[Diagnosis and multimodal therapy for hepatocellular carcinoma]. / Diagnose und multimodale Therapie des hepatozellulären Karzinoms.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in the world. The majority of HCCs develops on the basis of a chronic liver disease. This often complicates diagnosis and therapy. Non-invasive diagnostic criteria are based on dynamic imaging techniques and the serum level of AFP (alpha-fetoprotein). When evaluating HCC patients for therapy, besides tumor burden and localisation, the therapeutic evaluation must also consider the general condition of the patient and his/her liver function. For this purpose, the BCLC algorithm of the Barcelona Clinic for Liver Disease has proven helpful. Only one-third of the patients can be cured by resection, transplantation or local tumour ablation. In locally advanced cases transarterial procedures including transarterial chemoembolisation and radioembolisation are applied. HCC is a chemo-resistant tumour and chemotherapy is not accepted as standard of care in HCC. Sorafenib is the first systemic treatment with proven efficacy approved for the treatment of advanced and metastatic HCC. Interdisciplinary management of HCC patients is essential in order to provide every patient with the optimal therapy at his specific stage of disease.

Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer--a multi-centre randomised phase II study.

BACKGROUND: No standard treatment for locally advanced pancreatic cancer (LAPC) is defined. PATIENTS AND METHODS: Within a multi-centre, randomised phase II trial, 95 patients with LAPC were assigned to three different chemoradiotherapy (CRT) regimens: patients received conventionally fractionated radiotherapy of 50 Gy and were randomised to concurrent 5-fluorouracil (350 mg m(-2) per day on each day of radiotherapy, RT-5-FU arm), concurrent gemcitabine (300 mg m(-2)), and cisplatin (30 mg m(-2)) on days 1, 8, 22, and 29 (RT-GC arm), or the same concurrent treatment followed by sequential full-dose gemcitabine (1000 mg m(-2)) and cisplatin (50 mg m(-2)) every 2 weeks (RT-GC+GC arm). Primary end point was the overall survival (OS) rate after 9 months. RESULTS: The 9-month OS rate was 58% in the RT-5-FU arm, 52% in the RT-GC arm, and 45% in the RT-GC+GC arm. Corresponding median survival times were 9.6, 9.3, and 7.3 months (P=0.61) respectively. The intent-to-treat response rate was 19, 22, and 13% respectively. Median progression-free survival was estimated with 4.0, 5.6, and 6.0 months (P=0.21). Grade 3/4 haematological toxicities were more frequent in the two GC-containing arms, no grade 3/4 febrile neutropaenia was observed. CONCLUSION: None of the three CRT regimens tested met the investigators' definition for efficacy; the median OS was similar to those previously reported with gemcitabine alone in LAPC.

Primary advanced unresectable pancreatic cancer.

Median as well as overall survival of pancreatic cancer patients in the advanced stage is extremely low despite advances in cancer therapy regarding tumor cell biology, therapy resistance, and diagnosis. In matters of chemoradiation therapy (CRT) in locally advanced pancreatic cancer, favorable positive effect has been reached with different radiotherapy proceedings such as intraoperative radiation therapy with or without external chemo-/radiation therapy or with CRT alone with regard to local tumor pain, local tumor remission, or local control of disease and overall survival. Primary (chemo-) radiation therapy only rarely leads to local remission. Intraoperative radiation therapy (IORT) merely reaches pain palliation in most cases. By administering up-to-date primary CRT, especially with gemcitabine-associated CRT, local remission in up to 50% of patients can be observed. By applying neoadjuvant CRT, better resectability and the reduction of postoperative positive lymph node metastasis has been seen in patients with resectable or possibly resectable pancreatic cancer. With primary CRT, resectability can also be achieved in patients with primary unresectable pancreatic cancer. It has been shown at the evaluation of patients' progression samples--either treated with neoadjuvant or primarily with radiotherapy (with conventional radiation technique)--that the rate of local recurrence or local progression can be reduced in comparison with historical cohorts. By contrast, the rate on distant metastases was not affected. Whereas concurrent CRT leads to favorable local tumor control, this procedure has a minor effect as to the survival in most of the studies. Because metastases occur mostly out of the irradiation field and because of partly advanced local tumor progression, the concept of combined CRT with continuing chemotherapy was developed. Median survival of pancreatic patients in the advanced stage is approx. 3-5 months, with a 12-month survival probability of 10% despite advances in cancer therapy. On the other hand, the 5-year survival probability is 0.4%-3.0%. The causes of such a dismal prognosis can be understood first of all in the commonly late diagnosis, second in the aggressive tumor cell biology with continuing therapy resistance, and finally because an acceptable resection rate can be achieved only in specialized centers. Only 10%-15% of patients can be resected after the diagnosis of pancreatic cancer. Resection is considered a potential curative therapy. However, median survival of these patients amounts to only 13-18 months, with a 5-year survival of 10%-20%. The survival rate did not improve with a radical resection and extended lymphadenectomy. Furthermore, 15%-30% of primary nonmetastatic pancreatic cancer is unresectable due to extended vessel infiltration at time of diagnosis. The prognosis for these patients is very dismal due to lack of specific therapy; moreover, median overall survival is a maximum of 6-8 months.

Technical description, phantom accuracy, and clinical feasibility for single-session lung radiosurgery using robotic image-guided real-time respiratory tumor tracking.

To describe the technological background, the accuracy, and clinical feasibility for single session lung radiosurgery using a real-time robotic system with respiratory tracking. The latest version of image-guided real-time respiratory tracking software (Synchrony, Accuray Incorporated, Sunnyvale, CA) was applied and is described. Accuracy measurements were performed using a newly designed moving phantom model. We treated 15 patients with 19 lung tumors with robotic radiosurgery (CyberKnife, Accuray) using the same treatment parameters for all patients. Ten patients had primary tumors and five had metastatic tumors. All patients underwent computed tomography-guided percutaneous placement of one fiducial directly into the tumor, and were all treated with single session radiosurgery to a dose of 24 Gy. Follow up CT scanning was performed every two months. All patients could be treated with the automated robotic technique. The respiratory tracking error was less than 1 mm and the overall shape of the dose profile was not affected by target motion and/or phase shift between fiducial and optical marker motion. Two patients required a chest tube insertion after fiducial implantation because of pneumothorax. One patient experienced nausea after treatment. No other short-term adverse reactions were found. One patient showed imaging signs of pneumonitis without a clinical correlation. Single-session radiosurgery for lung tumor tracking using the described technology is a stable, safe, and feasible concept for respiratory tracking of tumors during robotic lung radiosurgery in selected patients. Longer follow-up is needed for definitive clinical results.

Randomized trial with early-stage Hodgkin's disease testing 30 Gy vs. 40 Gy extended field radiotherapy alone.

PURPOSE: To evaluate whether or not a total dose (TD) of 30 Gy is sufficient for treatment of assumed subclinical Hodgkin's Disease compared to 40 Gy TD with early stage Hodgkin's Disease (ESHD). METHODS AND MATERIALS: In a prospective multicenter trial, 376 patients with laparotomy-proven ESHD stages PS IA to PS IIB without risk factors such as large mediastinum, massive splenic involvement, extranodal disease, elevated erythrocyte sedimentation rate (ESR), and/or three or more involved lymph node areas were randomly allocated either to receive (ARM A) 40 Gy TD extended field-radiotherapy (EF-RT) or (ARM B) 30 Gy TD EF-RT plus 10 Gy TD involved field-radiotherapy (IF-RT), both arms without any chemotherapy. Three hundred sixty-six of these patients were evaluable for early and long-term response, such as remission status, freedom from treatment failure (FFTF), and overall survival (OAS). For quality control, all planning and verification films as well as dose charts were prospectively reviewed by a panel of four experts, all heads of a radiotherapy department, where protocol violations (PV) were seen either with regard to errors in treatment technique, treatment volume, in TD and/or in dose/time-relationship. RESULTS: Treatment resulted in a complete remission (CR) of 98%; in a 5-year FFTF of 76%, and a 5-year OAS of 97%. There was no difference between the two arms in favor of 40 Gy EF compared to 30 Gy EF regarding FFTF and OAS, without any in field relapse throughout the EF volumes. Expectedly, 5-years FFTF was significantly influenced by the quality of radiotherapeutical procedures: 70% with protocol violations (PV) vs. 82% without PV. CONCLUSION: Subclinical involvement in ESHD without risk factors is sufficiently treated by a TD of 30 Gy without chemotherapy, leading to a 5-years FFTF of 82% and a 5-year OAS of 97% in a multicenter treatment setting, where quality assurance is mandatory.

Complications of combined intraoperative radiation (IORT) and external radiation (ERT) of the upper abdomen: an experimental model.

An experimental model in the rabbit is presented which is suitable for analysis of clinically relevant, early side-effects of combined upper abdominal IORT and ERT. Fractionated ERT alone given through an upper abdominal a.-p. field including the entire stomach caused gastric ulcerations within < or = 58 days. Latent times decreased with increasing dose and the ED50 for occurrence of ulcers was 39 +/- 3.3 Gy. Single doses of IORT of 20-40 Gy alone administered through a 2-cm diameter field localized on the coeliac axis and carefully excluding any intestinal mucosa caused neither gastric ulcerations nor other clinical symptoms. When ERT with 40 Gy was preceded by IORT with 20-40 Gy or by sham IORT, 13 out of 15 animals developed ulcers after latent times which in a life-table analysis were shown to be significantly shorter than after ERT alone. However, a statistically significant IORT dose-dependence of latent time or incidence of ulcers could not be demonstrated in the present experiment. The most significant histological changes were observed in the areas of gastric ulcers. Already during ERT, the mucosal epithelium was depleted and regenerative activity was evident in spite of ongoing fractionated irradiation. However, profound irregularities in glandular structure and distribution, as well as number of proliferating epithelial cells were still present in healed ulcers at 80 days. In summary, IORT to the coeliac artery did precipitate the development of gastric ulcers induced by subsequent ERT. On the one hand, the data indicate that the surgical procedure of IORT did contribute to this effect. On the other hand, IORT to the coeliac artery could cause transient, functional alterations in blood supply to the depending organs, i.e. the stomach, and could thus precipitate the development of radiation-induced ulcers.

CA19-9: a pedictor of response in pancreatic cancer treated with gemcitabine and cisplatin.

The question was asked whether kinetics of CA19-9 would serve as a predictor of chemotherapeutic outcome in advanced pancreatic cancer treated with gemcitabine and cisplatin. Twenty one patients, 5 females and 16 males (median age 56 yrs, range 36-71 yrs) suffering from adenocarcinoma of the exocrine pancreas were analysed. Chemotherapy was applied for a median of 6 courses (range 2-21). Four patients achieved a complete remission, four a partial remission (OR = 38%), while stable disease was documented in 8 and progressive disease in 5 patients. Among 4 CR patients, all demonstrated a significant decline of CA 19-9 levels during the initial three treatment courses with apparent half-lifes of 15, 18, 24, and 33 days. At a cut-off level of 37 U/mL, all CR patients reached normal values in the course of treatment. All patients achieving PR showed a decrease of CA 19-9 values at apparent half-lifes of 9, 16, 88 and 89 days. Among patients with stable disease, CA19-9 transiently decreased in 7/8 patients and remained stable in 1 patient. However, values increased later in all patients after a median of 3 treatment courses (range 2-9). In patients with disease progression, CA 19-9 initially increased in 4/5 patients, while a further patient did so only beyound 100 days of treatment. In conclusion, kinetics of CA19-9 serum concentration may serve as an early indicator of response to gemcitabine/cisplatin chemotherapy in advanced pancreatic cancer.

Combined chemotherapy, radiotherapy, and immunotherapy for pancreatic carcinoma--a case report.

Therapeutic modalities for incompletely resected pancreatic carcinoma are rare. Effective treatment must not only prolong the period of palliation but also limit the adverse sequelae of the Whipple procedure so as not to compromise the quality of the remaining life span. New treatments include the use of gemcitabine and type I interferons. We treated a patient with incomplete resection of a pancreatic tumor with two cycles of gemcitabine (1000 mg/m2) and cisplatinum (50 mg/m2) followed by radiotherapy (45 Gy/5 weeks) combined with interferon-beta (three times a week/5 x 10(6) IU). Two small liver metastases occurred subsequently. In all, four cycles of gemcitabine/cisplatinum were delivered. The patient lived at least 9 months with stable metastatic liver disease and local control. He had no acute toxic reactions except for a decrease in the leukocyte count, no long-term side effects, and a satisfactory quality of life. A regimen of sequential gemcitabine/cisplatinum and radiotherapy in combination with interferon-beta deserves further consideration as therapy for pancreatic carcinoma.

[Surgical therapy of locally advanced and primary inoperable pancreatic carcinoma after neoadjuvant preoperative radiochemotherapy]. / Chirurgische Therapie des lokal fortgeschrittenen und primär inoperablen Pankreaskarzinoms nach neoadjuvanter präoperativer Radiochemotherapie.

INTRODUCTION: So far, surgery represents the only prospect for cure in patients with pancreatic cancer. Most patients, however, present with locally advanced pancreatic cancer at primary diagnosis. Recently, novel therapeutic regimens with preoperative radiochemotherapy have been developed that may improve long-term survival and resectability rates of patients with locally advanced pancreatic cancer. METHODS: This feasibility study evaluates the preliminary results of neoadjuvant therapy with gemcitabine and 5-fluorouracil (5-FU) or cisplatin. Twenty-six patients suffering from locally advanced pancreatic cancer were considered for preoperative radiochemotherapy. They received radiation (45 Gy) and chemotherapy with simultaneous or sequential gemcitabine and 5-FU (n = 15) or gemcitabine and cisplatin (n = 11) administration prior to surgical resection. RESULTS: Mean patient age was 62.4 +/- 2.6 years and 62% (n = 16) were male. The response rate was 69%, and 11 patients underwent curative surgical resection of the pancreatic cancer. Nine Whipple procedures and two complete pancreatectomies were carried out. In five patients a total of eight surgical complications were observed. Median overall survival was 9.8 months after primary cancer diagnosis (mean 12.0 +/- 1.2). During follow-up no local recurrent disease was detected. CONCLUSIONS: Our findings lead us to conclude that preoperative chemoradiation with 45 Gy, gemcitabine and 5-FU or cisplatin is a powerful therapeutic tool in patients with locally advanced non-resectable pancreatic cancer. Major resections, including vascular reconstructions, are nonetheless associated with increased mortality. Preoperative chemoradiation contributes to improved survival in patients with primary non-resectable pancreatic cancer.

[Interdisciplinary diagnosis of and therapy for cholangiocarcinoma]. / Interdisziplinäre Diagnostik und Therapie von Gallengangskarzinomen.

The diagnosis of and therapy for cholangiocarcinomas still remains an interdisciplinary challenge. For diagnostic and therapeutic purposes intra- and extrahepatic cholangiocarcinomas need to be distinguished. Multiple imaging tools such as sonography, multidetector computer tomography, magnetic resonance tomography as well as endoscopic ultrasound and endoscopic retrograde cholangiography for the diagnosis and localisation of these tumours are available. To date, surgical resection is the only curative treatment. At the time of diagnosis, most of the tumours are advanced. Therefore, only a small percentage of patients are suitable for curative surgery. Infiltration of the portal vein no longer constitutes a contraindication for surgery. Liver transplantation is not a reasonable option for intrahepatic cholangiocarcinomas but may be of advantage for perihilar Klatskin tumours. Severe cholangitis is the main cause of death of patients with obstructive cholangiocarcinomas. Drainage of the biliary tree system or surgery with construction of a biliary-digestive anastomosis is often necessary. If possible, a photodynamic therapy (PDT) should be performed in addition to biliary drainage. PDT has been shown to facilitate biliary drainage and to improve survival. The value of radiologist-assisted interventional procedures as well as percutaneous ablation and radiochemotherapy is not well established. In addition, so far, there is no standardised chemotherapy in a palliative situation established but there is some evidence for a benefit of gemcitabine-based chemotherapy. For the best care and treatment of patients with cholangiocarcinomas an interdisciplinary approach is required and to achieve progress in the therapy patients should be included in prospective clinical trials to test new approaches.

Radio-chemotherapy as a preoperative treatment for advanced rectal cancer. Evaluation of down-staging and morbidity.

BACKGROUND: The standard therapy for patients with clinically resectable rectal cancer is generally considered to be surgery. If the patient is diagnosed with advanced disease, postoperative radio-chemotherapy (RCT) is usually recommended. In our study we aimed to investigate and analyze the effectiveness and toxicity of preoperative pelvic radiotherapy in combination with 5-fluorouracil (5-FU) in locally advanced rectal cancer. PATIENTS AND METHODS: From June 1999 to September 2001 we evaluated 50 consecutive patients [37 male and 13 female; average age 65.1 (range 46-79.5) years] with locally advanced rectal carcinoma. 32 patients were staged as uT3, 14 as uT4, and 4 as uT2. Regarding N-staging, 22 patients were diagnosed as uN0. 2 patients had distant metastases, with liver metastases in both instances. Conformal irradiation was performed with a box technique (4-field technique) with a dose of 45 Gy (5 x 1.8 Gy per week for a total of 25 sessions). From days 1-5 and 29-33, all patients received 5-FU (500 mg/m(2 ) per day, as a continuous i.v. injection). RESULTS: Remission was observed in 28 patients (56%), with down-staging of at least one T-stage. A better success rate was achieved for patients with deep-seated tumors (64% of the patients in this group). Complete remission was observed in 4 patients (8.0%) and progression in 3 (6.0%). 15 patients had no detectable change in tumor staging (30.0%). A surgical R0 resection could be achieved in 43 patients, an R1 resection (minimal margin) in 7. Side effects and toxicity (common toxicity criteria) of RCT included grade I-II dysuria in 5 patients (10%), grade I-II diarrhea in 20 patients (40%), and severe diarrhea in 2 patients (4.0%). Grade I-II skin reaction was noticed in 22 patients (44.0%), severe skin reaction only in 1 patient. Regarding acute postoperative morbidity, abscess and fistula formation was noted in 8 patients (16.0%), with anastomosis leakage in 7 (14%). CONCLUSION: Preoperative radiotherapy appears to be a feasible therapeutic approach with moderate toxicity and the potential to induce down-staging. The data presented in this study confirm the preliminary reports on this neoadjuvant treatment.

Porphyrias associated with malignant tumors: results of treatment with ionizing irradiation.

BACKGROUND: Porphyrin metabolism disorders, known as porphyria, represent inherited or acquired diseases. The development of porphyria due to light sensibility occurs especially with exposure to wavelengths in the range of 300-700 nm. Skin reactions and neurovisceral dysfunctions are known side effects of ionizing irradiation. It can be postulated that during or after ionizing irradiation treatment of patients affected with tumor and porphyria, severe side effects might appear, in contrast to patients without porphyria. This paper describes the treatment of 2 patients affected with tumor and concomitant porphyria. PATIENTS: One female patient suffering from intermittent porphyria and breast cancer and one male patient suffering from porphyria cutanea tarda and bladder cancer were treated with ionizing irradiation (electrons and photons). No abnormalities nor any severe general or local side effects could be observed. CONCLUSION: Radiation therapy is not a 'stimulating' factor in activating porphyria symptoms.