Hans-Peter Heilmann

Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases.

PURPOSE Patients with small cell lung cancer (SCLC) and superior vena cava syndrome (SVCS) are widely believed to have a grave prognosis. The purpose of this study was to determine the prognosis of patients with SCLC and SVCS as compared to SCLC without SVCS. METHODS AND MATERIALS A retrospective analysis of 408 cases of SCLC +/- SVCS was performed. Three- hundred and sixty showed no clinical signs of SVCS and 43 (11%) had SVCS; in 5 patients no adequate information was available about clinical signs of SVCS. All patients were classified as limited disease cases. About 98% received chemotherapy usually as the first treatment followed by radiotherapy. A median total dose of 46 Gy (range 30 to 70 Gy) was given at 2.0 Gy per fraction five times weekly. A prophylactic cranial irradiation was applied if a complete remission was achieved after chemotherapy or after 30 Gy of irradiation. Kaplan-Meier survival curves are shown and comparisons were made by the log-rank and the Gehan/Wilcoxon test. To adjust for prognostic factors, a proportional hazards analysis was done. RESULTS Patients without SVCS had 5-year survival rates ( +/- SE) and a median survival time (MST; 95% confidence intervals) of 11% +/- 2% and 13.7 months (12.7-14.5) in UICC Stage I to III; in Stage III the figures were 9% +/- 2% and 12.6 months (11.2-13.7). In comparison, SCLC with SVCS had 5-year survival rates of 15% +/- 7% and MST of 16.1 months (13.8-20.5). The difference was significant in univariate analysis (Stage II disease: p = 0.008 by the log-rank test). In a multivariate analysis of all patients, Stage (Stage I + II > III; p = 0.0003), SVCS (yes > no; p = 0.005), and Karnofsky performance status ( < or = 70 < 80-100%; p = 0.008) were of significant importance. CONCLUSIONS SVCS is a favorable prognostic sign in SCLC. The treatment should be curatively intended.

Inoperable non-small cell lung cancer: A retrospective analysis of 427 patients treated with high-dose radiotherapy

PURPOSE The influence of patient and treatment characteristics on survival as well as normal tissue toxicity were retrospectively analyzed. METHODS AND MATERIALS Four hundred twenty seven patients with unresectable non-small cell lung cancer received at least 60 Gy and two-thirds were treated with 70 Gy. RESULTS Five-year survival rates and median survival time (95% confidence interval) were 2 +/- 2% (mean +/- s.e.) and 11.1 months (9.1-14.5) after 60-66 Gy (median 60 Gy); 8 +/- 2% and 14.9 months (13.3-16.5) after > or = 70 Gy (p = 0.0013). Stage I-II patients had significantly higher survival rates as compared to Stage III patients (p = 0.0015). Within the subgroup of Stage III patients those with Stage IIIA had significantly higher survival rates than Stage IIIB (p = 0.0167). Female patients achieved 5-year survival rates after 70 Gy of 15 +/- 7% as compared to only 7 +/- 2% of their male counterparts. Chemotherapy, histology, Karnofsky status, and age had no influence on survival after univariate and multivariate analysis. Nine percent and 11% of the patients suffered from moderate to severe pneumonitis and esophagitis. CONCLUSION High-dose radiotherapy of unresectable non-small cell lung cancer with total doses > 60 Gy conventionally fractionated is feasible. With doses of > or = 70 Gy significantly higher survival rates were achieved as compared to 60-66 Gy. Normal tissue toxicity was acceptable. For Stage IIIB patients, however, treatment results are disappointingly low even after 70 Gy with no 5-year survivor.

Is the time interval between surgery and radiotherapy important in operable nonsmall cell lung cancer? A retrospective analysis of 340 cases☆

PURPOSE To evaluate the influence of prognostic factors in postoperative radiotherapy of NSCLC with special emphasis on the time interval between surgery and start of radiotherapy. METHODS AND MATERIALS Between January 1976 and December 1993, 340 cases were treated and retrospectively analyzed meeting the following criteria: complete follow-up; complete staging information including pathological confirmation of resection status; maximum interval between surgery (SX) and radiotherapy (RT) of 12 weeks (median 36 days, range 18 to 84 days); minimum dose of 50 Gy (R0), and maximum dose of 70 Gy (R2). Two hundred thirty patients (68%) had N2 disease; 228 patients were completely resected (R0). One hundred six (31%) had adenocarcinoma, 172 (51%) squamous cell carcinoma. RESULTS In univariate analysis, Karnofsky performance status (90+ >60-80%; p = 0.019 log rank), resection status stratified for nodal disease (R+ <R0; p = 0.046), and the time interval between SX and RT were of significant importance. Patients with a long interval (37 to 84 days) had higher 5-year survival rates (26%) and a median survival time (MST: 21.9 months, 95% C.I. 17.2 to 28.6 months) than patients with a short interval (18 to 36 days: 15%; 14.9 months, 13 to 19.9 months; p = 0.013). A further subgroup analysis revealed significant higher survival rates in patients with a long interval in N0/1 disease (p = 0.011) and incompletely resected NSCLC (p = 0.012). In multivariate analysis, the time interval had a p-value of 0.009 (nodal disease: p = 0.0083; KPI: p = 0.0037; sex: p = 0.035). CONCLUSION Shortening the time interval between surgery and postoperative radiotherapy to less than 6 weeks even in R+ cases is not necessary. Survival of patients with a long interval between surgery and start of radiotherapy was better in this retrospective analysis as compared to patients with a short interval.

High-dose Radiation Therapy alone for Inoperable Non-small cell Lung Cancer: Experience with Prolonged Overall Treatment Times

The purpose of this study as to determine the impact of overall treatment time on long-term survival after high-dose radiation therapy alone for inoperable non-small cell lung cancer (NSCLC). Between 1978 and 1990, 229 patients with stage I-III disease and Karnofsky Performance Scores of 80-100 received a conventionally fractionated total dose of 70 Gy through a split-course technique. After a first treatment course of 40 or 50 Gy, a restaging was performed and only patients without any contraindications, such as newly diagnosed distant metastases or serious deterioration of performance status, were given a second course. In 83% of patients this break lasted for 4-6 weeks. Overall treatment time ranged between 7 and 24 weeks (median 12 weeks). Median follow-up time was 6.6 years (range 4.0-9.3 years). Actuarial overall survival rates at 2 and 5 years were 28% and 7% respectively. Complete radiological tumor response was observed in 31% of patients, and was found to be the strongest positive predictor of survival with 2- and 5-year rates of 50% and 12% respectively compared with 17% and 4% for patients without complete response. Treatment duration was not found to be a significant prognostic factor in univariate or multivariate analysis. For overall treatment times of 7-11 weeks (n = 50), 12 weeks (n = 79) and > 12 weeks (n = 100), 5-year survival was 4%, 6%, and 8%, respectively (p = 0.6). To conclude, in our experience and in contrast to other studies, prolonged overall treatment times in radiation therapy alone for inoperable NSCLC had no negative impact on long-term survival. It is hypothesized that accelerated tumor cell repopulation is absent in a significant number of these patients with the time-factor playing no apparent role for outcome of treatment.

[Combined breast-preserving surgery, chemotherapy and radiotherapy in the treatment of breast carcinoma. Effect of the interval between surgery and the beginning of radiotherapy].

ZusammenfassungHintergrundDie zeitliche Integration von Operation, Chemotherapie und Strahlentherapie bei der brusterhaltenden Behandlung des Mammakarzinoms ist in den letzten Jahren zunehmend in den Blickpunkt des Interesses gerückt.Patienten und MethodeDie Grundlage dieser Studie bilden 74 Patientinnen, die im Zeitraum 1985 bis 1992 an unserem Institut eine postoperative Strahlentherapie erhielten. Die mediane Nachbeobachtungszeit betrug fünf Jahre. In 73% der Fälle waren die Patientinnen prä- oder perimenopausal. Fast alle Patientinnen (91%) befanden sich im UICC-Stadium II. Axilläre Lymphknoten waren dabei in 95% befallen. Eine makroskopisch vollständige Tumorresektion wurde bei allen Patientinnen erreicht, und in 65% der Fälle waren die Resektionsränder frei von invasivem oder intraduktalem Karzinom. Postoperativ wurden in 70% der Fälle sechs Zyklen Polychemotherapie (hauptsächlich CMF) vor Bestrahlungsbeginn appliziert. Die Strahlendosis betrug fast ausschließlich 60 Gy inklusive 10 Gy Boost.ErgebnisseFünf Jahre nach Behandlungsbeginn betrug die Überlebensrate 86% (95%-Vertrauensbereich 76 bis 93%), die krankheitsfreie Überlebensrate 73% (61 bis 83%) und die Lokalrezidivrate 8% (3 bis 16%). Der einzige signifikante prognostische Faktor für das krankheitsfreie Überleben war die Anzahl befallener Lymphknoten: 0 bis 3=86%, ≥4=40% (p<0,0001). Das Intervall zwischen Operation und Bestrahlungsbeginn (≤ oder >20 Wochen) hatte keinen signifikanten Einfluß auf das krankheitsfreie Überleben oder die lokale Tumorkontrolle. Dagegen fand sich ein Hinweis auf eine vermehrte lymphogene und hämatogene Metastasierung bei Verkürzung des Intervalls, bedingt durch die Applizierung von weniger als sechs Zyklen Chemotherapie vor Beginn der Strahlentherapie.SchlußfolgerungenIn unserer Erfahrung hat die Verzögerung der Strahlentherapie, um die volle Anzahl von Chemotherapiezyklen vor Bestrahlungsbeginn applizieren zu können, keinen negativen Einfluß auf die lokale Tumorkontrolle. Dabei muß allerdings die niedrige statistische Power dieser Auswertung aufgrund der kleinen Patientenzahl beachtet werden. Es erscheint möglich, daß eine weniger intensive Chemotherapie vor Beginn der Bestrahlung mit einer Erhöhung der Fernmetastasierungsrate und einer entsprechenden Verschlechterung der krankheitsfreien Überlebensrate korreliert. Für Patientinnen mit erhöhtem Metastasierungsrisiko befürworten wir daher sechs Zyklen Polychemotherapie vor der Strahlenbehandlung.AbstractBackgroundThe timing of breast conserving surgery, chemotherapy, and radiotherapy in breast cancer treatment has become the subject of increasing interest over the last years.Patients and MethodSeventy-four patients who underwent postoperative radiotherapy at our institution between 1985 and 1992 form the basis of this study. Median follow-up time was 5 years. Seventy-three percent of patients were pre- or perimenopausal. Almost all patients (91%) were UICC-stage II. Axillary lymph nodes were positive in 95% of cases. Complete gross tumor resection was achieved in all patients, and in 65% final pathological margins were free of invasive or intraductal carcinoma. Postoperatively, 70% of patients received 6 cycles of polychemotherapy (predominantly CMF) before onset of irradiation. The radiation dose was in almost all cases 60 Gy including 10 Gy boost.ResultsFive years after start of treatment overall survival, disease-free survival, and local recurrence rates were 86% (95%-confidence limits, 76 to 93%), 73% (61 to 83%), and 8% (3 to 16%), respectively. For disease-free survival, the only significant prognostic factor was the number of involved lymph nodes: 0 to 3=86%, ≥4=40% (p<0,0001). The interval between surgery and radiation (≤versus >20 weeks) had no significant influence on disease-free survival or local tumor control. In contrast, there was a trend of increased regional and distant failure with shortening of the interval due to the delivery of less than 6 cycles chemotherapy before the onset of radiotherapy.ConclusionsIn our experience, there was no negative impact of a delay of radiotherapy in order to deliver full course chemotherapy before initiation of radiotherapy. However, the low statistical power of this analysis due to the small number of patients must be considered. It appears possible that a less intense chemotherapy before starting radiation treatment correlates with enhanced distant failure and subsequently decreased disease-free survival rates. Therefore, for patients at increased risk for distant metastasis, we prefer to give 6 cycles polychemotherapy before irradiation.BACKGROUND The timing of breast conserving surgery, chemotherapy, and radiotherapy in breast cancer treatment has become the subject of increasing interest over the last years. PATIENTS AND METHOD Seventy-four patients who underwent postoperative radiotherapy at our institution between 1985 and 1992 form the basis of this study. Median follow-up time was 5 years. Seventy-three percent of patients were pre- or perimenopausal. Almost all patients (91%) were UICC-stage II. Axillary lymph nodes were positive in 95% of cases. Complete gross resection was achieved in all patients, and in 65% final pathological margins were free of invasive or intraductal carcinoma. Postoperatively, 70% of patients received 6 cycles of polychemotherapy (predominantly CMF) before onset of irradiation. The radiation dose was in almost all cases 60 Gy including 10 Gy boost. RESULTS Five years after start of treatment overall survival, disease-free survival, and local recurrence rates were 86% (95%-confidence limits, 76 to 93%), 73% (61 to 83%), and 8% (3 to 16%), respectively. For disease-free survival, the only significant prognostic factor was the number of involved lymph nodes: 0 to 3 = 86%, > or = 4 = 40% (p < 0.0001). The interval between surgery and radiation (< or = versus > 20 weeks) had no significant influence on disease-free survival or local tumor control. In contrast, there was a trend of increased regional and distant failure with shortening of the interval due to the delivery of less than 6 cycles chemotherapy before the onset of radiotherapy. CONCLUSIONS In our experience, there was no negative impact of a delay of radiotherapy in order to deliver full course chemotherapy before initiation of radiotherapy. However, the low statistical power of this analysis due to the small number of patients must be considered. it appears possible that a less intense chemotherapy before starting radiation treatment correlates with enhanced distant failure and subsequently decreased disease-free survival rates. Therefore, for patients at increased risk for distant metastasis, we prefer to give 6 cycles polychemotherapy before irradiation.

Ein Jahrhundert Strahlentherapie

This review studies the historical development of fractionated X-ray therapy in the German speaking countries until World War II. Fractionated treatments appear to have their origin already in the first attempts of fractionation performed by Freund in 1896. In the following, fractionated treatments could not compete with the so-called single dose or intensive radiation treatment in Germany. However, until the 1920s there were repeated sporadic attempts of various motifs to distribute the radiation doses over a prolonged period of time. Only with the end of the 1920s the conditions for a rise of fractionated irradiation were favourable, mainly due the fiasco of the intensive treatments and their subsequent decline. The impulse for this rise, however, came from France where Coutard had developed an individual empirical treatment regimen with great clinical success. This technique and its modifications and developments spread over Europe and America fast. In spite of the similarities between the various fractionation methods used during the first decades of the century, review of the radiological literature of that time fails to show any logical scientific connection of these methods, but rather there was a mix and overlap of irradiation attempts of various motivations. Thus, radiation therapy, and thereby the current standard fractionation scheme of 1.8 to 2 Gy per fraction 5 times per week, obviously did not grow out of a scientific basis, but originated from individual observation of patients and empirical experience.ZusammenfassungVorliegender Rückblick untersucht die geschichtliche Entwicklung der fraktionierten Röntgentherapie im deutschsprachigen Raum bis zum Zweiten Weltkrieg. Die fraktionierte Behandlung scheint ihren Ursprung bereits mit den ersten Ansätzen der Fraktionierung durch Freund im Jahre 1896 zu haben. Die fraktionierte Strahlentherapie konnte sich in der Folge gegenüber der sogenannten Einzeit-oder Intensivbestrahlung in Deutschland nicht durchsetzen. Bis in die zwanziger Jahre hinein gab es aber immer wieder vereinzelte Versuche, die Strahlendosis aus verschiedenen Motivationen heraus über einen längeren Zeitraum zu verteilen. Erst Ende der zwanziger Jahre waren die Bedingungen für einen Aufschwung der fraktionierten Bestrahlungen im deutschsprachigen Raum günstig, vor allem da sich die Intensivbestrahlung aufgrund ihrer Mißerfolge im Niedergang befand. Der Anstoß hierfür kam jedoch aus Frankreich, wo Coutard eine individuell ausgerichtete, empirische Bestrahlungsform mit großem klinischen Erfolg entwickelt hatte. Diese verbreitete sich mit ihren Modifikationen und Weiterentwicklungen rasch in Europa und Amerika. Trotz der Ähnlichkeiten der verschiedenen Fraktionierungsmethoden in den ersten Jahrzehnten unseres Jahrhunderts läßt sich in der damaligen radiologischen Literatur jedoch keine logische, wissenschaftliche Verknüpfung dieser methoden entdecken, sondern vielmehr ein Durcheinander und Überlappen von Bestrahlungsversuchen unterschiedlichster Motivierungen. Die Strahlentherapie, und damit auch die heute gebräuchliche Standardfraktionierung von 1,8 bis 2 Gy pro Fraktion fünfmal pro Woche, entstand weniger aus einer wissenschaftlichen Grundlage heraus, sondern entsprang individueller Patientenbeobachtung und empirischer Erfahrungsgewinnung.AbstractThis review studies the historical development of fractionated X-ray therapy in the German speaking countries until World War II. Fractionated treatments appear to have their origin already in the first attempts of fractionation performed by Freund in 1896. In the following, fractionated treatments could not compete with the so-called single dose or intensive radiation treatment in Germany. However, until the 1920s there were repeated sporadic attempts of various motifs to distribute the radiation doses over a prolonged period of time. Only with the end of the 1920s the conditions for a rise of fractionated irradiation were favourable, mainly due the fiasco of the intensive treatments and their subsequent decline. The impulse for this rise, however, came from France where Coutard had developed an individual empirical treatment regimen with great clinical success. This technique and its modifications and developments spread over Europe and America fast. In spite of the similarities between the various fractionation methods used during the first decades of the century, review of the radiological literature of that time fails to show any logical scientific connection of these methods, but rather there was a mix and overlap of irradiation attempts of various motivations. Thus, radiation therapy, and thereby the current standard fractionation scheme of 1.8 to 2 Gy per fraction 5 times per week, obviously did not grow out of a scientific basis, but originated from individual observation of patients and empirical experience.

Kombinierte brusterhaltende Chirurgie, Chemotherapie und Strahlentherapie bei der Behandlung des Mammakarzinoms. Der Einfluß des Intervalls zwischen Operation und Bestrahlungsbeginn

BackgroundThe timing of breast conserving surgery, chemotherapy, and radiotherapy in breast cancer treatment has become the subject of increasing interest over the last years.Patients and MethodSeventy-four patients who underwent postoperative radiotherapy at our institution between 1985 and 1992 form the basis of this study. Median follow-up time was 5 years. Seventy-three percent of patients were pre- or perimenopausal. Almost all patients (91%) were UICC-stage II. Axillary lymph nodes were positive in 95% of cases. Complete gross tumor resection was achieved in all patients, and in 65% final pathological margins were free of invasive or intraductal carcinoma. Postoperatively, 70% of patients received 6 cycles of polychemotherapy (predominantly CMF) before onset of irradiation. The radiation dose was in almost all cases 60 Gy including 10 Gy boost.ResultsFive years after start of treatment overall survival, disease-free survival, and local recurrence rates were 86% (95%-confidence limits, 76 to 93%), 73% (61 to 83%), and 8% (3 to 16%), respectively. For disease-free survival, the only significant prognostic factor was the number of involved lymph nodes: 0 to 3=86%, ≥4=40% (p 20 weeks) had no significant influence on disease-free survival or local tumor control. In contrast, there was a trend of increased regional and distant failure with shortening of the interval due to the delivery of less than 6 cycles chemotherapy before the onset of radiotherapy.ConclusionsIn our experience, there was no negative impact of a delay of radiotherapy in order to deliver full course chemotherapy before initiation of radiotherapy. However, the low statistical power of this analysis due to the small number of patients must be considered. It appears possible that a less intense chemotherapy before starting radiation treatment correlates with enhanced distant failure and subsequently decreased disease-free survival rates. Therefore, for patients at increased risk for distant metastasis, we prefer to give 6 cycles polychemotherapy before irradiation.