Stereotactic radiotherapy of primary lung cancer and other targets: results of consultant meeting of the International Atomic Energy Agency.

To evaluate the current status of stereotactic body radiotherapy (SBRT) and identify both advantages and disadvantages of its use in developing countries, a meeting composed of consultants of the International Atomic Energy Agency was held in Vienna in November 2006. Owing to continuous developments in the field, the meeting was extended by subsequent discussions and correspondence (2007-2010), which led to the summary presented here. The advantages and disadvantages of SBRT expected to be encountered in developing countries were identified. The definitions, typical treatment courses, and clinical results were presented. Thereafter, minimal methodology/technology requirements for SBRT were evaluated. Finally, characteristics of SBRT for developing countries were recommended. Patients for SBRT should be carefully selected, because single high-dose radiotherapy may cause serious complications in some serial organs at risk. Clinical experiences have been reported in some populations of lung cancer, lung oligometastases, liver cancer, pancreas cancer, and kidney cancer. Despite the disadvantages expected to be experienced in developing countries, SBRT using fewer fractions may be useful in selected patients with various extracranial cancers with favorable outcome and low toxicity.

Stereotactic body radiotherapy for local boost irradiation in unfavourable locally recurrent gynaecological cancer.

PURPOSE: To evaluate outcome of radiotherapy for locally recurrent cervical and endometrial cancer. MATERIALS AND METHODS: Nineteen patients were treated for a locally recurrent cervical (n=12) or endometrial (n=7) cancer median 26 months after initial surgery (n=18) or radiotherapy (n=1). The whole pelvis was irradiated with 50Gy conventionally fractionated radiotherapy (n=16). Because of large size of the recurrent cancer (median 4.5 cm) and peripheral location (n=12), stereotactic body radiotherapy (SBRT; median 3 fractions of 5Gy to 65%) was used for local dose escalation instead of (n=16) or combined with (n=3) vaginal brachytherapy. RESULTS: After median follow-up of 22 months, 3-year overall survival was 34% with systemic progression the leading cause of death (7/10). Median time to systemic progression was 16 months. Three local recurrences resulted in a local control rate of 81% at 3 years. No correlation between survival, systemic or local control and any patient or treatment characteristic was observed. The rate of late toxicity>grade II was 25% at 3 years: two patients developed a grade IV intestino-vaginal fistula and one patient suffered from a grade IV small bowel ileus. CONCLUSION: Image-guided SBRT for local dose escalation resulted in high rates of local control but was associated with significant late toxicity.

Prospective phase II study of preoperative short-course radiotherapy for rectal cancer with twice daily fractions of 2.9 Gy to a total dose of 29 Gy--long-term results.

BACKGROUND: To evaluate clinical outcome after preoperative short-course radiotherapy for rectal cancer with twice daily fractions of 2.9 Gy to a total dose of 29 Gy and adjuvant chemotherapy for pathological stage UICC >or= II. METHODS: 118 patients (median age 64 years; male : female ratio 2.5 : 1) with pathological proven rectal cancer (clinical stage II 50%, III 41.5%, IV 8.5%) were treated preoperatively with twice daily radiotherapy of 2.9 Gy single fraction dose to a total dose of 29 Gy; surgery was performed immediately in the following week with total mesorectal excision (TME). Adjuvant 5-FU based chemotherapy was planned for pathological stage UICC >or= II. RESULTS: After low anterior resection (70%) and abdominoperineal resection (30%), pathology showed stage UICC I (27.1%), II (25.4%), III (37.3%) and IV (9.3%). Perioperative mortality was 3.4% and perioperative complications were observed in 22.8% of the patients. Adjuvant chemotherapy was given in 75.3% of patients with pathological stage UICC >or= II. After median follow-up of 46 months, five-year overall survival was 67%, cancer-specific survival 76%, local control 92% and freedom from systemic progression 75%. Late toxicity > grade II was observed in 11% of the patients. CONCLUSIONS: Preoperative short-course radiotherapy, total mesorectal excision and adjuvant chemotherapy for pathological stage UICC >or= II achieved excellent local control and favorable survival.

Dose-response relationship for image-guided stereotactic body radiotherapy of pulmonary tumors: relevance of 4D dose calculation.

PURPOSE: To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) and pulmonary metastases. METHODS AND MATERIALS: A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6-26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. RESULTS: With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose-response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. CONCLUSIONS: Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation.

Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer: mature results of a phase II trial.

PURPOSE: The objective of this expanded phase II trial was to confirm the safety results of the preceding phase I study and establish the efficacy of neoadjuvant radiochemotherapy with capecitabine in rectal cancer in a multicenter setting. PATIENTS AND METHODS: 96 patients (63% male, age 34-81 years) with advanced rectal cancer (cT3-4 or cN+) from seven university centers in Germany were recruited. All were to receive a total irradiation dose of 50.4-55.8 Gy with conventional fractions. Capecitabine was given at an oral dosage of 825 mg/m(2)bid on each day of the radiotherapy period with the first daily dose applied 2 h before irradiation, followed by surgery 6 weeks later. RESULTS: Most of the patients suffered from an advanced primary tumor (cT3: 57%, cT4: 40%) with lymph node involvement in 60%. After neoadjuvant treatment, with a mean of 99% of the scheduled radiation dose actually delivered, a clinical response rate of 68% (95% confidence interval: 57-78%) was observed. Out of 87 evaluable patients undergoing surgery, a sphincter-preserving procedure could be performed in 51% and R0 resection in 94%. A pathologically complete response was achieved in six patients (7%, 95% confidence interval: 3-14%). The comparison of initial diagnosis and pathologic findings showed a downstaging in 61%. Acute toxicity with > 5% incidence of NCI (National Cancer Institute) grade >/= 3 included lymphopenia (12%), leukopenia (6%), and diarrhea (7%). Mild to moderate hand-foot syndrome occurred in 12% only. After a median follow-up of 48 months, the 5-year overall survival and tumor control data were, with regard to patient selection, in the expected range with an overall survival of 65%, a relapse-free survival of 47%, and a local recurrence rate after 5 years of 17%. CONCLUSION: The data clearly confirm that capecitabine is an adequate substitute for 5-fluorouracil in preoperative chemoradiation of rectal cancer with a favorable safety profile.

Pulmonary injury and tumor response after stereotactic body radiotherapy (SBRT): results of a serial follow-up CT study.

PURPOSE: To evaluate the CT morphological pattern of tumor response and pulmonary injury after stereotactic body radiotherapy (SBRT) for early stage non-small lung cancer (NSCLC) and pulmonary metastases. MATERIALS AND METHODS: Seventy patients (lesions n=86) with pulmonary metastases (n=48) or primary early stage NSCLC (n=38) were analyzed. Patients were treated with hypofractionated SBRT (three to eight fractions with a single dose between 6 and 12.5 Gy; n=56) or with radiosurgery (26 Gy; n=30). The pattern and sequence of pulmonary injury and of tumor response was evaluated in 346 follow-up CT studies, 4.9 on average. RESULTS: Symptomatic pneumonitis was observed in 10% after a median interval of 5 months. No pulmonary reaction was observed in most patients 6 weeks after treatment; spotted-streaky condensations were characteristic between 3 months and 6 months. Dense consolidation and retraction started after 9 months and the fibrotic remodelling process continued for years. Ten targets relapsed after a median of 7 months. At 12 months complete response was seen in 43% and the differentiation of residual tumor from pulmonary reaction was not possible in 33%. CONCLUSIONS: A typical sequence of pulmonary reactions was observed without differences between hypofractionated treatment and radiosurgery. Onset of pneumonitis was later compared to conventionally fractionated radiotherapy.

Stereotactic radiotherapy of primary liver cancer and hepatic metastases.

The purpose was to evaluate the clinical results of stereotactic radiotherapy in primary liver tumors and hepatic metastases. Five patients with primary liver cancer and 39 patients with 51 hepatic metastases were treated by stereotactic radiotherapy since 1997. Twenty-eight targets were treated in a "low-dose"-group with 3 x 10 Gy (n = 27) or 4 x 7 Gy (n = 1) prescribed to the PTV-encl. 65%-isodose. In a "high-dose"-group patients were treated with 3 x 12 - 12.5 Gy (n = 19; same dose prescription) or 1 x 26 Gy/PTV-enclosing 80%-isodose (n = 9). Median follow-up was 15 months (2-48 months) for primary liver cancer and 15 months (2-85 months) for hepatic metastases. While all primary liver cancers were controlled, nine local failures (3-19 months) of 51 metastases were observed resulting in an actuarial local control rate of 92% after 12 months and 66% after 24 months and later. A borderline significant correlation between dose and local control was observed (p = 0.077): the actuarial local control rate after 12 and 24 months was 86% and 58% in the low-dose-group versus 100% and 82% in the high-dose-group. In multivariate analysis high versus low-dose was the only significant factor predicting local control (p = 0.0089). Overall survival after 1 and 2 years was 72% and 32% for all patients and was impaired due to systemic progression of disease. No severe acute or late toxicity exceeding RTOG/EORTC-score 2 were observed. Stereotactic irradiation of primary liver cancer and hepatic metastases offers a locally effective treatment without significant complications in patients, who are not amenable for surgery. Patient selection is important, because those with low risk for systemic progression are more likely to benefit from this approach.

Cone-beam CT based image-guidance for extracranial stereotactic radiotherapy of intrapulmonary tumors.

Cone-beam CT (CB-CT) based image-guidance was evaluated for extracranial stereotactic radiotherapy of intrapulmonary tumors. A total of 21 patients (25 lesions: prim. NSCLC n = 6; pulmonary metastases n = 19) were treated with stereotactic radiotherapy (1 to 8 fractions). Prior to every fraction a CB-CT was acquired in treatment position, errors between planned and actual tumor position were measured and corrected. Intra- and inter-observer variability of manual evaluation of tumor position error was investigated and this manual method was compared with automatic image registration. Based on CB-CTs from 66 fractions the discrepancy (3-D vector) between planned and actual tumor position was 7.7 mm +/-1.3 mm. Tumor position error relative to the bony anatomy was 5.3 mm +/-1.2 mm, the correlation between bony anatomy and tumor position was poor. Intra-observer and inter-observer variability of manual evaluation of tumor position error was 0.9 mm +/-0.8 mm and 2.3 mm +/-1.1 mm, respectively. Automatic image registration showed highly reproducible results (<1 mm). However, compared with manual registration a systematic error was found in direction of predominant tumor breathing motion (2.5 mm vs 1.4 mm). Image-guidance using CB-CT was validated for high precision radiotherapy of intrapulmonary tumors. It was shown that both the planning reference and the verification image study have to consider tumor breathing motion.

Dose-response in stereotactic irradiation of lung tumors.

The dose-response for local tumor control after stereotactic radiotherapy of 92 pulmonary tumors (36 NSCLC and 56 metastases) was evaluated. Short course irradiation of 1-8 fractions with different fraction doses was used. After a median follow-up of 14 months (2-85 months) 11 local recurrences were observed with significant advantage for higher doses. When normalization to a biologically effective dose (BED) is used a dose of 94Gy at the isocenter and 50Gy at the PTV-margin are demonstrated to give 50% probability of tumor control (TCD50). Multivariate analysis revealed the dose at the PTV-margin as the only significant factor for local control.

Influence of calculation model on dose distribution in stereotactic radiotherapy for pulmonary targets.

PURPOSE: To compare the pencil beam (PB) and collapsed cone (CC)-based three-dimensional dose calculation used for stereotactic irradiation of pulmonary targets. METHODS AND MATERIALS: Three-dimensional conformal dose distributions (using 6-MV and 18-MV photon beams) were generated for 33 pulmonary targets using the PB algorithm implemented in the Helax-TMS treatment planning system and then recalculated with the CC algorithm of TMS using an identical beam setup and parameters. The differences were analyzed by evaluating the dose-volume histograms for the planning target volume (PTV) and clinical target volume (CTV) and evaluating the computed absolute monitor units (MUs). The influence of the photon energy was also studied. For three cases, the results were compared with Monte-Carlo calculations. RESULTS: Use of the CC model typically showed increased dose inhomogeneity. Owing to a more accurate modeling of secondary charged particle disequilibrium at the tumor-lung interface, the beam penumbra is broadened. The median and mean target dose decreased by 13.9% and 11.2% for the PTV and 9.2% and 9.4% for the CTV, respectively, using the CC algorithm. Consequently, the average PTV dose coverage decreased by 7.1% (SD, 6.5%). On average, the MUs calculated to achieve the prescribed dose were 5.4% (SD, 5.8%) greater for the CC algorithm. The difference in MUs between the PB and CC increased with decreasing PTV size and high photon energy (18 MV; r = -0.68), reaching 26% at the maximum. CONCLUSION: The absorbed dose at the lung-tumor interface calculated by the PB algorithm was considerably greater than the dose calculated using the CC algorithm. In small targets (PTV < or = 100 cm(3)) and for 18-MV photons, the MUs calculated with PB may lead to an insufficient dose to the target volume.

Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients.

PURPOSE: The clinical results of dose escalation using stereotactic radiotherapy to increase local tumor control in medically inoperable patients with Stage I-II non-small-cell lung cancer or pulmonary metastases were evaluated. METHODS AND MATERIALS: Twenty patients with Stage I-II non-small-cell lung cancer and 41 patients with 51 pulmonary metastases not amenable to surgery were treated with stereotactic radiotherapy at 3 x 10 Gy (n = 19), 3 x 12-12.5 Gy to the planning target volume enclosing 100%-isodose, with normalization to 150% at the isocenter; n = 26) or 1 x 26 Gy to the planning target volume enclosing 80%-isodose (n = 26). The median follow-up was 11 months (range, 2-61 months) for primary lung cancer patients and 9 months (range, 2-37 months) for patients with metastases. RESULTS: The actuarial local control rate was 92% for lung cancer patients and 80% for metastasis patients > or =1 year after treatment and was significantly improved by increasing the dose from 3 x 10 Gy to 3 x 12-12.5 Gy or 1 x 26 Gy (p = 0.038). The overall survival rate after 1 and 2 years was 52% and 32%, respectively, for lung cancer patients and 85% and 33%, respectively, for metastasis patients, impaired because of systemic disease progression. After 12 months, 60% of patients with primary lung cancer and 35% of patients with pulmonary metastases were without systemic progression. No severe acute or late toxicity was observed, and only 2 patients (3%) developed symptomatic Grade 2 pneumonitis, which was successfully treated with oral steroids. CONCLUSION: Stereotactic radiotherapy for lung tumors offers a very effective treatment option locally without significant complications in medically impaired patients who are not amenable to surgery. Patient selection is important, because those with a low risk of systemic progression are more likely to benefit from this approach.