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Phase-II-Studie zur präoperativen Radio-Chemo-Thermo-Therapie beim lokal fortgeschrittenen Rektum-Karzinom

Preoperative radio-chemo-thermotherapy in locally advanced rectal cancer — A phase II study

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Zusammenfassung

Hintergrund

Aktuelle Studien zeigen, daß eine präoperative Radiochemotherapie beim lokal fortgeschrittenen Rektumkarzinom Resektabilität und lokale Kontrolle erhöhen kann. Inwieweit durch zusätzlichen Einsatz der regionalen Hyperthermie Ansprechraten und Tumorrückbildung verbessert werden, sollte in einer Phase-II-Studie beim lokal fortgeschrittenen Rektumkarzinom geprüft werden.

Patienten und Methode n

37 Patienten mit primär fortgeschrittenem Rektumkarzinom uT3 oder uT4 wurden einer präoperativen Radio-Chemo-Thermo-Therapie unterzogen. Die initiale Tiefeninfiltration wurde mittels Endosonographie, CT und MRT bestimmt. Die Strahlentherapie wurde in Bauchlage (im Bauchkasten) in üblicher. Technik mit 5 ×1,8 Gy wöchentlich bis 45 Gy im Referenzpunkt durchgeführt. 5-Fluorouracil (300 bis 350 mg/m3) mit Leucovorin in niedriger Dosis (50 mg) wurde an den Tagen 1 bis 5 sowie 22 bis 28 verabreicht. Die regionale Hyperthermie mit dem Sigma-60-Ring des Systems BSD-2000 erfolgte wöchentlich vor der Bestrahlung und gegebenenfalls parallel zur Chemotherapie. Temperatur-Orts-Kurven und Temperatur-Zeit-Kurven wurden in endokavitär positionierten Kathetern (Tumorkontakt, Blase, Vagina) gemessen. Nach einem endosonographischen Restaging wurde vier bis sechs Wochen nach Abschluß der präoperativen Therapie die Operation durchgeführt und anschließend die Chemotherapie adjuvant in vier Zyklen fortgesetzt. Bei inkompletter Resektion oder Nichtresektabilität wurde eine kleinfeldrige Aufsättigung bis 64 Gy angestrebt.

Ergebnisse

Von den 37 Patienten konnten 31 (84%) lokal radikal operiert werden (R0-Resektion), bei nur einer R1-Resektion (3%) und fünf nichtresektablen Primärtumoren (13%). Bei den R0-resezierten Tumoren wurde im Operationspräparat bei 53% eine Reduktion der Tiefeninfiltration gegenüber dem initialen endosonographischen Befund beobachtet. Die aktuarische Überlebensrate nach vier Jahren beträgt 65% (progressionsfrei 57%). Die aktuarische Vier-Jahres-Überlebensrate war für die Gruppe der Responder besonders günstig. Insgesamt wurde die präoperative multimodale Therapie gut toleriert, ein vorzeitiger Abbruch der Radiotherapie war nur in einem Fall erforderlich (3%). Grad-III/IV-Toxizitäten an Darm und Haut wurden durch Feldausblockungen und Kühlung der Perinealregion soweit wie möglich reduziert und betrugen 5/37 (13%) gastrointestinal und 6/37 (16%) an der Haut. Die thermischen Daten wurden einer statistischen Analyse unterzogen. Die Qualität der Temperaturverteilung (T90, cum min T90 ≥40,5 °C) hängt von den Leistungspegeln und relativen Leistungsdichten ab. Das Ansprechen (Tumorverkleinerung und Rückgang der Tiefeninfiltration) ist statistisch signifikant mit Qualitätsparametern der Temperaturverteilung korreliert. Im Trend gilt dies auch für das rezidivfreie Überleben.

Schlußfolgerung en

Eine präoperative Radio-Chemo-Thermo-Therapie erwies sich als gut durchführbar und effektiv mit ermutigenden Remissionsraten sowie exzellenten lokalen Kontrollraten. Daher wird die Prüfung der regionalen Hyperthermie in einer Phase-III-Studie fortgesetzt. Parallel wird an technischen Verbesserungen der regionalen Hyperthermie gearbeitet.

Abstract

Background

Recent studies show that preoperative radio-chemotherapy can increase resectability and local control of locally advanced rectal carcinomas. Additional regional hyperthermia might increase remission rates and tumor response. We therefore tested regional hyperthermia together with radio-chemotherapy in a phase-II study on locally advanced rectal carcinomas.

Patients and Methods

Thirty-seven patients with primary advanced stage uT3/T4 rectal carcinomas were treated with preoperative radio-chemo-thermo-therapy. The initial tumor depth was determined using endosonography, CT, and MRI. Radiotherapy was carried out in prone position (on a belly board) using standard techniques, with 5 × 1.8 Gy per week up to 45 Gy at the reference point. 5-Fluorouracil (300 to 500 mg/m2) was administered with low doses of leucovorin (50 mg) on days 1 to 5 and 22 to 28. The patients were treated with regional hyperthermia each week prior to radiotherapy and simultaneously with chemotherapy, using the Sigma 60 ring from the BSD-2000 system. Temperature/position curves and temperature/time curves were recorded in endocavitary (endorectal) catheters in tumor contact and as well in bladder and vagina. Following endosonographic restaging, the operation was carried out 4 to 6 weeks after the end of preoperative therapy and adjuvant chemotherapy continued in four cycles. In cases where tumors were non-resectable, a boost up to 64 Gy was aimed.

Results

Thirty-one of the 37 patients (84%) with primary carcinoma proved locally R0-resectable. In addition we had 1 R1-resection (3%) and 5 non-resectable tumors (13%). Among the resected tumors, 53% experienced a reduction of depth infiltration from the initial endosonographic stage during preoperative therapy. The actuarial, survival rate after 4 years is 65% (free of progression 57%). The actuarial 4-year survival rate was particularly favorable for the group of responders. Overall, the preoperative multimodal therapy was well tolerated, and premature termination was only necessary in 1 case (3%). Grade III/IV toxicities in the intestine and skin were reduced as far as possible by field blockings and cooling of the perineal region. They occurred only in 5/37 patients (13%) at the intestine and in 6/37 patients (16%) at the skin. The thermal data were subjected to a statistical analysis. The quality of temperature distribution (T90, cum min T90≥40.5 °C) depends on the power level and relative power density. The response (reduction of tumor size or depth infiltration) correlated significantly with quality parameters of the temperature distributions. This dependency is found as a trend for progression-free survival, too.

Conclusions

Preoperative radio-chemo-thermo-therapy proved to be practical and effective, with encouraging remission rates and excellent local control rates. For this reason, a phase-III study to test regional hyperthermia has been initiated. At the same time, certain technical improvements are still under development for regional hyperthermia.

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Authors and Affiliations

  1. Strahlenklinik und Poliklinik, Charité-Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353, Berlin

    Peter Wust, Johanna Gellermann, Wolfgang Tilly, Holger Stahl & Roland Felix

  2. Abteilung für Chirurgie und Chirurgische Onkologie, Charité-Campus Buch, Humboldt-Universität, Berlin

    Beate Rau, Michael Hünerbein & Peter Schlag

  3. Medizinische Klinik und Poliklinik, Charité-Campus Virchow-Klinikum, Humboldt-Universität, Berlin

    Jürgen Löffel & Hanno Riess

  4. Klinik und Poliklinik für Strahlentherapie, Charité-Campus Charité Mitte, Humboldt-Universität, Berlin

    Volker Budach

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  1. Beate Rau
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  2. Peter Wust
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  3. Johanna Gellermann
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  10. Roland Felix
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  11. Peter Schlag
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Correspondence to Peter Wust.

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Diese Arbeit wurde gefördert von der Deutschen Forschungsgemeinschaft — Sonderforschungsbereich 273, Teilprojekte A1, B1, B2.

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Rau, B., Wust, P., Gellermann, J. et al. Phase-II-Studie zur präoperativen Radio-Chemo-Thermo-Therapie beim lokal fortgeschrittenen Rektum-Karzinom. Strahlenther Onkol 174, 556–565 (1998). https://doi.org/10.1007/BF03038292

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