized trials. Moreover, data from 20 prospective studies, 5 retrospective studies and 22 other articles were used. A total of 63 scientific articles are included, involving 8051 patients. The results were compared with those of a similar overview from 1996 including 13,054 patients. The conclusions reached can be summarized as follows: Irradiation of skeletal metastases is, with few exceptions, a palliative treatment. There is strong evidence that radiotherapy of skeletal metastases gives an overall (complete and partial pain relief) in more than 80% of patients. There is strong evidence that the duration of pain relief in at least 50% of patients lasts for > or = 6 months. There is convincing evidence that pain relief, in terms of degree and duration, does not depend on the fractionation schedules applied. Irrespective of the fractionation schedule used at irradiation, the number of later complications, such as spinal cord compression or pathological fractures, at the index fields are low. There are some data showing that the difference in cost between single and multifraction treatment is small. However, these data do not permit any firm conclusions to be drawn. Several reports indicate that early diagnosis and early therapy of spinal cord compression are the two most important predictors of a favourable clinical outcome after radiotherapy. However, no controlled studies have been undertaken. When the diagnosis of spinal cord compression is late, a favourable outcome might depend on the radio-responsiveness of the tumour. The documentation is weak and no conclusions can be drawn. There is some evidence that a small proportion of totally paralytic patients can regain walking function after radiotherapy. There is strong evidence that the radionuclides 89Sr and 153Sm are efficient when they are used as a systemic treatment of generalized bone pain due to metastasis from carcinomas of the prostate and breast. Overall bone pain relief occurs in about 60-80% of patients with a median response duration of 2-4 months. There is strong evidence that intravenous treatment with bisphosphonates in patients with myeloma and osteolytic bone metastasis due to carcinoma of the breast significantly decreases the number of skeleton-related events and bone pain.

The aim of this study was to investigate whether external beam radiation treatment with three or four fields affects the risk of long-term distressful symptoms. The study included 145 patients who had been treated in Stockholm from 1993 to 1996 for localized prostate cancer. Bowel, urinary and sexual function as well as symptom-induced distress were assessed by means of a postal questionnaire 29-59 months after therapy. Among patients treated with a multileaf collimator, defecation urgency, diarrhoea and loose stools were more common after four fields than after three fields, but faecal leakage necessitating the use of pads and distress from the gastrointestinal tract were less common (although not statistically significantly so). Among bowel symptoms, the strongest association with gastrointestinal distress was found for faecal leakage. Three fields without a multileaf collimator entailed a higher risk of defecation urgency than three fields with a multileaf collimator. We conclude that the choice of three or four fields may imply a contrasting risk scenario for defecation urgency or diarrhoea in comparison with faecal leakage.