Joern Wulf

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 3×10 Gy (n = 27) or 4×7 Gy (n = 1) prescribed to the PTV-encl. 65%-isodose. In a “high-dose”-group patients were treated with 3×12 − 12.5 Gy (n = 19; same dose prescription) or 1×26 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.

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.

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.

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.

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/m2bid 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.Ziel:Diese multizentrische Phase-II-Studie sollte Effektivität und Toxizität einer neoadjuvanten Radiochemotherapie mit Capecitabine prüfen.Patienten und Methodik:96 Patienten (davon 63% männlich, Alter 34–81 Jahre) mit lokal fortgeschrittenem Rektumkarzinom (cT3–4 oder cN+) aus sieben deutschen Universitätskliniken wurden rekrutiert. Alle erhielten eine präoperative Radiotherapie (50,4–55,8 Gy in konventioneller Fraktionierung mit 5 × 1,8 Gy) und zusätzlich 2 × täglich 825 mg/m2Capecitabin während gesamten Radiotherapie (erste Dosis 2 h vor Radiotherapie, keine Pause am Wochenende). 6 Wochen nach der Radiochemotherapie war die Resektion geplant.Ergebnisse:97% der Patienten hatten T3/T4-Tumoren (T3: 57%; T4: 40%). Lymphknotenbefall (cN+) lag in 60% vor. Die präoperative Therapie war gut durchführbar (mittlere Strahlendosis 99%, mittlere Capecitabindosis 96% der geplanten Dosis). Die klinische Ansprechrate betrug 68% (95%-Konfidenzintervall: 57–78%) und entsprach der Studienhypothese. Von 87 auswertbaren operierten Patienten wurden 94% R0-reseziert; ein Sphinktererhalt war in 51% möglich. Sechs Patienten (7%, 95%-Konfidenzintervall: 3–14%) hatten eine histologisch komplette Remission (ypT0) im Resektat. Ein Downstaging wurde in 61% erreicht. Akute Nebenwirkungen CTC-Grad ≥ 3 (Common Toxicity Criteria) mit einer Frequenz von > 5% wurden für Lymphopenie (12%), Diarrhö (7%) und Leukopenie (6%) beobachtet. Ein Hand-Fuß-Syndrom trat in 12% auf und war jeweils nur mild (Grad 1–2). Die 5-Jahres-Überlebensrate betrug 65%, das rezidivfreie Überleben 47% und die lokale Kontrolle nach 5 Jahren 83%.Schlussfolgerung:Die Daten dieser multizentrischen Phase-II-Studie bestätigen, dass die Kombination von präoperativer Radiotherapie und Capecitabin eine wirksame und nebenwirkungsarme Behandlung beim lokal fortgeschrittenen Rektumkarzinom darstellt. Capecitabin eignet sich als Ersatz für eine kontinuierliche 5-Fluorouracil-Infusion.

Neoadjuvant Capecitabine Combined with Standard Radiotherapy in Patients with Locally Advanced Rectal Cancer

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/m2bid 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.Ziel:Diese multizentrische Phase-II-Studie sollte Effektivität und Toxizität einer neoadjuvanten Radiochemotherapie mit Capecitabine prüfen.Patienten und Methodik:96 Patienten (davon 63% männlich, Alter 34–81 Jahre) mit lokal fortgeschrittenem Rektumkarzinom (cT3–4 oder cN+) aus sieben deutschen Universitätskliniken wurden rekrutiert. Alle erhielten eine präoperative Radiotherapie (50,4–55,8 Gy in konventioneller Fraktionierung mit 5 × 1,8 Gy) und zusätzlich 2 × täglich 825 mg/m2Capecitabin während gesamten Radiotherapie (erste Dosis 2 h vor Radiotherapie, keine Pause am Wochenende). 6 Wochen nach der Radiochemotherapie war die Resektion geplant.Ergebnisse:97% der Patienten hatten T3/T4-Tumoren (T3: 57%; T4: 40%). Lymphknotenbefall (cN+) lag in 60% vor. Die präoperative Therapie war gut durchführbar (mittlere Strahlendosis 99%, mittlere Capecitabindosis 96% der geplanten Dosis). Die klinische Ansprechrate betrug 68% (95%-Konfidenzintervall: 57–78%) und entsprach der Studienhypothese. Von 87 auswertbaren operierten Patienten wurden 94% R0-reseziert; ein Sphinktererhalt war in 51% möglich. Sechs Patienten (7%, 95%-Konfidenzintervall: 3–14%) hatten eine histologisch komplette Remission (ypT0) im Resektat. Ein Downstaging wurde in 61% erreicht. Akute Nebenwirkungen CTC-Grad ≥ 3 (Common Toxicity Criteria) mit einer Frequenz von > 5% wurden für Lymphopenie (12%), Diarrhö (7%) und Leukopenie (6%) beobachtet. Ein Hand-Fuß-Syndrom trat in 12% auf und war jeweils nur mild (Grad 1–2). Die 5-Jahres-Überlebensrate betrug 65%, das rezidivfreie Überleben 47% und die lokale Kontrolle nach 5 Jahren 83%.Schlussfolgerung:Die Daten dieser multizentrischen Phase-II-Studie bestätigen, dass die Kombination von präoperativer Radiotherapie und Capecitabin eine wirksame und nebenwirkungsarme Behandlung beim lokal fortgeschrittenen Rektumkarzinom darstellt. Capecitabin eignet sich als Ersatz für eine kontinuierliche 5-Fluorouracil-Infusion.

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

BackgroundTo 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 ≥ II.Methods118 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 ≥ II.ResultsAfter 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 ≥ 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.ConclusionsPreoperative short-course radiotherapy, total mesorectal excision and adjuvant chemotherapy for pathological stage UICC ≥ II achieved excellent local control and favorable survival.

Neoadjuvant Capecitabine Combined with Standard Radiotherapy in Patients with Locally Advanced Rectal Cancer@@@Präoperative Radiochemotherapie mit Capecitabin beim lokal fortgeschrittenen Rektumkarzinom: Langzeitergebnisse einer Phase-II-Studie: 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/m2bid 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.Ziel:Diese multizentrische Phase-II-Studie sollte Effektivität und Toxizität einer neoadjuvanten Radiochemotherapie mit Capecitabine prüfen.Patienten und Methodik:96 Patienten (davon 63% männlich, Alter 34–81 Jahre) mit lokal fortgeschrittenem Rektumkarzinom (cT3–4 oder cN+) aus sieben deutschen Universitätskliniken wurden rekrutiert. Alle erhielten eine präoperative Radiotherapie (50,4–55,8 Gy in konventioneller Fraktionierung mit 5 × 1,8 Gy) und zusätzlich 2 × täglich 825 mg/m2Capecitabin während gesamten Radiotherapie (erste Dosis 2 h vor Radiotherapie, keine Pause am Wochenende). 6 Wochen nach der Radiochemotherapie war die Resektion geplant.Ergebnisse:97% der Patienten hatten T3/T4-Tumoren (T3: 57%; T4: 40%). Lymphknotenbefall (cN+) lag in 60% vor. Die präoperative Therapie war gut durchführbar (mittlere Strahlendosis 99%, mittlere Capecitabindosis 96% der geplanten Dosis). Die klinische Ansprechrate betrug 68% (95%-Konfidenzintervall: 57–78%) und entsprach der Studienhypothese. Von 87 auswertbaren operierten Patienten wurden 94% R0-reseziert; ein Sphinktererhalt war in 51% möglich. Sechs Patienten (7%, 95%-Konfidenzintervall: 3–14%) hatten eine histologisch komplette Remission (ypT0) im Resektat. Ein Downstaging wurde in 61% erreicht. Akute Nebenwirkungen CTC-Grad ≥ 3 (Common Toxicity Criteria) mit einer Frequenz von > 5% wurden für Lymphopenie (12%), Diarrhö (7%) und Leukopenie (6%) beobachtet. Ein Hand-Fuß-Syndrom trat in 12% auf und war jeweils nur mild (Grad 1–2). Die 5-Jahres-Überlebensrate betrug 65%, das rezidivfreie Überleben 47% und die lokale Kontrolle nach 5 Jahren 83%.Schlussfolgerung:Die Daten dieser multizentrischen Phase-II-Studie bestätigen, dass die Kombination von präoperativer Radiotherapie und Capecitabin eine wirksame und nebenwirkungsarme Behandlung beim lokal fortgeschrittenen Rektumkarzinom darstellt. Capecitabin eignet sich als Ersatz für eine kontinuierliche 5-Fluorouracil-Infusion.