High-dose definitive concomitant chemoradiotherapy in non-metastatic locally advanced esophageal cancer: toxicity and outcome.

This study is a retrospective analysis of high-dose definitive concomitant chemoradiotherapy in locally advanced esophageal cancer in a single institution. The aim of the study was to identify and quantify the toxicity associated with the high-dose treatment and to analyze the outcome of this treatment. Forty-six patients (41 men and 5 women, median age of 67.5 years) with disease stage IIA-III esophageal cancer were treated with high-dose definitive chemoradiotherapy. Thirty patients had squamous cell carcinomas and 16 had adenocarcinomas. The patients were treated with three courses of chemotherapy. Each chemotherapy course consisted of cisplatin 100 mg/m(2), day 1 and 5-Fluorouracil 1000 mg/m(2)/day, day 1-5. One course was given every 3 weeks. Concurrent radiotherapy (66 Gy/33 fractions) was administered during the last two courses of chemotherapy. Toxicity grades three and four were seen in 47.5% and 40% of the patients, respectively. Treatment related mortality occurred in one patient (2.5%) due to neutropenic septicemia. Follow-up time for surviving patients (2/46) was 45 and 112 months. For the entire study population, the median time to local recurrence in the radiotherapy field was 33 months and the median time to distant metastasis was 8.7 months, whereas median overall survival was 10.8 months and median disease-specific survival 11 months. For responders to chemoradiotherapy, the median time to local recurrence was 76 months, the median time to distant metastasis 16.8 months, the median overall survival and the median disease-specific survival for the responders were both 17 months. The 2, 3 and 5-year survival rates were 22%, 15% and 11% for the entire study population, and 31%, 24% and 17% for the responders to chemoradiotherapy, respectively. By multivariate analysis response to chemoradiotherapy and lower disease stage were positive prognostic factors for survival. The results of our study have shown that concurrent high-dose chemoradiotherapy provides long-term local tumor control in locally advanced esophageal cancer. However, toxicities following this high-dose treatment, while manageable, were significant. Survival rates were not improved by high-dose chemoradiotherapy compared with what is reported in previous studies applying lower doses of definitive chemoradiotherapy.

Posterior uveal melanoma treated with I-125 brachytherapy or primary enucleation.

PURPOSE: To study the incidence, clinical findings, and tumour characteristics of posterior uveal melanoma in Western Norway, and to report the results of a consistent treatment strategy (I-125 brachytherapy or primary enucleation) over a 13-year period. METHODS: The clinical records of all patients with posterior uveal melanoma referred between January 1993 and December 2005 were reviewed. Clinical data, radiation parameters, visual outcome, and mortality were analysed in a dedicated database. RESULTS: The study included 111 consecutive patients. The annual age-adjusted incidence (per million population) of posterior uveal melanoma was 8.5 for women and 8.9 for men. Fifty-six patients underwent I-125 brachytherapy, 52 were enucleated, and three received no treatment. The median follow-up time was 36 months (mean, 52 months; range, 2 months to 13 years). In the brachytherapy group, two eyes were enucleated owing to tumour recurrence and two because of neovascular glaucoma. A visual acuity of 0.1 or better, present in 87% of the patients before brachytherapy, was retained in 40% after a median follow-up of 61 months. After brachytherapy, the 5- and 10-year melanoma-specific mortality rates were 13.4 and 23.8%, respectively. The corresponding mortality rates for patients treated with primary enucleation were 49.5 and 49.5%. CONCLUSION: After brachytherapy, many patients lost useful vision due to radiation-induced complications. The probability of retaining the eye was high and only two patients experienced recurrent tumour growth. The mortality rates compare well with published series, and the differences in tumour size explain the difference in mortality between the two treatment groups.

Dosimetric verification of a dedicated 3D treatment planning system for episcleral plaque therapy.

PURPOSE: Episcleral plaque therapy (EPT) is applied in the management of some malignant ocular tumors. A customized configuration of typically 4 to 20 radioactive seeds is fixed in a gold plaque, and the plaque is sutured to the scleral surface corresponding to the basis of the intraocular tumor, allowing for a localized radiation dose delivery to the tumor. Minimum target doses as high as 100 Gy are directed at malignant tumor sites close to critical normal tissues (e.g., optic disc and macula). Precise dosimetry is therefore fundamental for judging both the risk for normal tissue toxicity and tumor dose prescription. This paper describes the dosimetric verification of a commercially available dedicated treatment planning system (TPS) for EPT when realistic multiple-seed configurations are applied. MATERIALS AND METHODS: The TPS Bebig Plaque Simulator is used to plan EPT at our institution. Relative dose distributions in a water phantom, including central axis depth dose and off-axis dose profiles for three different plaques, the University of Southern California (USC) #9 and the Collaborative Ocular Melanoma Study (COMS) 12-mm and 20-mm plaques, were measured with a diode detector. Each plaque was arranged with realistic multiple 125I seed configurations. The measured dose distributions were compared to the corresponding dose profiles calculated with the TPS. All measurements were corrected for the angular sensitivity variation of the diode. RESULTS: Single-seed dose distributions measured with our dosimetry setup agreed with previously published data within 3%. For the three multiple-seed plaque configurations, the measured and calculated dose distributions were in good agreement. For the central axis depth doses, the agreement was within 4%, whereas deviations up to 11% were observed in single points far off-axis. CONCLUSIONS: The Bebig Plaque Simulator is a reliable TPS for calculating relative dose distributions around realistic multiple 125I seed configurations in EPT.

Transillumination for accurate placement of radioactive plaques in brachytherapy of choroidal melanoma.

PURPOSE: To present a technique for accurate plaque placement in episcleral brachytherapy of choroidal melanoma. METHODS: The tumor margins are marked on the scleral surface, and a dummy plaque is temporarily sutured to the globe. A fiber optic light pipe is then wedged into the space between the sclera and the plaque. Because of the reflecting inner surface of the plaque, the perimeter of the plaque can easily be observed during indirect ophthalmoscopy as a circle of light surrounding the tumor. By this method, it is possible to determine the exact position of the entire plaque in relation to the tumor and make the necessary adjustments. When the correct position is found, the dummy plaque is replaced by a radioactive plaque. RESULTS: Since 1993, we have routinely used this procedure in episcleral brachytherapy. CONCLUSION: This modified transillumination technique facilitates a correct positioning of episcleral plaques.

Chemotherapy in Ewing's sarcoma. The Scandinavian Sarcoma Group experience.

During the past 15 years the Scandinavian Sarcoma Group has treated 140 patients with Ewing's sarcoma. Two protocols have been used. SSG IV included 52 patients between 1984 and 1990 and SSG IX, 88 patients since 1990. After 5 years of treatment, local recurrences occurred in 19% of the patients (M0 + M1) in the SSG IV group and 10% in the SSG IX group. Distant metastases developed in 57% of the M0-patients in the SSG IV group and in 33% in the SSG IX group. Tumor-related survival (overall) of M0-patients was 49% in SSG IV and 70% in SSG IX, and the metastasis-free survival rate 45% and 58%, respectively. Patients having a localized extremity tumor had a survival rate of 90% (SSG IX). In both treatment groups, good responders to chemotherapy had a better survival rate than poor ones (SSG IV, p < 0.02, GI-II vs. G II-IV and SSG IX, p < 0.003, GI-III vs. G IV). In conclusions local control and survival rates were better with SSG IX than SSG IV.

Ewing's sarcoma treatment in Scandinavia 1984-1990--ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV.

A report on the long-term follow up of the first cooperative Scandinavian Sarcoma Group study in Ewing's sarcoma of bone is presented. Fifty-two previously untreated patients entered the study between 1984 and 1990. Half of the tumors were located in the extremities and one quarter in the pelvis. The combined modality treatment consisted of 5 cycles of chemotherapy--including vincristine, methotrexate, doxorubicin, cyclophosphamide, bleomycin and dactinomycin. The first two cycles were followed by local resection or amputation in 35 patients and by radiotherapy alone in 17 patients. When surgery was not performed, was incomplete or yielded poor margins radiotherapy was given at a dose of 40-60 Gy. Local tumor relapses developed in 10 patients and in all but one patient were accompanied by metastatic disease. Five patients had metastasis at diagnosis and distant metastases developed after primary treatment in 27 patients after a median of 14 months. The median follow-up time for the 20 surviving patients is 10 years. At 5 years the tumor-related survival was 46% and the metastasis-free survival 43%. Late tumor relapses occurred in 4 patients, which reduced the 10-year tumor related survival to 41% and the metastasis-free survival to 38%. Histopathological tumour response correlated with survival with 5-year metastasis-free survival rates of 73% for the good responders and 35% for the poor responders.

Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma. A Scandinavian Sarcoma Group Phase II Study.

The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma, with dose escalations under G-CSF (granulocyte colony-stimulating factor) support. Of 92 eligible patients (median age 51 years), 85% had tumours of high-grade malignancy and 82% had metastatic disease. Chemotherapy, the baseline dose, consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days, followed by G-CSF support (VIG regimen). Stepwise 10% dose escalations were performed depending on haematological toxicity. For patients considered operable after induction chemotherapy, surgical resection of all identifiable residual tumour was attempted. Complete and partial response rates were 11% and 31%, for an overall response rate of 42% (95% CI 31-52%). Forty-eight per cent of courses were dose escalated by a median of 20%. Complete responders had significantly higher, and patients with progressive disease had significantly lower, dose levels than other patients. None of 20 patients with liver metastases responded despite high dose levels. Compared to a preceding pilot study, the addition of G-CSF led to significantly higher dose levels, improved schedule adherence and less haematological toxicity, but no apparent increase in response rate. In view of the modest dose of ifosfamide applied in this study, it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen's antitumour activity, although this can only be determined definitively in a randomised study.

Fibrosarcoma in children--a rare tumour with long-term survival even with advanced disease--a report of 3 cases.

Fibrosarcoma is a rare tumour in children. The potential of malignancy has been questioned. We present three cases of fibrosarcoma in children . The follow-up periods range from 10 to 37 years. The first patient had pulmonary metastases at the time of diagnosis in 1958. The primary tumour in fossa ischio-rectalis was resected in 1960. Lung metastases were resected in 1960 and 1989. Radiotherapy was given in 1992. He is still alive with metastases 37 years after the first manifestation of disease. The second patient had a primary tumour and several local recurrences in the mandible. He is alive without evidence of disease 4 years after resection of pulmonary metastases and 21 years after resection of the primary tumour. The third patient has no signs of recurrence or metastatic spread 10 years after a wide excision of subcutaneous tumours of the left upper arm. The cases demonstrate a special tumour-entity of low-grade malignancy, which show a good prognosis and a wide spectrum of biological behaviour.

Prediction of treatment temperatures in clinical hyperthermia of locally advanced breast carcinoma: the use of contrast enhanced computed tomography.

PURPOSE: Nineteen patients with locally advanced breast carcinoma were subjected to computed tomography examinations prior to thermoradiotherapy. Pre- and postcontrast computed tomography images were obtained, and tumor contrast enhancement was studied in relation to tissue perfusion, PERF, and steady state temperature, TS, in an attempt to develop an assay for prediction of treatment temperatures in clinical hyperthermia of breast carcinoma. METHODS AND MATERIALS: PERF and TS were calculated from temperature data achieved during the first fraction of the heat treatment regimen. The computed tomography images were subjected to image analysis, and two parameters representing tumor contrast enhancement were calculated from the computed tomography numbers; the absolute increase in mean attenuation, delta N, and the fraction of the postcontrast attenuation values that was higher than the mean precontrast attenuation value, F+C. RESULTS: delta N and F+C were clearly correlated to each other. The two parameters differed considerably among the patients, showing that the accumulation of contrast medium was higher in some tumors than in others. Tumor contrast enhancement increased with increasing PERF, suggesting that the accumulation of contrast medium in the tumors was determined mainly by the effective tissue perfusion. There was also a clear correlation between tumor contrast enhancement and TS. The tumors showing a high accumulation of contrast medium were more difficult to heat than those showing a low accumulation. CONCLUSION: The results indicate that contrast enhanced computed tomography images may give information about the treatment temperatures that can be achieved in clinical hyperthermia of breast carcinoma. The computed tomography images may possibly be used to predict those tumors that can be heated to therapeutic temperatures.

Changes in temperatures and thermal doses with fraction number during hyperthermic treatment of locally advanced breast carcinoma.

Seventeen patients with locally advanced breast cancer were given hyperthermic treatment, and changes in temperatures and thermal doses with fraction number were studied. The changes were related to the vascular density of the treated volume before treatment. Multi-point thermistor probes were used for temperature measurements. Two parameters were determined for each probe location, a steady-state temperature, Ts, and a thermal dose, t43. To quantify changes in Ts and t43, linear curves were fitted to plots of these temperature parameters versus fraction number. The slopes of the curves, kTs and kt43, were used to represent the changes in Ts and t43, respectively. Vascular density was determined by histological analysis of biopsies taken from the temperature probe locations before the first heat treatment. Generally, Ts and t43 increased with increasing fraction number. kTs and kt43 were positively correlated to the vascular density of the normal tissue in the treatment volume, i.e. the increase in Ts and t43 was largest in the best-vascularized tissue. The cooling capacity of the normal tissue was probably reduced during the later heat fractions, either because of direct damage to the blood vessels or because of an impaired thermoregulative response. No relationship was found between the temperature parameters and the vascularization of the malignant tissue in the treatment volume. The present results show that the use of a fractionated schedule for heat treatment of locally advanced breast carcinoma may increase the temperatures and thermal doses achieved during treatment. A more uniform heating of the tumours can therefore be achieved by giving multiple heat fractions in the tumour areas that are difficult to heat adequately in one session.

Fractionated thermochemotherapy in vivo of a C3H mouse mammary carcinoma.

The interaction between fractionated heat treatment and fractionated drug treatment with cyclophosphamide (CTX) was investigated in a transplantable C3H mouse mammary carcinoma inoculated into the hind leg of C3D2F1/Bom mice. A tumour core temperature of 43.5 +/- 0.1 degrees C was achieved by immersing the tumour-bearing leg into a water bath thermostatically maintained at 43.7 +/- 0.1 degrees C. CTX was administered i.p. using the maximum tolerated dose (MTD) (LD 1%) for single fraction treatment (100 mg/kg) as the maximum fraction dose. For combined treatment CTX was given 15 min prior to heating. The endpoint was the time to reach a tumour volume of 5 times the volume at first treatment. Specific growth delay was used as effect parameter. In dose-effect experiments using total treatment time at 43.5 degrees C as dose parameter, drug enhancement ratio (DER) was determined as the ratio of the slope of the dose-effect curve for MTD of CTX plus heat to the slope of the curve for heat alone. In dose-effect experiments using total CTX dose as dose parameter, thermal enhancement ratio (TER) was determined as the ratio of the slope of the dose-effect curve for CTX plus 43.5 degrees C for 30 min to the slope of the curve for CTX alone. The regimens investigated were single fraction treatment and 3 and 5 fractions with time intervals of 3 and 5 days. For single fraction treatment DER was 1.4 +/- 0.1 and TER 2.3 +/- 0.2. The drug sensitization of the effect of heat treatment tended to increase with increasing number of fractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Temperature distribution in locally advanced breast carcinoma during hyperthermic treatment: relationship to perfusion, vascular density, and histology.

Temperature distributions achieved during hyperthermic treatment of 16 patients with locally advanced breast cancer were analyzed in relation to tissue perfusion, vascular density, and histology of treated volume. Temperatures were measured using multi-sensor thermistor probes inserted in the center and periphery of the treatment volume. A steady state temperature, Ts, and a perfusion related parameter, PERF, were determined for each probe location. Vascular density and tissue composition were determined by histologic analysis of biopsies taken from the temperature probe locations before treatment. Both malignant and normal tissue were found in the biopsies, reflecting a diffusive tumor growth pattern. The malignant and normal tissue compartments were analyzed separately using stereologic techniques. Ts, PERF, vascular density, and tissue composition differed significantly between patients. There was a clear relationship between Ts and PERF, showing that the local tissue perfusion was decisive for the temperatures achieved. Ts and PERF showed a clear correlation with the normal tissue vascular density, but not with the malignant tissue vascular density; that is, the treatment temperatures achieved were mainly determined by the vascularization of the normal tissue compartment. Fraction of necrosis was the only tissue compartment parameter that showed a clear relationship to Ts and PERF. Ts increased and PERF decreased with increasing necrotic fraction.

The relevance of tumour and surrounding normal tissue vascular density in clinical hyperthermia of locally advanced breast carcinoma.

It follows from the present work that the vascularization of the normal tissue present in the treatment volume limits the temperatures achieved during heat treatment of invasive ductal breast carcinoma. The temperatures can often be increased by giving fractionated heat treatment because heat treatment may reduce the cooling capacity of the normal tissue vasculature. Significant damage to supplying vessels occurs at the heat doses necessary to cause necrosis in the tumour and surrounding normal tissue, indicating that secondary cell death is an important mechanism for cell inactivation following hyperthermic treatment of breast carcinoma.

Relationships between thermal dose and heat-induced tissue and vascular damage after thermoradiotherapy of locally advanced breast carcinoma.

Twenty-four patients with locally advanced breast carcinoma were given thermoradiotherapy, and heat-induced damage to tissue and vasculature was studied in relation to thermal dose. Thermometry was performed using six to eight multi-point thermistor probes. Heat-induced damage was quantified by histopathological analysis of biopsies taken from the temperature probe locations shortly after treatment. Both tumour and normal tissue were found in the biopsies. Fraction of tissue and fraction of vessels with heat-induced damage were determined for the malignant and the normal tissue compartment separately, using stereological techniques. Clear relationships were found between these parameters and the largest thermal dose achieved in one heat fraction. The data were subjected to logit analysis, and the thermal doses (eqv. min at 43 degrees C) that caused massive necrosis in 50% of the tissue were calculated to be 116 +/- 31 for the malignant tissue compartment and 205 +/- 49 for the normal tissue compartment. Similarly, the thermal doses that caused damage to 50% of the vessels were found to be 63 +/- 34 and 144 +/- 46 for the malignant and the normal tissue compartment, respectively. Thus, the tumour tissue was more sensitive to heat than was the surrounding normal tissue, irrespective of whether necrosis or vessel damage was considered. This was probably a consequence of physiological and vascular differences between the two tissue compartments. Evidence for primary and secondary cell death was found both in the malignant and the normal tissue, although primary cell death probably was of minor importance in the normal tissue. The data indicate that selective heat-inactivation of tumour tissue is possible by external microwave hyperthermia of locally advanced breast carcinoma.

Positioning of temperature measurement points using multiplanar computed tomography.

A method is described for the use of computed tomography and multiplanar reconstruction to depict in single images the full course of obliquely running thermometry catheters. In 14 patients given thermoradiotherapy for locally advanced breast carcinoma, reformatted images of the full catheter course were obtained for all 98 catheters so far tested. The main clinical advantage of this time-consuming procedure was the ability to determine the localization within the catheters of individual temperature measurement points of multipoint thermistor probes. It was also possible to study the localization of the measurement points in relation to the tumour margins.

[Locally advanced breast cancer--primary treatment with tamoxifen]. / Lokalavansert brystkreft--primaerbehandling med tamoxifen.

Tamoxifen was given as primary systemic treatment to 28 patients with locally advanced breast cancer. In all tumours, receptors for estrogen (ER) and/or progesterone (PGR) were positive. All patients (15) with high levels of hormone receptors (ER greater than or equal to 100 mumols/g protein and/or PGR greater than or equal to 200 mumols/g protein) were alive after two years of observation as against 60% of the patients (13) with lower hormone receptor values.

Thermochemotherapy in vivo of a C3H mouse mammary carcinoma: thermotolerant tumours.

The ability of cyclophosphamide (CTX) and mitomycin C (MMC) to modify the expression of thermotolerance in vivo at 43.5 degrees C was investigated in a transplantable C3H mouse mammary carcinoma grown s.c. in feet of C3D2F1/Bom mice. Dose-effect curves subjected to linear regression analysis were constructed for single-fraction treatment and for a second treatment 24 h after a priming heat treatment of 43.5 degrees C for 30 min. Tumour volume doubling time during regrowth showed no significant variation among treatment groups, justifying the use of tumour growth time as effect parameter. Thermotolerance ratio for heat alone was 11.6 +/- 2.3. Drug enhancement ratio in thermotolerant tumours was 6.2 +/- 1.4 for CTX (100 mg/kg) and 3.5 +/- 0.9 for MMC (3 mg/kg). These values are about 4 and 3 times larger than the corresponding enhancement ratios found for previously untreated tumours. Thermotolerance ratio for thermochemotherapy was 2.6 +/- 0.3 for CTX and 4.4 +/- 0.7 for MMC, i.e. the degree of thermotolerance was substantially reduced by both drugs, but not completely overcome. Thermal enhancement ratio for CTX and MMC was about equally large in thermotolerant and previously untreated tumours. Thermotolerant tumours showed a tendency for increased resistance to drug treatment alone. Both CTX and MMC may be used clinically to reduce the expression of thermotolerance, particularly in situations with inhomogeneous heating and short fractionation intervals.

Thermochemotherapy in vivo of a C3H mouse mammary carcinoma: single fraction heat and drug treatment.

The interaction between water bath hyperthermia (43.5 degrees C) and six cancer chemotherapeutic agents in vivo was studied in a transplantable C3H mouse mammary carcinoma grown s.c. in the feet of C3D2F1/Bom mice. Due to differences in tumour regrowth rate between treatment groups, both tumour growth time (TGT) and specific growth delay (SGD) were used as effect parameters. The largest tumour response was observed when the drug was given 15 min prior to heat--this timing was used for dose-effect experiments. Enhancement ratios were the ratios of slopes of dose-effect curves subjected to linear regression analysis. The drug enhancement ratio (DER) was not significantly larger than 1.0 for LD 1% of adriamycin, 5-fluorouracil, methotrexate and vincristine. For cyclophosphamide (CTX) and mitomycin C (MMC) both DER and TER (thermal enhancement ratio) were significantly larger than 1.0. The TGT ratios (SGD ratios in parentheses) were: DER (LD 1%): CTX 1.4 +/- 0.1 (2.1 +/- 0.1), MMC 1.3 +/- 0.1 (1.4 +/- 0.1); TER (43.5 degrees C 30 min): CTX 1.6 +/- 0.1 (2.7 +/- 0.2), MMC 2.8 +/- 0.5 (3.3 +/- 0.7). The data support the choice of CTX and MMC in preference to the other drugs investigated for clinical thermochemotherapy studies.

Epithelial ovarian tumor in a phenotypic male.

Laparotomy in a 41-year-old married man with non-treated left cryptorchidism revealed female internal genitals on the left side, and an epithelial ovarian tumor of intermediate malignancy. Germinal malignancies are frequent in intersexes, but non-germinal gonadal neoplasms are rare. This is the second reported case of epithelial ovarian tumor in intersexes, and the first case of epithelial ovarian tumor in an intersex registered as male.