Angiosarcoma of the eyelid and periorbital region. Experience in Leiden with iridium192 brachytherapy and low-dose doxorubicin chemotherapy.

AIM: To report on the use of iridium(192) brachytherapy and doxorubicin chemotherapy as adjuvant therapy in 6 patients with angiosarcoma of the eyelid and periorbital region. MATERIAL AND METHODS: Tumor localization and diameter, signs of inflammation, histology and treatment are discussed in this retrospective study of 6 patients (age 46-87 yrs.) presenting with primary angiosarcoma in the eyelid. RESULTS: Six patients (4 elderly) with angiosarcoma localized in one or more eyelids, the face or multilocular were seen between 1987 and 2000. In one patient, a small nodular tumor did not recur within 4 years after radical excision. In another patient, the tumor was treated with surgery and iridium(192) wire brachytherapy and did not recur in 17 years of follow-up. In four patients with large diffuse tumors that were treated with doxorubicin, partial regression was achieved. The follow-up was >3 years (median 5 years). CONCLUSION: If radical surgery for angiosarcoma of the eyelid and periorbital region is not possible, adjuvant iridium(192) wire brachytherapy may prove beneficial. For widespread, diffusely growing tumors, and in elderly patients, low-dose (slowly, 20 mg i.v.) doxorubicin can be used weekly as adjuvant therapy, resulting in partial regression and longer survival rates than previously published by other authors.

Risk factors for catheter-related thrombosis in cancer patients.

We investigated the risk factors for venous thrombosis in cancer patients with implantable ports undergoing chemotherapy. One hundred and seventy one ports were placed in a central ("chest ports") and 84 in a peripheral vein ("arm ports"), 181 received prophylactic nadroparin and 10 coumarin. Clinically overt thrombosis was confirmed by ultrasound or angiography. Catheter-related thrombosis incidence without anticoagulants was 28% in arm and 33% in chest ports, but with anticoagulants this was 32% in arm and only 1% in chest ports (odds ratio (OR) 34.8 95% confidence interval (CI) 7.3-165). Left-sided placement compared with right-sided and catheter tip position in the superior vena cava compared with right atrium were associated with a 3.5 respectively 2.6-fold increased risk. Thrombosis was associated with elevated homocysteine levels (OR=3.8, 95% CI 1.3-11.3), but not with factor V Leiden or prothrombin 20210A gene mutations, or high concentration of factor VIII, IX or XI. Prophylaxis with anticoagulants is recommended for chest, but not for arm ports. Determination of plasma homocysteine levels may identify patients at an increased risk for thrombosis.

Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature.

PURPOSE: To evaluate the risk of major thromboembolic complications in male germ cell cancer patients receiving cisplatin-based chemotherapy and to review the literature on this subject. PATIENTS AND METHODS: One hundred seventy-nine germ cell cancer patients treated between January 1979 and May 1997 in our hospital were analyzed with respect to risk factors for developing thromboembolic events, such as baseline tumor characteristics, prior tumor therapy, administration of cytostatic agents, and the use of antiemetic drugs. The patients were treated with a variety of combination chemotherapy regimens, primarily cisplatin-containing combination regimens. RESULTS: Of the 179 patients, 15 patients (8.4%) were identified who developed a total of 18 major thromboembolic complications in the time period between the start of chemotherapy and 6 weeks after administration of the last cytostatic drug in first-line treatment. Of these 18 events, three (16.7%) were arterial events, including two cerebral ischemic strokes, and 15 (83. 3%) were venous thromboembolic events, including 11 pulmonary embolisms. One (5.6%) of the 18 events was fatal. Liver metastases (odds ratio, 4.9; 95% confidence interval, 1.1 to 20.8) and the administration of high doses of corticosteroids (>/= 80 mg dexamethasone per cycle; odds ratio, 3.5; 95% confidence interval, 1. 2 to 10.3) as antiemetic therapy were identified as risk factors for the development of major thromboembolic complications. CONCLUSION: Germ cell cancer patients who receive chemotherapy, in particular those who have liver metastases or receive high doses of corticosteroids, are at considerable risk of developing thromboembolic complications.

Chondroblastic osteosarcoma: characterisation by gadolinium-enhanced MR imaging correlated with histopathology.

OBJECTIVE: To identify specific features of chondroblastic osteosarcoma on gadopentetate dimeglumine (Gd)-enhanced magnetic resonance (MR) imaging. DESIGN AND PATIENTS: Nine patients with chondroblastic osteosarcoma and a control group of 20 patients with conventional central osteosarcoma were included in this study. The histopathological findings of the surgical specimens were compared with enhancement patterns on static Gd-enhanced MR images. RESULTS: In chondroblastic osteosarcoma septonodular and peripheral rim enhancement represented tumour with a pure chondroid matrix. Non-enhancing and heterogeneous enhancing areas represented tumour with both chondroid and osteoid matrix. In the tumours in the control group enhancement was predominantly heterogeneous but in one it was homogeneous. All these areas corresponded to necrotic or viable osteoid tumour tissue or fibrovascular tissue in areas of necrosis. CONCLUSION: Gd-enhanced MR imaging can assist in obtaining diagnostic biopsy material of chondroblastic osteosarcoma by identifying both osteoid- and chondroid-forming areas.

Patients' utilities for cancer treatments: a study of the chained procedure for the standard gamble and time tradeoff.

OBJECTIVE: Temporary health states cannot be measured in the traditional way by means of techniques such as the time tradeoff (TTO) and the standard gamble (SG), where health states are chronic and are followed by death. Chained methods have been developed to solve this problem. This study assesses the feasibility of a chained TTO and a chained SG, and the consistency and concordance between the two methods. PATIENTS AND METHODS: Seventy female early-stage breast cancer patients were interviewed. In using both chained methods, the temporary health state to be evaluated was weighed indirectly with the aid of a temporary anchor health state. The patients were asked to evaluate their actual health states, a hypothetical radiotherapy scenario, and a hypothetical chemotherapy scenario. RESULTS: Sixty-eight patients completed the interview. The use of the anchor health state yielded some problems. A significant difference between the means of the TTO and the SG was found for the anchor health state only. For the other health states, the results were remarkably close, because the design avoided some of the bias effects in traditional measurements. CONCLUSION: The feasibility and the consistency of the chained procedure were satisfactory for both methods. The problems regarding the anchor health state can be solved by adapting the methods and by the use of a carefully chosen anchor health state. The chained method avoids biases present in the conventional method, and thereby the TTO and the SG may be reconciled. Moreover, there are several psychological advantages to the method, which makes it useful for diseases with uncertain prognoses.

Can conventional radiographs be used to monitor the effect of neoadjuvant chemotherapy in patients with osteogenic sarcoma?

OBJECTIVE: The objective of this study was to assess the effectiveness of conventional radiography in predicting histopathologic response in patients with osteogenic sarcoma who were treated with preoperative chemotherapy. DESIGN AND PATIENTS: The radiographs of 22 patients with an osteogenic sarcoma, taken before and after neoadjuvant chemotherapy, were reviewed. Tumour location, size, radiographic appearance, margination, cortical destruction and periosteal reaction were evaluated. The findings were correlated with the histopathologic response of the surgical specimen. RESULTS: None of the findings proved to be of predictive value for the histopathologic response. Increase in tumour diameter and increase in ossification and/or calcification, which were seen in more than half of the patients, did not correlate with response. CONCLUSION: Conventional radiographs do not contribute to the identification of good or poor responders.

Osteosarcoma and Ewing's sarcoma after neoadjuvant chemotherapy: value of dynamic MR imaging in detecting viable tumor before surgery.

OBJECTIVE: This study analyzed the value of dynamic contrast-enhanced and subtraction MR images in detecting residual viable tumor before surgery, with emphasis on timing of enhancement, in patients with high-grade osteosarcoma and Ewing's sarcoma after neoadjuvant chemotherapy. SUBJECTS AND METHODS: Twenty-one patients with proved osteosarcoma or Ewing's sarcoma were treated with neoadjuvant chemotherapy followed by surgery. After IV administration of gadopentetate dimeglumine, dynamic enhancement patterns on preoperative MR images were compared with corresponding areas on histologic sections of the resected specimens. On dynamic subtraction images obtained with high temporal resolution (1.5-3 sec), the interval between arrival of the bolus of contrast agent in an artery and start of tumoral enhancement was used to distinguish residual viable tumor. Early enhancing foci (interval artery-tumor < 6 sec) and late or nonenhancing areas seen on MR images were correlated with the histopathologic findings in these areas of the resected specimens. RESULTS: Early and progressively enhancing structures seen on MR images corresponded to feeding arteries, physeal vessels, or residual viable tumor at specific preferential sites on corresponding histologic sections of the resected specimens. Tumor foci as small as 3-5 mm2 could be detected on dynamic MR images. Remnant viable tumor was often located subperiosteally and at the margins of the tumor. Occasionally, active periosteal reaction without presence of viable tumor contributed to early enhancement. Late and gradually enhancing or nonenhancing areas corresponded histopathologically to regions of chemotherapy-induced necrosis, mucomyxoid degeneration, or fibrosis. Alternatively, late or nonenhancing areas were associated with reactive changes such as edema, hemorrhage, or osteomyelitis or with tumor-related extracellular matrices such as abundant osteoid or chondroid. Viable tumor areas with scarce formation of matrix on microscopy, such as small cell osteosarcoma areas or Ewing's sarcoma, showed early enhancement with rapid washout of contrast agent on the dynamic MR images. CONCLUSION: Fast dynamic contrast-enhanced sequences are essential for identifying residual tumor before surgery. A short time interval of less than 6 sec between arterial enhancement and tumoral enhancement strongly correlates with presence of viable tumor. Both therapy-related alterations of tissue and tumor-related matrices must be considered when late or lack of enhancement is noted on dynamic MR images.

Treatment of high-grade bone sarcomas with neoadjuvant chemotherapy: the utility of sequential color Doppler sonography in predicting histopathologic response.

OBJECTIVE: The purpose of this study was to use color Doppler flow imaging to predict the response to preoperative chemotherapy in patients with Ewing's sarcoma or high-grade osteosarcomas early in treatment. SUBJECTS AND METHODS: Color Doppler flow imaging was done in 31 patients before, during, and after chemotherapy. In each phase of treatment, semiquantitative changes in intratumoral blood flow, changes in maximum intratumoral Doppler shifts, and changes in resistive indexes of arteries feeding limbs that contained tumors relative to contralateral normal arteries were compared with the histopathologic response, as evaluated on the resected specimens. RESULTS: Before chemotherapy, pathologic flow was found in the extraosseous component of all but two patients. Resistive indexes in arteries that fed tumors were significantly lower (p < .001) than the resistive indexes in the contralateral normal arteries. Histopathologic response could not be predicted on the basis of the initial measurements of Doppler shifts and resistive indexes taken before or after the first cycle of chemotherapy. Histopathologic response could be predicted after the second cycle of chemotherapy. After the second cycle of chemotherapy, the resistive index in the arteries that fed tumors increased in eight of nine good respondents but did not change or decreased in eight of nine poor respondents (p = .03). Lower intratumoral Doppler shifts were measured in six of 10 good respondents but also in five of 13 poor respondents (p = .07). After the full course of chemotherapy, persistent lower resistive indexes were measured in the arteries that fed tumors in all poor respondents but one. Intratumoral flow and Doppler shifts further decreased in all good respondents but one. Changes in Doppler shifts (p = .001) and resistive indexes (p < .001) were statistically significant between good and poor respondents, irrespective of the tumor type studied. CONCLUSION: Decreased or unaltered resistive index in the arteries that feed tumors in addition to persistent intratumoral flow and high-frequency Doppler shifts after two cycles of chemotherapy suggest poor histologic response to chemotherapy in osteosarcoma and Ewing's sarcoma. An increased resistive index after two cycles is indicative of good response.

Can MRI predict the histopathological response in patients with osteosarcoma after the first cycle of chemotherapy?

The magnetic resonance (MR) changes after one cycle of chemotherapy were compared with the prechemotherapy studies in 39 patients with osteosarcoma, in order to identify MR changes which can be used to assess early response to chemotherapy. Measurements of total tumour volume, signal intensity, and tumour enhancement of the intra- and extraosseous tumour component were performed. Change in the amount of oedema was subjectively assessed. Changes observed were correlated with histopathological response. Changes in tumour volume and of the signal intensity of the extraosseous tumour component on T2-weighting were the only two parameters which correlated significantly (P < 0.05) with histopathological response. Increase of tumour volume is the most significant parameter and indicates poor response (sensitivity 89%, specificity 73%). Only one good responder showed increase of tumour volume. Decreased or stable tumour volume was observed in both good and poor responders. Increase of signal intensity was found exclusively in five poor responders (sensitivity 100%, specificity 23%). Decreased or stable signal intensity was observed in both good and poor responders. Changes in the amount of oedema and contrast enhancement could not predict response at an early stage. We conclude that increase of tumour volume and increase of T2 signal intensity of extraosseous tumour can be predictive for poor response. MR criteria are not helpful in the early identification of good responders.

Classification of histopathologic changes following chemotherapy in Ewing's sarcoma of bone.

A uniform classification of response to chemotherapy is essential to allow comparison of local effect and ultimate prognosis between different therapy schedules. We define a histological grading system for assessment of the response to chemotherapy in Ewing's sarcoma, based on the amount and architectural pattern of residual histologically viable-appearing tumour, the preferential sites of minimal residual tumour and the amount of tumour necrosis. Twenty-six consecutive patients with a biopsy-proven Ewing's sarcoma were treated with chemotherapy prior to surgery. The effect of chemotherapy was evaluated microscopically on the specimens obtained after surgery. Response to chemotherapy was classified as minimal or no effect (< 10% tumour necrosis), moderate effect (solid areas of remnant viable tumour), minimal residual disease, and no evidence of disease (100% tumour necrosis or well-vascularized fibrous tissue). The subperiosteal area in particular and, less frequently, soft tissues and intramedullary compartment were identified as sites of predilection for persistence of microscopic viable tumour foci, frequently depicted as pseudo-rosettes in a characteristic scattered pattern. Although it is not well known whether morphological viability of these residual clusters in Ewing's sarcoma indicates biological viability, accurate preoperative local staging, with special attention to preferential sites of residual viable tumour, is essential. The proposed grading system can be used to standardize assessment of chemotherapy in trials, and may serve as a standard for non-invasive monitoring of preoperative chemotherapy with magnetic resonance imaging.

Monitoring the effect of chemotherapy in Ewing's sarcoma of bone with MR imaging.

Magnetic resonance (MR) imaging was performed in 26 patients with Ewing's sarcoma of bone preceding and following neoadjuvant chemotherapy, to assess tumour response non-invasively prior to surgery. T1- and T2-weighted spin echo images were obtained. Changes including intra- and extramedullary signal intensities, tumour demarcation, tumour volume and the appearance of residual extramedullary tumour were compared with histopathology of the resected specimens. Reduction of tumour volume was significantly higher in good responders. Other single parameters did not correlate with histologic tumour response. However, when several MR parameters summarized in a classification system were combined, a positive correlation with histopathologic response was found. A limited decrease of tumour volume (< 25%) and/or residual soft tissue mass following chemotherapy correlated with a poor response. An inhomogeneous, well-defined cuff of abnormal tissue encircling the bone and/or radiological disappearance of the soft tissue tumour component following chemotherapy correlated with good response. Twenty-three out of 26 patients were correctly classified by MR as good or poor responders. Minimal residual disease (< 10% of the entire tumour volume), observed histologically, could not be identified with MR imaging. Tumour volume reduction and residual extramedullary tumour, rather than changes of signal intensity, are major features for evaluating the response to chemotherapy in Ewing's sarcoma.

Changes in tumor perfusion induced by chemotherapy in bone sarcomas: color Doppler flow imaging compared with contrast-enhanced MR imaging and three-phase bone scintigraphy.

PURPOSE: To prospectively evaluate color Doppler flow imaging (CDFI) with spectral analysis versus dynamic gadolinium-enhanced magnetic resonance (MR) imaging and three-phase bone scintigraphy in monitoring the effect of chemotherapy on bone sarcomas. MATERIALS AND METHODS: Seventeen osteosarcomas and five Ewing sarcomas were examined with these imaging techniques before and after chemotherapy. Results were compared with the histopathologic response. RESULTS: Before chemotherapy, high systolic Doppler frequency shifts (DFSs) and/or low-impedance Doppler signals were found in all but one tumor. Resistive indexes (RIs) in tumor-feeding arteries were substantially lower than in contralateral normal arteries. After chemotherapy, DFSs disappeared in five of seven good respondents and remained substantial in all but one poor respondent. RIs increased substantially in all good respondents and decreased or showed minor changes only in all but one poor respondent. CONCLUSION: CDFI with spectral analysis has an advantage over the other two techniques in monitoring the efficacy of chemotherapy in bone sarcomas because of its superior accuracy, noninvasive nature, availability, and low cost.

Magnetic resonance relaxation times of normal tissue in the course of chemotherapy: a study in patients with bone sarcoma.

To study the effect of chemotherapy on normal fat, skeletal muscle, and bone marrow, T1 and T2 relaxation times were measured in 15 patients with bone sarcoma before and after each cycle of preoperative chemotherapy. A section plane containing the tumor and if possible the nonaffected extremity was imaged with combined multiecho spin echo and inversion recovery pulse sequences. T1 and T2 relaxation times were calculated in the normal-appearing tissues. Although some variation was found in the values in the individual patient and between patients, no systematic changes of relaxation times of fat, muscle, or bone marrow occurred in the course of treatment. We conclude that the chemotherapy used in bone sarcoma has no effect on relaxation times of normal fat, muscle, and bone marrow, and that therefore these tissues may serve as a reference for the signal intensity of tumor.

[Intraperitoneal administration of interferon gamma. An efficient adjuvant to the chemotherapy of ovarian cancers. Apropos of an European study of 108 patients]. / Interféron-gamma par voie intrapéritonéale. Un complément efficace de la chimiothérapie des cancers de l'ovaire. A propos d'une étude européenne de 108 patientes.

One hundred and eight patients with residual epithelial ovarian cancer at second laparotomy, after first line plastine-based chemotherapy were treated with intraperitoneal rHU-interferon-gamma at a dose of 20 x 10(6) U/m2, twice a week for 3-4 months. 86% of the patients had residual macroscopic tumors and 33% bulky tumors (> 2 cm). From the 99 evaluable patients, 62 had an evaluative third laparotomy and nine additional patients a laparotomy. Complete pathologic and global response rates to interferon-gamma were 23 and 32% respectively. Age and tumor size were independently correlated with treatment response. Patients (n = 41) under the age of 60 with a tumor size less than 2 cm had a complete and global response rate of 42 and 54% respectively. Interferon-gamma was equally effective in chemo-resistant and chemosensitive tumors. Median duration of response was 21 months and median survival of responder patients was 86% at 2 years. In multivariate analysis, response to interferon-gamma was the most prominent prognostic factor of this population of patients with residual ovarian cancer.

Osteosarcoma: chemotherapy-induced changes at MR imaging.

Fifty-seven patients undergoing chemotherapy for osteosarcoma underwent evaluation with magnetic resonance (MR) imaging to identify changes related to a good or poor response. Spin-echo MR images obtained after preoperative chemotherapy were compared with images obtained before treatment. Histopathologic examination of each resected specimen was used to quantify the response. An increase in tumor volume and increased or unchanged edema were predictive of a poor histopathologic response (predictive values, 85%-92%). Decreased or unchanged tumor volume and a decrease in edema were poor predictors of a good response (predictive values, 56%-62%). Improved tumor demarcation, an increase in the size of areas of low signal intensity, and a decrease in joint effusion occurred independently of histopathologic response in almost half of the patients. With a subjective interpretation of MR images, poor respondents can be identified if an increase in tumor volume or no decrease in the amount of edema is seen. Subjective criteria do not contribute to the identification of good respondents.

Dose intensity of chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil in the elderly with advanced breast cancer.

Toxicity and results of two different dose levels of chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in older (greater than 70 years) patients with advanced breast cancer were evaluated in a prospective (non-randomised) study. During the first three courses of chemotherapy dose reduction for haematological toxicity was necessary in all of 10 and 8 of 13 patients treated with an intended dose of 100% and 75% of standard dose CMF, respectively. The median percentages of CMF, administered during the first three courses were about 75% in both groups of patients corresponding with a median dose intensity of 72% (range 49-87%) and 64% (range 36-78%) for patients of the 100% and 75% dose group, respectively. In 34 younger postmenopausal women (mean age 57 years) treated in our institution for advanced breast cancer the median percentages of CMF in the second and third course were 86% and 84%, respectively with a median dose intensity during the three courses of 82%. Dose reductions of CMF and bone marrow toxicity, though interdependent, were statistically significantly correlated with the endogenous creatinine clearance, but not with age. 1 patient died during severe leukopenia and thrombocytopenia. Non-haematological side effects were most pronounced in the 100% group. Results of therapy in both groups of patients were about equal and compared well with those of CMF therapy in general. It is advised that the dose of CMF in patients above 70 years should not exceed 75% of standard dose. Further dose reduction of methotrexate in case of severe renal failure is required.

Pulmonary metastasectomy in patients with osteosarcoma.

Between 1980 and 1990, 70 patients with high malignant osteosarcoma of the extremities were treated according to the European Osteosarcoma Intergroup trials. Of the 31 patients with metachronous metastases (group I), 17 underwent pulmonary metastasectomy. Six of the 17 survived 8 months to 4 years after metastasectomy without evidence of recurrent metastatic disease. The type of orthopedic surgical treatment had no influence on the disease free interval (DFI), nor on the overall survival. The DFI was significantly longer (P less than 0.003) in patients with resectable pulmonary metastases. Overall survival was not influenced by the length of the DFI. Six of 11 patients with synchronous metastases (group II) underwent pulmonary metastasectomy, 1 survived longer than 7 months. Nevertheless, overall survival is not significantly different between group I and group II (P = 0.2): 28 patients without pulmonary metastases (group III) had a 95% survival at 5 years. In patients with metachronous metastases, metastasectomy independently had a positive effect on survival (P less than 0.001), but did not cure the patients. Strict patient selection and additional therapy to prevent micrometastases is needed to improve survival.