Rudolf Raab

Prognostic Significance of Tumor Regression After Preoperative Chemoradiotherapy for Rectal Cancer

PURPOSE We assessed the impact of tumor regression grading (TRG) and its value in correlation to established prognostic factors in a cohort of rectal carcinoma patients treated by preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS TRG was evaluated on surgical specimens of 385 patients treated within the preoperative CRT arm of the CAO/ARO/AIO-94 trial: 50.4 Gy was delivered, fluorouracil was given in the first and fifth week, and surgery was performed 6 weeks thereafter. TRG was determined by the amount of viable tumor versus fibrosis, ranging from TRG 4 when no viable tumor cells were detected, to TRG 0 when fibrosis was completely absent. TRG 3 was defined as regression more than 50% with fibrosis outgrowing the tumor mass, TRG 2 was defined as regression less than 50%, and TRG 1 was defined basically as a morphologically unaltered tumor mass. We performed an initially unplanned, hypothesis-generating analysis with respect to the prognostic value of this TRG system. RESULTS TRG 4, 3, 2, 1, 0 was found in 10.4%, 52.2%, 13.8%, 15.3%, and 8.3% of the resected specimens, respectively. Five-year disease-free survival (DFS) after CRT and curative resection was 86% for TRG 4, 75% for grouped TRG 2 + 3, and 63% for grouped TRG 0 + 1 (P = .006). On multivariate analysis, the pathologic T category and the nodal status after CRT were the most important independent prognostic factors for DFS. CONCLUSION In this exploratory analysis, complete (TRG 4) and intermediate pathologic response (TRG 2 + 3) suggested improved DFS after preoperative CRT. TRG assessment should be implemented in pathologic evaluation and prospectively validated in further studies.

Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation

PURPOSE Tumor recurrence is the major limitation of long-term survival after liver transplantation for hepatocellular carcinoma (HCC) or fibrolamellar carcinoma (FLC). Understanding tumor-biologic characteristics is important for selection of patients and for development of adjuvant therapeutic strategies. PATIENTS AND METHODS The study included 69 patients who underwent potentially curative liver transplantation for HCC/FLC and survived for more than 150 days; minimum follow-up was 33 months. Frequency, localization, and timing of recurrence were analyzed and compared with primary tumor and patient characteristics. RESULTS Tumor recurrence was observed in 39 patients at 67 locations. Hematogenous spread was the major route of tumor recurrence (87%), and the most frequent sites were the liver (62%), lung (56%), and bone (18%). Parameters associated with recurrence were absence of cirrhosis, tumor size greater than 5 cm, more than five nodules, vascular infiltration, and International Union Against Cancer (UICC) stage IVA. Selective intrahepatic recurrence was found in nine patients (23%); it was associated with highly differentiated tumors, lack of vascular infiltration, and male sex. Recurrence at multiple sites was found predominantly in young patients (< or = 40 years) and for multicentric (> 5) primary tumors. Recurrences were observed within a wide time range after transplantation (43 to 3,204 days; median, 441 days); late recurrences (> 1,000 days, n = 8) were associated with highly differentiated or fibrolamellar tumors and low UICC stages. Surgical treatment was the only therapeutic option associated with prolonged survival after recurrence. CONCLUSION In transplant recipients, hepatocellular carcinomas vary considerably in their pattern and kinetics of metastases. Tumor cells may persist in a dormant state for long time periods before giving rise to clinical metastases. Surgical treatment of recurrence should be considered whenever possible.

Adjuvant vs. neoadjuvant radiochemotherapy for locally advanced rectal cancer: the German trial CAO/ARO/AIO-94.

Aim  The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy (RCT) is recommended for advanced disease (pT3/4 or pN+). In recent years, encouraging results of pre‐operative radiotherapy have been reported. This prospective randomized phase‐III‐trial (CAO/ARO/AIO‐94) compares the efficacy of neoadjuvant RCT to standard postoperative RCT. We report on the design of the study and first results with regard to toxicity of RCT and postoperative morbidity.

Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer. A progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94).

Aim: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy is recommended for patients with advanced disease (pT3/4 or pN+). In recent years, encouraging results of preoperative radiotherapy have been reported. This prospective randomized phase-III trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant radiochemotherapy to standard postoperative radiochemotherapy. We report on the design of the study and first results with regard to toxicity of radiochemotherapy and postoperative morbidity. Patients and Methods: Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre- or postoperative radiochemotherapy: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumor and the pelvic lymph nodes. 5-FU (1,000 mg/m2/d) was administered concomitantly in the first and fifth week of radiation as 120-h continuous infusion. Four additional cycles of 5-FU chemotherapy (500 mg/m2/d, iv bolus) were applied. Radiochemotherapy was identical in both arms except for a small-volume boost of 5.4 Gy in the postoperative setting. Time interval between radiochemotherapy and surgery was 4–6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. In addition, stratification according to surgeons involved has been provided for. Primary endpoints of the study are 5-year overall-survival, local and distant control, secondary endpoints include rate of curative (R0) resections and sphincter saving procedures, toxicity of radiochemotherapy, surgical complications and quality of life. Results: As of 15th November 2000, 628 patients were randomized from 26 participating institutions: 310 patients were randomized to postoperative radiochemotherapy, 318 patients to preoperative radiochemotherapy. Acute toxicity (WHO) of radiochemotherapy was low, with less than 15% of patients experiencing Grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative radiochemotherapy arm and 10% in the preoperative radiochemotherapy arm having Grade-3, and 1% in either arm having Grade 4 diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering Grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postoperative radiochemotherapy) and 13% (preoperative radiochemotherapy) of patients, respectively, suffering from anastomotic teakage, 4% (postoperative radiochemotherapy) and 3% (preoperative radiochemotherapy) from postoperative bleeding, and 6% (postoperative radiochemotherapy) and 5% (preoperative radiochemotherapy) from delayed wound healing. Conclusion: The patient accrual of our trial is satisfactory, neoadjuvant radiochemotherapy is well tolerated and bears no higher risk for postoperative morbidity.Ziel: Die Standardbehandlung des operablen Rektumkarzinoms ist die sofortige Operation. Eine postoperative Radiochemotherapie wird für Patienten mit fortgeschrittenen Tumoren (pT3/4 oder pN+) empfohlen. In den letzten Jahren wurden vielversprechende Ergebnisse durch eine präoperative Bestrahlung erzielt. Wir beschreiben das Design einer prospektiv randomisierten Phase-III-Studie (CAO/ARO/AIO-94), die die Wirksamkeit einer neoadjuvanten Radiochemotherapie mit der postoperativen Standardbehandlung vergleicht, und berichten über erste Ergebnisse zur Toxizität der Radiochemotherapie und zur postoperativen Komplikationsrate. Patienten und Methoden: Patienten mit lokal fortgeschrittenem operablen Rektumkarzinom (uT3/4 oder uN+, Mason CS III/IV) wurden auf den prä- oder postoperativen Radiochemotherapiearm randomisiert: Tumor(-bett) und pelvines Lymphabflussgebiet erhielten 50,4 Gy (Einzeldosis: 1,8 Gy). In der ersten und fünften Bestrahlungswoche erfolgte eine simultane 5-FU-Chemotherapie in einer Dosierung von 1000 mg/m2/Tag, appliziert als 120-stündige Dauerinfusion. Vier weitere Zyklen 5-FU (500 mg/m2/Tag, appliziert als Bolusgabe) schlossen sich an. Das Radiochemotherapieregime war in beiden Armen (bis auf einen Boost von 5,4 Gy im postoperativen Radiochemotherapiearm) identisch. Das Intervall zwischen Radiochemotherapie und Operation betrug in beiden Armen 4–6 Wochen. Die Operationstechnik war standardisiert und beinhaltete die totale Entfernung des Mesorektums. Außerdem erfolgte eine Stratifizierung nach beteiligten Chirurgen. Primäre Endpunkte der Studie sind das 5-Jahres-Überleben, die lokale und systemische Tumorkontrolle; sekundäre Endpunkte umfassen die Rate an R0-Operationen und kontinenzerhaltenden Verfahren, die Toxizität der Radiochemotherapie, die postoperative Komplikationsrate und die Lebensqualität. Ergebnisse: Bis 15. November 2000 wurden 628 Patienten in 26 beteiligten Zentren randomisiert: 310 Patienten in den postoperativen Radiochemotherapiearm, 318 Patienten in den präoperativen Radiochemotherapiearm. Die Akuttoxizität war insgesamt gering; bei weniger als 15% der Patienten trat eine Grad-3 oder -4-Toxizität nach WHO auf. Die häufigste Nebenwirkung war die Diarrhö, die mit Grad 3 bzw. 4 bei 12% bzw. 1% im postoperativen Arm und mit 10% bzw. 1% im präoperativen Arm auftrat. Hauterythem, Übelkeit und Leukopenie waren weitere häufige Nebenwirkungen, Grad-3-Leukopenie und Übelkeit wurden bei weniger als 3% beobachtet. Die postoperative Komplikationsrate war in beiden Armen ähnlich; nach sofortiger Operation (postoperative Radiochemotherapie) entwickelten 12% der Patienten, nach präoperativer Radiochemotherapie 13% eine Anastomoseninsuffizienz, bei 4% (postoperative Radiochemotherapie) und 5% (präoperative Radiochemotherapie) Wundheilungsstörungen auf. Schlussfolgerung: Die Patientenrekrutierung verläuft sehr zufriedenstellend. Die neoadjuvante Radiochemotherapie wird gut toleriert und erhöht die postoperative Komplikationsrate nicht.

Reconstructive surgery for ischemic-type lesions at the bile duct bifurcation after liver transplantation.

OBJECTIVE To assess the feasibility, morbidity, mortality, and clinical success rate of surgical reconstruction of the biliary system in patients with ischemic-type biliary lesions in their liver graft. SUMMARY BACKGROUND DATA After liver transplantation, strictures in the biliary tree with secondary sludge formation can occur in the absence of vascular problems. Jaundice, pruritus, and recurrent cholangitis are predominant clinical features leading to considerable morbidity. Interventional measures are the first-line treatment but are frequently only of transient success. Retransplantation is usually considered when interventional treatment is not effective. METHODS Surgical exploration and reconstruction was performed in 17 patients with ischemic-type biliary strictures at a median of 2 years after liver transplantation. Findings during surgery, surgical strategies, and postsurgical courses are described. Clinical symptoms and biochemical parameters of cholestasis and liver function were analyzed in the postsurgical course. RESULTS During surgery, all 17 patients were found to have strictures or sclerotic changes involving the hepatic bifurcation and extrahepatic bile duct. Sludge or stones were present in nine patients. In 14 patients with viable bile ducts proximal to the bifurcation, surgical reconstruction was performed by resection of the bifurcation and hepaticojejunostomy. In three patients with more extensive biliary destruction, portoenterostomy with or without peripheral hepatojejunostomy was performed. The prevalence rate of biliary infection at surgery was 93%; the predominant organisms were Candida and enterococci. The perioperative mortality rate was 0%. Clinical symptoms and biochemical parameters became normal or were considerably improved in 14 of 16 patients (88%). CONCLUSIONS The hepatic bifurcation seems to be a predominant site for ischemic-type biliary changes after liver transplantation. Surgical treatment by resection of the bifurcation and reconstruction by high hepaticojejunostomy is a safe and highly effective approach leading to cure or persistent major improvement in most patients.

Cultured human intestinal mast cells express functional IL-3 receptors and respond to IL-3 by enhancing growth and IgE receptor-dependent mediator release

Mast cells are immunoregulatory effector cells capable of releasing different mediators and cytokines implicated in inflammatory tissue processes. Previous studies suggested that IL‐3 regulates growth and function of murine mast cells and human mast cell precursors, but does not affect mature human mast cells. In the present study, we found expression of IL‐3 receptors (IL‐3R) in freshlyisolated human intestinal mast cells by reverse transcriptase (RT)‐PCR and in mast cells cultured with stem cell factor (SCF) using RT‐PCR and flow cytometry. IL‐3R expression was enhanced when theculture medium was supplemented with IL‐4 in addition to SCF. In the presence of SCF, IL‐3 significantly enhanced mast cell growth in a dose‐dependent fashion (179±51% of control, p⩽0.004, n=9, ED50 ≈ 15 ng/ml) by decreasing mast cell apoptosis rather than inducing proliferation. Furthermore, IL‐3 selectively enhanced histamine (from 39.6±12.4 to 51.2±15.7% specific release, p<0.02, n=8) and leukotriene C4 (LTC4, 5.1±3.4 to 10.8±5.5 ng/106 mast cells, p<0.03, n=6) release triggered by IgE receptor cross‐linking without affecting prostaglandin D2 production. In conclusion, our data show that human intestinal mast cells express functional IL‐3R, indicating that IL‐3 not only regulates growth and function of immature, but also that of mature human mast cells.

Appraisal of transplantation for malignant tumours of the liver with special reference to early stage hepatocellular carcinoma

The enthusiasm to treat or even cure patients with unresectable hepatobiliary malignancy by total hepatectomy and liver transplantation has considerably diminished. Nowadays, due to organ-donor shortage, patients have to be selected with predictable likelihood for long-term survival. According to own experience and a review of the literature, liver transplantation may be considered in unresectable early stage hepatocellular and proximal bile duct carcinoma, the uncommon entities fibrolamellar carcinoma, epithelioid haemangioendothelioma and hepatoblastoma as well as in liver metastases from neuroendocrine tumours. At present, advanced stages of hepatocellular and proximal bile duct carcinoma, as well as intrahepatic bile duct carcinoma, haemangiosarcoma and metastases from nonendocrine tumours, should be excluded from transplantation. In order to cure the cancer-bearing disease, liver transplantation might be the ideal treatment for small but still resectable hepatocellular carcinoma with underlying cirrhosis. Our retrospective comparison of survival after resection and transplantation for early stage hepatocellular carcinoma does not reveal a significant difference. Although a tendency has been observed in favour of transplantation, resection of these tumours is still justifiable, not least because of donor organ shortage.

Attitude of patients toward transplantation of xenogeneic organs

Abstract Background: The prospect of xenotransplantation has stimulated considerable hopes as well as major concerns. The question of whether or not patients accept xenografts is influenced not only by scientific facts but also by psychological factors. It was the aim of this study to analyze the attitudes of patients toward transplantation of xenogeneic organs and evaluate factors influencing these attitudes. Methods: To this end, attitudes toward xenogeneic compared with allogeneic organ grafts were evaluated by means of detailed questionnaires in 1049 patients in Germany, who either had received transplants (n=722) or were on the waiting list for various organ grafts (n=327). Answers were correlated to demographic data as well as to the physical and mental conditions of the patients. Results: The survey indicates that 77% of patients would accept xenografts while 7% would refuse them if results of xenotransplantation were comparable with those of allotransplantation. If xenotransplantation were associated with increased risks due to more intensive medication 58% would still basically accept xenografts. Acceptance of xenografts was significantly higher in patients who had received transplants and among males. Age, religion, waiting time, and type of organ were not found to influence acceptance rates. Xenografts were thought to be associated with considerable or severe emotional stress by 23% of patients, versus 3% for allografts. The pig was the preferred donor animal, and gene therapeutic manipulation for improvement of results would be accepted by 84%. Inadequate graft function/increased risk of rejection and risk of disease transmission were the major concerns for 60% and 52% of patients, respectively; emotional concerns were the major concerns for 24% and animal-rights concerns for 15%. Conclusions: These findings show that the potential acceptance rate of xenografts would be quite high, with a more positive attitude in transplanted patients than in waiting-list patients; there was no major difference in acceptance rate for various types of organs. Major concerns about xenotransplantation currently are functional inferiority and transmission of diseases.

Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer : is it time for a randomized phase III trial?

Background:In the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity.Material and Methods:This review article focuses on phase II–III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings.Results:After preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients’ refusal, or investigator’s discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease.Conclusion:Whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.Hintergrund:Nach Einführung der präoperativen Radiochemotherapie (RCT) und der totalen mesoerektalen Excision manifestieren sich Rezidive beim Rektumkarzinom am häufigsten als Fernmetastasen. Daher ist die Integration einer systemisch effektiveren Therapie in das multimodale Behandlungskonzept derzeit die entscheidende Herausforderung. Die Frage ist, wann und wie diese Systemtherapie mit adäquater Dosis und Intensität verabreicht werden kann.Material und Methoden:Der Übersichtsartikel beschreibt Phase II–III Studien, deren Ziel es war, die allein 5-FU-basierte multimodale Behandlung durch Hinzunahme einer Kombinations-Chemotherapie, simultan zur Radiotherapie, adjuvant oder als Induktionstherapie, zu verbessern. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstrakts von ASCO/ASTRO/ESTRO-Konferenzen.Ergebnisse:Nach präoperativer RCT und Operation erhalten etwa ein Drittel aller Patienten wegen postoperativer Komplikationen, patientenseitiger Ablehnung oder Entscheidung des betreuenden Arztes keine adjuvante Chemotherapie. Ein innovativer Ansatz ist die Induktionschemotherapie vor präoperativer RCT und Operation, um die systemische Therapie in ausreichender Dosierung und Intensität durchführen zu können. Eine Vielzahl an Phase II-Studien, und zuletzt auch randomisierter Phase- II-Studien, zeigte, dass dieses Konzept durchführbar ist, die anschließende RCT und Operation nicht kompromittiert sowie die systemische Komponente in adäquater Dosis und Intensität applizierbar macht. Wenngleich dadurch die lokale Wirksamkeit (histopathologisch bestätigte Komplettremission, Tumorregression, R0-Resektionsrate, lokale Kontrolle) nicht verbessert wurde, könnte sich dieses Vorgehen positiv auf die systemische Tumorkontrolle auswirken.Schlussfolgerung:Eine Phase-III-Studie muss klären, ob die verbesserte Durchführbarkeit und Dosisdichte einer Induktionschemotherapie das krankheitsfreie Überleben verbessern kann.

Differences Between Clinical Trial Participants and Patients in a Population-Based Registry : the German Rectal Cancer Study vs. the Rostock Cancer Registry

PURPOSE: There are few data on whether the samples of randomized phase III studies are representative for cancer patients in general populations. METHODS: We compared patient and disease characteristics of patients with stage II or III rectal cancer from the German Rectal Cancer Study (657 patients, 1995-2002) or the Rostock Cancer Registry (371 patients, 1997-2003). Differences between the Study and the Registry were analyzed for subgroups who received neoadjuvant chemoradiotherapy before resection or primary resection with or without postoperative chemoradiotherapy. RESULTS: Study and Registry patients differed in age (median, 61.7 vs. 65.0 years, P < 0.001) and proportion of women (31.3 percent vs. 38.4 percent, P < 0.004). Significant age and gender differences were seen in primary resection but not in neoadjuvant subgroups. In neoadjuvant and in primary resection subgroups, Study participants were more likely than Registry patients to have tumor location in the lower third of the rectum, a higher rate of R0 resection, a greater number of lymph nodes assessed, and fewer T4 tumors. In the primary resection subgroups, Study participants were more likely to have received postoperative chemoradiotherapy. Multivariate analyses showed no effect of population type (Study vs. Registry) on disease-free or overall survival in neoadjuvant subgroups, but increased risk for Registry patients in primary resection subgroups. CONCLUSIONS: Participants in clinical trials such as the German Rectal Cancer Study are not representative of all cancer patients of a general population. To enable wider extrapolation of results, future studies should include elderly and high-risk patients.