Therapeutic strategies in the treatment of pancreatic carcinoma are based on the high number of non-resectable cancers, the high relative radioresistance and the high distant metastases rate. Even in curatively resected carcinomas, a locally effective treatment modality is needed because of the risk of microscopical residual disease in the peripancreatic tissue. The efficacy of radiotherapy is dose dependent. Based on an analysis of published data a dose of more than 50 Gy is recommended, resulting in a high morbidity rate with external beam radiotherapy alone. The use of intraoperative radiotherapy allows locally restricted dose escalation without increased perioperative morbidity. In adjuvant and in primary treatment, local tumor control was improved (70-90%). With palliative intent, pain relief was obtained rapidly in over 60% of patients and led to improved patient performance. As a result of the high distant metastases rate, even in curatively resected carcinomas, the overall prognosis could not be significantly improved. Further dose escalation is limited by the increasing incidence of upper gastrointestinal bleeding (20-30%).

Combined Modality Therapy↗

PubMed1995

Intraoperative radiotherapy for primary and recurrent rectal cancer.

A total of 40 primary and 20 recurrent adenocarcinomas of the rectum were treated. Intraoperative radiation therapy was combined with pre- or postoperative irradiation and 5-FU and leucovorin treatment. An abdomino-perineal excision was performed in 32 and an anterior resection in 26 cases. A Hartmann's procedure was performed in two patients. Forty-two tumours were completely resected. Residual disease was microscopically detectable in 10 cases. In eight patients, tumour residual was evident macroscopically. Postoperatively, wound infection was observed in six and anastomotic dehiscence in four cases. After a follow-up of 20 months, 46 patients revealed no evidence of disease. Local recurrences and distant metastases were detected in two patients each. Ten patients died of their disease.

Adenocarcinoma↗

PubMed1995

[Value of local radiotherapy in treatment of osseous metastases, pathological fractures and spinal cord compression].

Local radiotherapy plays an important and responsible role in the management of bone metastases. The valence will be described according to the different treatment objectives in the sense of pain relief, remineralization and cord decompression. Radiotherapy schedules, aimed at the relief pain, need to take into consideration life expectancy. Patients with a reduced life expectancy could have a good high chance of achieving pain relief with a single dose of 8 Gy. Patients with a solitary metastasis, patients with a longer life expectancy and patients with a pathological fracture should be treated with 'curative' irradiation doses, aimed at killing the maximum number of tumor cells. In addition to pain relief, remineralization is also an important treatment goal. Conventional radiotherapy with doses of 40-50 Gy resulted in pain relief in 70-100% and in remineralization in 60-80% of the patients. Remineralization could not be accelerated by short-course fractionation courses, but resulted in faster pain relief. Short-course fractionation schedules are not indicated as a 'standard' treatment in the vertebral column. Surgery is the treatment of choice for immediate cord decompression and stabilization of a pathological vertebral fracture. Radiotherapy alone could decrease neurological impairment and is suitable for patients with gradual onset and progression of symptoms, no spinal instability and lesions of the cauda equina.

Bone Neoplasms↗

PubMed1995

[Intraoperative radiotherapy within the treatment concept of retroperitoneal soft tissue sarcomas].

Sarcomas of the retroperitoneum are characterized by a high rate of local recurrence. External beam radiotherapy is known to improve local control after surgical therapy. To increase local dosage of radiotherapy without affection of sensitive structures we applied intraoperative radiotherapy (IORT) since 1991 in a dedicated operative unit. To compare morbidity and tumor control we used a partly historic control group of patients treated since 1988 for retroperitoneal soft tissue sarcoma. 25 patients with a mean age of 53 years were operated. Tumor histology was dominated by liposarcoma and leiomyosarcoma, UICC stage IIB (T2 G2 N0 M0) was present in 45% of cases. Distant metastasis were diagnosed in 19% at therapeutic intervention. Tumor free margins were achieved in 55% while 29% showed microscopic and 16% macroscopic tumor residues after surgical intervention. 11 patients received IORT with a mean of 18 Gy, eight of those patients were treated additionally with a mean of 40,4 Gy externally. There were no differences in distribution of known risk factors for recurrence in the group of patients treated with or without IORT. The analysis showed no difference for perioperative morbidity. Tolerance for IORT and additional external beam radiotherapy was good. Local tumor control tended to be improved by IORT (p = 0.082) while overall survival was not affected at a mean follow-up of 24 months.

Adolescent↗

PubMed1995

[Locally restricted dose escalation in radiotherapy of primary advanced and recurrent rectal cancers].

PURPOSE: Prognosis in patients with resected rectal carcinomas is correlated to local tumor control. Percutaneous (EBRT) and intraoperative boost irradiation (IORT) can improve local control. The aim of this study was to analyse the role of locally restricted dose escalation and the possibility to integrate IORT in a multi-modality adjuvant treatment approach. PATIENTS AND METHODS: A total of 128 and 71 patients with primary and recurrent disease were eligible for analysis. More than 60% of patients suffered from a stage III carcinoma. Between 26.3 and 38.8% of patients revealed lymphangiosis carcinomatosa in pathohistological examination. A dose of 40.2 Gy was applied using multiple field techniques. Either a percutaneous boost dose of 18.3 Gy or an intraoperative boost dose of 12.1 Gy was given in 97 and 62 patients. 40 patients with non-resectable recurrent carcinomas were treated with radiotherapy alone. In respectively 67.4% and 52.6% of IORT patients (primary and recurrent) a simultaneous chemotherapy was given, whereas only 16.5% and 8.3% of patients with EBRT alone had additional chemotherapy. RESULTS: Five-year overall survival was 64% and 41% in stage II and III (T2-3) carcinomas. All patients with stage III (T4) carcinomas died within 3 years. Overall the local failure rate was correlated to tumor stage (12.7 to 19.7%) and lymphangiosis carcinomatosa (12.5 vs. 22.9%). In patients with radiotherapy alone, local failure rate decreased with increasing irradiation dose (32%/40 to 48 Gy, 25%/49 to 56 Gy, 20.5%/57 to 66 Gy 0%/40.2 Gy + IORT). The overall 2-year survival was significantly improved after IORT and IORT plus simultaneous chemotherapy in both primary and recurrent disease. Perioperative morbidity was not increased. The toxicity of the multi-modality approach with IORT was low and acceptable. CONCLUSION: The local tumor control in rectal carcinoma after radiotherapy was dose dependent, IORT could be integrated in an adjuvant multi-modality treatment concept, without increasing morbidity. Local failure rate could be markedly reduced.

Chemotherapy, Adjuvant↗

PubMed1995

[Three-dimensional planned radiotherapy in rectal cancer. Feasibility study and preliminary clinical results].

PURPOSE: Since 1991 the use of three-dimensional planned radiation therapy for rectal cancer was evaluated as a part of a clinical project funded by the Deutsche Krebshilfe at the Radiological Department of the University of Heidelberg. First clinical experiences are reported. PATIENTS AND METHODS: 32 patients who were irradiated loco-regional for rectal cancer were analysed retrospectively. Radiation therapy techniques: patient's position was prone by the use of a belly board. Three-dimensional treatment (3D) planning system was voxelplan. The radiation therapy was started using a 3-field-box technique modified by 3D-technique after 22 to 42 Gy, depending on therapeutic concept. RESULTS: On average 92% of the planning target volume were encompassed with the 80% isodose. The average maximum dose was 108% (isocenter = 100%), of the small bowel volume received less than 34% of the dose, 70% of the bladder volume less than 40% respectively. Total average dose was 52.4% Gy. Irregular fields were used in all patients, a non-coplanar field was used to optimize dose-distribution in 41% of the patients, 21 patients received chemotherapy simultaneously. Acute side effects according to gastrointestinal tract reached grade 1 (WHO) in 9 patients, grade 2 in 2 patients. Side effects according to bladder reached grade 1 in 5 patients grade 2 in 1 patient respectively. In 4 patients suffered from acute side effects concerning the bladder. In one patient acute side effects grade 1 concerning gastrointestinal tract was observed. Portal films were analysed to evaluate precision of radiation therapy. On average the error was 3.1/4.5/4.0 mm in the x/y/z direction respectively. The standard deviation was 4.4/6.8/6.3 mm for x/y/z respectively. A median time of 2 hours was necessary for all planning procedures. CONCLUSIONS: Three-dimensional treatment planning optimizes dose-distribution in a relevant number of patients. Its clinical use for treatment of large targets or in order to applicate high doses is justified. Planning target volume should cover the clinical target volume with a margin of 1.5 cm.

Feasibility Studies↗

PubMed1994

[Developments up to now and current status of adjuvant chemo- and radiotherapy in colonic and rectal carcinoma].

A review is given of the historical and current concepts of adjuvant chemo- and radiotherapy of colorectal cancer. Early studies analyzing the use of single drug regimens were followed by a second study generation investigating adjuvant chemotherapeutic combinations. 5-FU proved to be the most efficient single drug investigated and 5-FU/MeCCNU/vincristin the most efficient chemotherapeutic combination, but no significant improvement in 5-year survival rates was achieved. Clear progress was noted with the introduction of levamisol (LEV) for modulation of 5-FU. A 33% improval in the 5-year survival rate in patients with stage III colon carcinoma was documented. It was therefore recommended (NIH consensus conference 1990) that all patients with stage III colon carcinoma be treated with this regimen unless admitted to other trials of adjuvant therapy. Preoperative radiotherapy with a dosage of 35-45 Gy can lead to downstaging of rectal cancer. Nevertheless, significant improvement in patient survival has not been proved convincingly using either isolated pre- or postoperative adjuvant radiotherapy. However, combined radiochemotherapy has been shown to improve both patient survival and local tumor control compared to surgical resection alone. It is therefore recommended that all stage II and III rectal cancer patients be treated with adjuvant combined radiochemotherapy. 5-FU/MeCCNU is currently expected to be the most efficient chemotherapy in combination with radiotherapy. Early data point out that MeCCNU could possibly be omitted. Intraoperative radiotherapy (IORT) allows further dosage escalation in order to improve local tumor control without affecting radiosensitive structures. Available data are still sparse and mostly based on the treatment of advanced carcinoma. A general validation of IORT is not yet possible, but current data are promising.

Antineoplastic Agents↗

PubMed1994

A modified computer-assisted colorimetric microtitre assay (MTT) to assess in vitro radiosensitivity of V79, CaSki, HeLa and WiDr cells.

The non-clonogenic MTT assay, based on the reduction of a tetrazolium salt to a purple formazan precipitate by living cells, was modified and a new procedure of analysis is proposed. The colorimetric assay could be performed semi-automatically using microtitre plate reader connected to a personal computer. Data are processed and plotted with a customized program. To ensure that both control and irradiated microtitre plates contain exponentially growing cells at the time of analysis, the calculation of relative survival is based on a series of well-defined cell numbers initially seeded. To make the two endpoints of non-clonogenic and clonogenic assays comparable, i.e. counting of living cells versus counting of colonies, radiation-induced progression delay was incorporated into the calculation. Radiation-induced cell killing and progression delay could be determined in a single analysis, but in an independent way. X-ray survival curves were generated for V79, CaSki, WiDr and HeLa cells using the non-clonogenic and a standard clonogenic assay. Using the linear-quadratic formula, the resulting parameters alpha, beta and the mean inactivation dose were not significantly different. The described assay is a feasible and reproducible technique for determination of cellular survival, which may be able to incorporate progression delay. The equivalence to a clonogenic survival assay could be proven.

Animals↗

PubMed1994

[Intraoperative radiotherapy of locally advanced and recurrent rectal cancer].

Intraoperative radiotherapy (IORT) offers a technique to increase radiation dose to the residual tumor or tumor bed while sparing neighboring radiosensitive organs. Beyond the mostly employed dedicated electron beam facilities, the afterloading--'flab'-technique was also used. In first prospective studies IORT was performed in patients with not completely resected locally advanced (T4) or recurrent tumors after complete external beam radiotherapy (50.4 Gy) as an additional boost dose, using small field sizes. This locally restricted dose escalation yielded higher local control and an increased prognosis. Nerves and ureters were dose limited. In our series IORT was performed for rectal carcinomas stages II and III. After an external beam radio- or radio-chemotherapy with 41.4 Gy, shrinking field boost irradiation was done intraoperatively with moderate doses and larger IORT field sizes. Compared to a historical control with high-dose external beam radiotherapy alone local control rate was increased. Radiogenic neuropathy or stenosis of the ureter was not observed. The impact on prognosis must awaited. Randomized studies are required to clearly describe the role of IORT in rectal carcinoma.

Brachytherapy↗

PubMed1994

[Intraoperative electron irradiation (IORT) of urologic tumors. Initial results of a pilot study of local recurrences of renal cell cancers].

The efficacy of radiotherapy of renal cell carcinomas is limited by its side effects. To avoid gastrointestinal problems the dose must not exceed 45 Gy, but with corresponding protocols no effect has been seen in curative and adjuvant trials. A new three-step protocol combining surgery with intraoperative radiotherapy focussed on the tumor bed fading out the intestine (IORT) and external boost radiotherapy (40 Gy) was used in six patients with local recurrences after tumor nephrectomy. No increase in morbidity was induced by IORT. One year after radiotherapy no recurrences have been seen in the radiation field. We recommend this protocol for patients with solitary local recurrences and for tumors of clinical stage T3 and T4.

Adult↗

PubMed1993

[Fundamentals and possibilities of intraoperative radiotherapy].

Explore the source record for details and available documents.

Combined Modality Therapy↗

PubMed1993

[The value of radiotherapy for liver metastases].

The role of palliative irradiation was analysed in 55 patients with liver metastases from colorectal (n = 35), breast (n = 10) and lung cancer (n = 10), treated between January 1982 and June 1992 with irradiation doses more than 10 Gy. In 47 patients irradiation alone was done. The great majority of patients were treated because of pain (n = 21) or cholestasis (n = 22). In 29 patients the disease involved not only the liver, but was disseminated. A mean dose of 23.8 Gy was delivered, with daily fractions of 1.5 (n = 30), 1.8 (n = 1) or 2 Gy (n = 16). Complete and near complete pain relief was obtained in six (28.6%) and nine (42.9%) patients. Normalized and near normalized values of bilirubin serum levels were obtained in five (22.7%) and seven (31.9%) patients. As well relief of pain as normalisation of cholestasis were significantly correlated with the irradiation doses applied. Median survival was 36.5 days for patients with lung cancer, 70.5 and 73 days for patients with breast and colorectal cancer. Irradiation doses given (10 to 18 Gy vs. 19 to 28 Gy vs. 29 to 48 Gy) and the status of disease (liver only vs. disseminated) were significantly correlated to prognosis (p = 0.00001, p = 0.0007). Patients of the high-dose group or patients with liver metastases alone revealed a median survival of 174 or 175 days. Since May 1991 simultaneous radio-chemotherapy, with the systemic application of leukovorine and 5-FU, was performed in eight patients with colorectal cancer. After performing a three-dimensional radiotherapy planning, which enclosed the whole liver inside the target volume, a mean dose of 29.4 Gy, with daily single fractions of 1.5 Gy was delivered. The follow-up, done with CT or NMR revealed in seven patients a progression free interval of three to 8.5 (5.5) months. After a median follow-up of 221 days the median survival was 333 days. In the treatment of patients with liver metastases a clear therapeutic selection has to be done according to valid prognostic criteria. In the majority of our patients with clinical symptoms, i.e. pain or cholestasis, irradiation alone was sufficient for palliation of these symptoms. Prognosis is limited because of the disseminated state of disease in 62% of the patients. In a group of patients, suffering from colorectal cancer with good prognostic criteria, the simultaneous application of radiotherapy and systemic chemotherapy was able to increase significantly the survival with minor toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗

PubMed1993

[Methodology, technical prerequisites and postoperative morbidity of intraoperative radiotherapy (IORT) of soft tissue sarcomas. Heidelberg Krankengut 6/91-9/92].

Since June 1991 the IORT facility has operated a dedicated linear accelerator, which was installed within the central operating theater of the Department of Surgery. As of 9/92 a total of 28 patients suffering from peripheral (n = 20) or centrally (n = 8) located soft tissue sarcomas had been were treated. Thirteen patients revealed a primary and 15 patients a recurrent tumor. Tumor resection with negative margins was performed in 20 patients, positive margins remained in 5 patients, and gross macroscopic residual disease in 3 patients. Combined intraoperative and external beam radiotherapy was applied in 22 patients, using IORT doses of 10-20 Gy and an external beam dose of 26-50 Gy. Three patients were irradiated intraoperatively twice with a time interval of 24 h. After a median follow-up of 9.9 months, 20 patients are disease free. Two patients died 4 and 5 months after the end of therapy with rapidly progressive distant metastases. An infield failure within the external beam target volume was seen in 1 patient and local failure at the field margin of the external field in 3 patients. So far, there have been no IORT infield failures. Follow-up is performed with magnetic resonance imaging. In 3 patients a second operation was necessary because of a severe wound infection, including one patient suffering from osteomyelitis of a neighboring bone. Mild sensory neuropathy occurred in 1 patient 7 months after treatment. Overall only mild and reversible postoperative and posttherapeutic complications were seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

[The primary radiotherapy of inoperable or recurrent pancreatic carcinoma--Heidelberg patients from 1982 to 1992].

Between 1982 and 1992, 34 patients with locally advanced or relapsed adenocarcinoma of the pancreas were treated at the Department of Radiotherapy in Heidelberg. 14 patients were treated with a combined radiochemotherapy with 5-FU, the other patients were irradiated alone. In all cases irradiation was done with high energy photons. 15 patients received an irradiation with doses between 30 and 44 Gy, and twelve patients between 45 and 66 Gy (median 50 Gy). Seven patients were treated intraoperatively during an exploration laparotomy with fast electrons (10 to 18 MeV, 15 to 20 Gy) and postoperatively with additional 30 to 41 Gy. The median survival of the patients treated with the higher doses or in combination with the IORT showed a significant advantage of nine vs. 2.9 months. There was no benefit in median survival for the patients treated with radiochemotherapy. In retrospective analysis of the percutaneous treated patient collective a pain relief was observed in nine patients. In the prospective treatment protocol of the IORT in 4/4 patients a pain relief was rapidly reached.

Adenocarcinoma↗