Stereotactic body radiotherapy of primary and metastatic renal lesions for patients with only one functioning kidney.

BACKGROUND: About 2% of patients with a carcinoma in one kidney develop either metastases or a new primary tumor in the contralateral kidney. Often, renal cancers progress rapidly at peripheral sites and a metastasis to the second kidney may not be the patient's main problem. However, when an initial renal cancer is more indolent yet spreads to the formerly unaffected kidney or a new primary tumor forms there, local treatment may be needed. Stereotactic body radiotherapy (SBRT) has been demonstrated as a valuable treatment option for tumors that cause local symptoms. Presented here is a retrospective analysis of patients in whom SBRT was used to control primary or metastatic renal disease. PATIENTS AND METHODS: Seven patients with a mean age of 64 (44-76) were treated for metastases from a malignant kidney to its contralateral counterpart. Dose/fractionation schedules varied between 10 Gy x 3 and 10 Gy x 4 depending on target location and size, given within one week. Follow-up times for patients who remained alive were 12, 52 and 66 months and for those who subsequently died were 10, 16, 49 and 70 months. RESULTS: Local control, defined as radiologically stable disease or partial/complete response, was obtained in six of these seven patients and regained after retreatment in the one patient whose lesion progressed. Side effects were generally mild, and in five of the seven patients, kidney function remained unaffected after treatment. In two patients, the creatinine levels remained moderately elevated at approximately 160 micromol/L post treatment. At no time was dialysis required. CONCLUSION: These results indicate that SBRT is a valuable alternative to surgery and other options for patients with metastases from a cancer-bearing kidney to the remaining kidney and provides local tumor control with satisfactory kidney function.

Thymidylate synthase expression: an independent prognostic factor for local recurrence, distant metastasis, disease-free and overall survival in rectal cancer.

Several studies have suggested that the intratumoral level of thymidylate synthase (TS) in colorectal tumors correlates with survival. We have studied the correlation between TS expression in primary rectal cancer and locoregional recurrence, distant metastases, and survival. TS enzyme levels were evaluated immunohistochemically using the specific monoclonal antibody TS 106 in paraffin-embedded tumors from 243 patients who had undergone primary surgery for rectal cancer during the years 1980-1993. All patients were included in prospective randomized trials aimed at determining the clinical value of a short preoperative course of local radiation therapy (five doses of 5 Gy each). With a median follow-up of 94 months (range, 43-202 months), it was observed by multivariate analysis that Dukes' stage and TS expression were independent prognostic markers of locoregional recurrence (P < 0.001 and P = 0.038, respectively) distant metastasis (P < 0.001 and P = 0.011, respectively) disease-free survival (P < 0.001 and 0.014, respectively), and overall survival (P < 0.001 and 0.020, respectively). By multivariate analysis, preoperative irradiation therapy showed a borderline improvement in locoregional recurrence (P = 0.051). No other factors, such as age, sex, differentiation of the tumor, or p53 expression, were noted to be independent prognostic factors for clinical outcome in these patients. We concluded that the intratumoral expression of TS in primary rectal cancer is an independent prognostic factor for locoregional recurrence, distant metastases, disease-free survival, and overall survival. Patients with low intratumoral TS expression had a significantly better outcome than those with high TS expression.

Immunohistochemically detected thymidylate synthase in colorectal cancer: an independent prognostic factor of survival.

Intratumoral thymidylate synthase (TS) expression and M(r) 53,000 phosphoprotein (p53) overexpression were studied immunohistochemically in sections from stored paraffin-embedded primary colorectal cancers in 70 patients who had undergone surgery during the years 1987-1990. These cancers were classified according to Dukes' stage A-D, using monoclonal antibodies TS 106 and DO-7. In patients with Dukes' stage A-C tumors, univariate analyses showed that there was a significant correlation (P = 0.048) between disease-free survival and TS expression and between TS expression and time to death with colorectal cancer (P = 0.038). In patients with Dukes' stage A-D tumors, overall survival was correlated to TS expression (P = 0.015), Dukes' stage (P < 0.001), and level of tumor differentiation (P = 0.044) but not to p53 overexpression. Patients with low intratumoral TS expression survived significantly longer than patients with high expression. Cox multivariate analysis showed that Dukes' stage (P < 0.001) and TS expression (P = 0.043) could independently serve as prognostic factors for time to death with colorectal cancer in patients with Dukes' stage A-D tumors.

Precautions taken to prevent adhesions--a questionnaire study among Swedish obstetricians and gynaecologists.

OBJECTIVE: To collect data on the current practice and knowledge about surgical techniques for prevention of adhesions and types of surgical gloves used by Swedish obstetricians and gynaecologists. DESIGN: Postal questionnaire during 1995. SETTING: Sweden. MATERIAL: All 1200 Swedish gynaecologists were invited to participate. MAIN OUTCOME MEASURES: Methods in use to prevent the formation of adhesions such as glove selection criteria, operative techniques, and laparoscopic surgery. RESULTS: At this time there were 72 hospitals in Sweden carrying out gynaecological operations and responses were received from obstetricians and gynaecologists at 61 of these hospitals. The response rate was 27% of gynaecologists routinely carrying out such operations. There were no consistent methods in use to prevent the formation of adhesions. The most common method used was the atraumatic technique. For laparotomy 19.5% always used powdered gloves whereas half had changed to powder-free gloves. The use of powdered gloves was highest in the university hospitals (62%). 95% always closed the visceral peritoneum for gynaecological or obstetric procedures although there is no documentation to support the benefit of doing so. CONCLUSION: There was a low percentage response, probably indicating lack of interest. Swedish gynaecologists seem unaware of the need to prevent adhesions.

Anaplastic giant cell carcinoma of the thyroid gland: treatment and survival over a 25-year period.

Anaplastic giant cell carcinoma of the thyroid is a rare but highly malignant tumor. At the Karolinska Hospital in Stockholm, surgery, chemotherapy, and radiotherapy have been used separately or in various combinations in 81 patients admitted with this diagnosis during 1971-1997. In this study, we present the various multimodality treatment regimens and their changes over the years and the subsequent differences in survival and local tumor control. Overall, eight patients (10%) survived more than 2 years. All survivors were treated with combinations of chemotherapy, radiotherapy, and surgery. Among the patients who died, local tumor control was achieved by the therapy given in many cases. The results suggest that our current strategy with a combination of preoperative hyperfractionated accelerated radiotherapy, doxorubicin pre- and postoperatively, and debulking surgery whenever possible results in better local tumor control and an increased chance of survival.

Immunohistochemical determination of thymidylate synthase in colorectal cancer--methodological studies.

With the aid of specific monoclonal antibodies, an immunohistochemical technique has recently been developed for the detection of intratumoral thymidylate synthase (TS). This technique can be applied to paraffin-embedded material suitable for retrospective studies. In order to examine this technique further, the TS enzyme activity of lysates from frozen-stored colorectal cancer (CRC) specimens were compared with their immunohistochemical TS staining intensity (arbitrarily graded from 0 to 3). A statistically significant correlation between these two methods on a total of 25 tumour specimens (P < 0.001) was observed. The staining intensity in different areas of 48 paraffin-embedded CRCs was examined. Sixty-seven per cent of the tumours were homogeneously stained (either grades 0-1 or 2-3), 33% showed a heterogeneity in TS staining. Increased TS expression correlated with more advanced Dukes' stage (P < 0.001). It is concluded that TS immunostaining intensity reflects TS enzyme activity in colorectal tumours and is well suited for paraffin-embedded material. The TS immunostaining pattern is heterogeneous in up to one-third of the tumours.

Dual effects of folinic acid in 5-fluorouracil induced killing of human tumor cell lines in vitro.

Folinic acid (leucovorin) is frequently used to augment and modulate the clinical activity of 5-fluorouracil (5-FU) in patients with advanced gastrointestinal (Gl) cancer. However, there are conflicting opinions concerning the optimal doses for these patients, and whether folinic acid modulates the clinical activity of 5-FU in patients with non-Gl cancer. To elucidate these questions, model experiments have been performed on human tumor cell lines in vitro to determine the modulatory activity of various concentrations of folinic acid on 5-FU mediated cytotoxicity using a clonogenic assay. Three cell lines of colon cancer and 3 of glioblastoma origin were exposed to 5-FU alone or with folinic acid for 24 hours. It was observed that relatively low concentrations of folinic acid enhanced the cytotoxicity of 5-FU against the colon cancer lines whereas higher concentrations were less effective. Folinic acid did not enhance the 5-FU mediated killing of the glioma cell lines at any concentration (0.01-100 micrograms/ml). On the contrary, folinic acid seemed to counteract the cytotoxic effect of 5-FU in a reasonably dose-dependent fashion. These results may suggest that the value of folinic acid in the treatment of non-Gl cancer with 5-FU should be evaluated within the framework of controlled clinical trials, and that high doses of folinic acid may not necessarily be more effective than low.

Social support and immune status during and after chemotherapy for breast cancer.

Social support and immune status were assessed in women treated with adjuvant chemotherapy for breast cancer. Perception of enhanced attachment was associated with an increased number of white blood cell levels three months after, but not during, chemotherapy. After treatment, patients with high attachment ratings had higher numbers and proportions of granulocytes, and lower proportions of lymphocytes and monocytes. It is concluded that the support experienced by a cancer patient can be associated with counts and proportions of leukocytes, but that this effect, if present during chemotherapy, is overridden by the biological factor that affects the haematopoetic process.

Brain tumors.

This synthesis of the literature on radiotherapy for brain tumors, ie, cancer originating in the central nervous system (CNS), is based on 81 scientific articles, including 25 randomized studies, 13 prospective studies, and 25 retrospective studies. These studies involve 11,081 patients. A more comprehensive chapter on brain tumors may be ordered from SBU. Curative treatment is not available for patients with highly malignant glioma (grades III and IV). Postoperative radiotherapy for highly malignant glioma extends patients' survival, with good quality of life, by several weeks to several months. Virtually all patients die from this disease. Although the clinical benefits from radiotherapy, measured as survival, appear to be modest, it is more effective than any chemotherapy tested thus far. The clinical effects of radiotherapy for highly malignant glioma are improved only marginally by altering factors such as absorbed dose, fractionation, irradiated tissue volume, radiation quality, or by adding radiosensitizing substances. Radiotherapy alone usually provides a clear but temporary improvement in patients with highly malignant glioma, hence it clearly has a palliative benefit. Postoperative radiotherapy for low-grade malignant gliomas (grades I and II) may extend survival. It also reduces tumor volume. No evidence shows that radiotherapy alone or postoperatively can lead to cure. In patients who have undergone subtotal meningioma resection, postoperative radiotherapy substantially reduces the risk for recurrence and extends life, and is thereby indicated. Radiotherapy is not indicated following macroscopic radical meningioma surgery. Patients with brain metastases experience rapid neurological improvement following radiotherapy to the whole brain, and this palliative effect often remains throughout the remainder of the patient's life. Palliative radiotherapy, often to large volumes of the CNS, is therefore motivated in a large proportion of the patient groups. In a smaller group of patients with solitary metastases, radiotherapy may be given postoperatively following radical neurosurgery. Life may be extended in this group, otherwise radiotherapy does not influence survival. Stereotactic radiotherapy of solitary, mainly spherical metastases in the brain is often superior to other known methods with respect to palliation and survival. The number of patients is, however, relatively small.

Rectal cancer.

This synthesis of the literature on radiotherapy for rectal cancer is based on 73 scientific articles, including 1 meta-analysis, 32 randomized studies, 22 prospective studies, and 1 retrospective study. These studies involve 15042 patients. The reviewed studies show that adjuvant radiotherapy for operable rectal cancer can reduce the risk for local recurrence. A meta-analysis of 11 randomized studies reported a 25% risk reduction. The same meta-analysis suggests that adjuvant radiotherapy can reduce mortality by 10%, but this has not been statistically confirmed. The clinical effects of radiotherapy may depend on when it is given in relation to surgery. The issue of preoperative or postoperative radiotherapy is being investigated in several prospective randomized studies. Fractionation, administration of anticancer drugs during radiotherapy, and surgical methods, including associated radicality, also appear to be of importance. Local recurrence of rectal cancer is accompanied by severe suffering for the patient, eg, severe pain that is difficult to control by medication and surgery. Hence, there are major benefits from avoiding local recurrence. Given current knowledge, radiotherapy (preferably preoperative) is indicated in conjunction with operable rectal cancer, mainly Dukes' group C. External radiotherapy provides valuable palliation in many patients with locally advanced rectal cancer. In isolated cases, treatment appears to lead to prolonged disease-free survival, mainly in patients with local recurrence who have not already received pre- or postoperative radiotherapy. Experiences from different models of combination therapy involving chemotherapy and intraoperative radiotherapy are too limited to permit reliable conclusions: mainly since observation times are relatively short.

Different dose regimens of 5-fluorouracil and interferon-alpha in patients with metastatic colorectal carcinoma.

Three different 5-fluorouracil (5-FU)-interferon-alpha-2b (IFN)-containing regimens were designed for treatment of patients with advanced colorectal cancer. 87 patients with a Karnofsky index > or = 70 were included in three sequential non-randomised phase II trials. Regimen A consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by weekly 1-h intravenous infusions until week 8. IFN (5 MU) was given subcutaneously on days 1, 3 and 5 followed by injections (9 MU) every second day until week 8. The cycle was then repeated. Regimen B consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by 5-min intravenous injections on days 12 and 19. IFN (3 MU) was given subcutaneously on days 1-5 followed by injections (5 MU) on days 11-13 and 18-20. The cycle was repeated every fourth week. Regimen C consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5. IFN (3 MU) was given subcutaneously on days 1-5. The cycle was repeated every third week. The objective response rates (complete response (CR) and partial response (PR)) after approximately 4 months of therapy or longer were as follows: regimen A (n = 27) 22% (2 CR, 4 PR), regimen B (n = 33) 42% (4 CR, 10 PR) and regimen C (n = 27) 22% (1 CR, 5 PR). The corresponding response figures for previously untreated patients were regimen A 50%, regimen B 64% and regimen C 38%. Response durations varied from a few weeks up to 142 + weeks. Toxicities were generally mild and reversible, and the treatments were convenient for the patients and cost effective since the 5-day infusions could be given by a portable pump without hospitalisation. Our results are in agreement with those of others showing that 5-FU/IFN combinations can be highly effective in advanced colorectal cancer, and that a number of factors such as doses, dose intensities, infusion rates and timing of the two drugs may be crucial for the anti-tumour activity of this drug combination.

Anticipatory immune changes in women treated with chemotherapy for ovarian cancer.

Immune parameters were assessed in 22 women before chemotherapy for ovarian cancer and compared with assessment made at home 2 days earlier. In the hospital, as compared to home measures, patients had a lower percentage of lymphocytes and monocytes and a higher percentage of granulocytes. Absolute numbers of lymphocytes were lower at the hospital as compared to at home. T-cell proliferative responses to concanavalin A were elevated for cells isolated from hospital blood samples as compared to home samples. The observed changes in immune parameters were not related to levels o r state anxiety at home or at the hospital. The results show anticipatory immune changes in a group of patients receiving chemotherapy that did not include cyclophosphamide.

Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients.

A stereotactic body frame with a fixation device has been developed for stereotactic radiation therapy of extracranial targets, a precision localization and positioning system in analogy with the stereotactic head frames used for intracranial targets. Results of the first 42 treated tumors in 31 patients are presented. Most of the patients had solitary tumors in liver, lung or retroperitoneal space. Clinical target volumes ranged from 2 to 622 cm3 (mean 78 cm3) and minimum doses to the planning target volumes (PTV) of 7.7-30 Gy/fraction (mean 14.2 Gy) were given on 1-4 occasions to a total minimum dose to the PTVs of 7.7-45 Gy (mean 30.2 Gy) to the periphery of the PTV and total mean doses to the PTVs of 8-66 Gy (mean 41 Gy). The central part of the tumor was usually given about 50% higher dose compared to that of the periphery of the PTV by a planned inhomogeneous dose distribution. Some of the patients received stereotactic radiation therapy concomitantly to more than one target, in others new metastases were also treated which appeared during the follow-up period. We observed a local rate of no progressive disease of 80% during a follow-up period of 1.5-38 months. Fifty percent of the tumors decreased in size or disappeared.

Does early administration of thyroxine reduce the development of Graves' ophthalmopathy after radioiodine treatment?

The roles of thyroid hormones and thyrotropin (TSH) in the development of Graves' ophthalmopathy are not clear. Some studies suggest a protective effect of thyroid hormones on experimental exophthalmos and an adverse effect of increased TSH levels. In September 1988 we introduced early thyroxine (T4) administration after 131I therapy for hyperthyroidism caused by Graves' disease. We carried out a retrospective study of records from all patients with this disease treated with 131I for 4 years. During the first 2 years 248 patients were treated (group A). They received T4 when the serum concentration of TSH and/or T4 indicated hypothyroidism. During the next 2 years 244 patients were treated (group B). They were all given 0.05 mg of T4 daily, starting 2 weeks after therapy, and 0.1 mg after a further 2 weeks. With a follow-up of 18 months, 45 patients (18%) in group A and 27 patients (11%) in group B developed or deteriorated in an already present ophthalmopathy (p = 0.03, relative risk = 1.64, 95% confidence interval = 1.05-2.55). Twenty-six patients in group A required specific therapy for the ophthalmopathy (e.g. antithyroid drugs, steroids, etc.) compared to 11 patients in group B (p = 0.02, relative risk = 2.33; 95% confidence interval = 1.18-4.60). Our results suggest that early administration of T4 after 131I therapy reduces the occurrence of Graves' ophthalmopathy.

Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects.

A method for stereotactic high-dose radiotherapy of malignancies in the abdomen has been developed. A stereotactic frame for the body has been developed and a method for fixation of the patient in the frame is described. The reproducibility in the stereotactic system of tumours in the liver and the lung was found to be within 5-8 mm for 90% of the patient set-ups. The diaphragmatic movements were reduced to 5-10 mm, by applying a pressure on the abdomen. An analytical method is used to calculate dose distributions for a continuum of beams in an isocentric treatment technique. The advantage of a heterogeneous target dose is demonstrated and proposed for the present application. A non-coplanar treatment technique, using eight individually shaped beams is proposed and has been used for patient treatments. The dose distribution for a patient with a metastasis in the liver is shown as well as dose volume histograms for the target and the liver.

Does informed adjuvant placebo chemotherapy for breast-cancer elicit immune changes.

To study psychological effects on the immune system, a saline infusion was administered to 24 fully informed patients who previously had received adjuvant chemotherapy for breast cancer. Blood samples were drawn before and after treatment, and compared to samples obtained at home two days earlier. Patients displayed a rise in natural killer-cell activity and a tendency to lowered percentage of suppressor/cytotoxic cells when assessed before treatment as compared to at home. Trait anxiety was associated with numbers of leukocytes. It is concluded that immune status partly reflects psychological factors.

Route of administration may determine the biological effects of RU 41,740 (Biostim). Trapping of 99mTc-labelled human albumin colloids in mice.

Experiments have been conducted in mice to examine whether treatment with the immunostimulating drug RU 41,740 (Biostim) may change the distribution of i.v. injected radiolabelled human albumin colloids. It was observed that a single i.p. injection of Biostim (1 ng-1000 micrograms) significantly enhanced trapping of the particles in spleen and lungs. The effect, which was dose-dependent, was most pronounced in the lungs where more than a 10-fold increase could take place. On the contrary, oral administration of Biostim caused a dose-dependent decrease of colloid trapping in the lungs. Further experiments showed that oral administration of Biostim resulted in the appearance of soluble factors in the blood which inhibited the phagocytic activity of lung macrophages, for example, sera from such mice inhibited lung colloid trapping when injected into new hosts. I.p. administration of Biostim, however, resulted in the appearance of factors in the blood which enhanced phagocytosis of lung macrophages. Our conclusion is that the biological activity of Biostim in vivo may be highly dependent on its route of administration.

Trait anxiety and anticipatory immune reactions in women receiving adjuvant chemotherapy for breast cancer.

We compared peripheral blood cell counts as well as mitogen activity and natural killer-cell activity in women undergoing adjuvant chemotherapy for breast cancer in the hospital prior to chemotherapy with assessment at home 2 days earlier. Patients compared to controls had an increased number of white blood cell counts in the hospital as compared to those at home, mediated by an increased total number of granulocytes. Among patients, those with high compared to low trait anxiety evidenced immune system changes. Total number of monocytes were reduced in patients with high compared to low trait anxiety and natural killer-cell activity tended to be compromised in the high anxiety group. Helper/inducer T-cells isolated from hospital blood samples were lower in patients with high as compared to low trait anxiety, while no difference was observed in samples taken at home. Conditioned nausea was associated with trait anxiety and patients with as compared to without conditioned nausea displayed immune changes similar to changes observed as a function of trait anxiety. State anxiety measured at the hospital did not relate to immune measures. The observed increase in granulocytes is consistent with an interpretation both in terms of conditioning and anticipatory stress. The anticipatory immunosuppression in patients with high compared to low trait anxiety is consistent with the hypothesis that chemotherapy patients may develop conditioned immunosuppression after repeated pairings of treatment-related stimuli with the unconditioned immunosuppressive effect of chemotherapy.

Blood lymphocyte subsets in operable breast-cancer - relation to extent of tumor disease and prognosis.

Previously we have reported that a high frequency of E-rosette forming cells (T-cells) in the blood of newly diagnosed breast cancer patients was associated with the development of distant metastases and a short survival. In the present investigation, comprising 204 untreated breast cancer patients, we showed that the proportion of the total T-cell population (CD2 and CD3 positive cells) and the proportion of helper/inducer T-cells (CD4 positive) was positively linked to spread of cancer cells to axillary nodes which in turn Was strongly correlated to prognosis. The latter subset also correlated significantly to time to development of distant metastases. Cox multivariate regression analysis showed that the frequency of these lymphocytes, independently of other variables, predicted prognosis. Our present as well as our previous results do not support the view that a high proportion of T-cells in the blood forecast a good prognosis.