We retrospectively reviewed the results of stereotactic body radiotherapy (SBRT) in 46 patients with a total of 136 metastases from primary sarcoma. The purpose of this study was to evaluate the overall response rate and side effects of SBRT in metastatic sarcoma. The patients were treated at Karolinska University Hospital between 1994 and 2005, using 3D conformal multifield technique and a stereotactic body-frame. Prescribed doses ranged from 4 to 20 Gy per fraction in 1-5 fractions, with total doses of 10-48 Gy. All 46 patients were diagnosed with a primary sarcoma. The treated metastases were localized mainly in the lungs. A total number of 136 metastases were treated (1-14 per patient). Overall response rate (local control = CR, PR and SD) for each tumour was 88 % (119/135). Median follow-up was 21.8 months (range 2.7-112.8 months). Thirteen patients (31 %) were long-term survivors (>36 months), and 5 patients are still alive after last follow-up. Two cases of serious non-lethal side effects were seen, one patient had a colon perforation and another patient had contracture of the hip region. SBRT is a safe, convenient and effective non-invasive treatment with high local control for patients with metastatic sarcoma.

Hypofractionated liver stereotactic radiotherapy has produced long-term survival, but the hepatobiliary system is radiosensitive and may be severely damaged by the treatment. We have evaluated long-term radiation effects on hepatobiliary functions in the first long-term survivors reported after radiotherapy to the hepatobiliary system for liver tumors. Eleven patients were followed for up to 13 years after treatment of tumors≤9 cm in size. Conventional blood chemistry, clearance of indocyanine green and segmental uptake and excretion of radiolabeled mebrofenin were assayed. Slightly abnormal routine blood chemistry was found during the first 2 years in some patients with pre-existing liver damage. Other parameters were seemingly unaffected, and liver segments which received differing mean doses did not differ measurably with regard to parenchymal or ductal function. Late liver functions were therefore not demonstrably affected by the radiotherapy in most patients even in the presence of mild cirrhosis, after previous exposure to liver toxic agents, or after resection. However, slight to moderate late dysfunction occurred in one patient after three courses of irradiation, and in a cirrhotic patient after two major liver resections following radiotherapy. Our previous doses for irradiation of liver tumors gave no measurable chronic side effects and may be increased in order to control tumors more effectively. In selected patients, irradiation is possible even in the presence of liver dysfunction, and previous irradiation or resection does not absolutely contraindicate salvage treatment by re-irradiation or resection.

A series of 203 consecutive patients with operable carcinoma of the breast was analysed with regard to correlations between a set of immunologic and clinical variables existing at the time of the diagnosis. No major correlations were revealed between immunologic variables on the one hand and clinical features or the course of the disease on the other. The well-known prognostic relevance of tumour size, involvement of the axilla and the histological grade of malignancy was evident.

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.

Nine patients with 11 primary or secondary liver non-neuroendocrine malignancies with mean and maximum diameters of 4.0 and 7.7 cm became long-term survivors after precision irradiation in a stereotactic body frame. Doses varied from 20 to 45 Gy split at 2-4 occasions a few days apart, with higher doses in the target centers. Occasional chemotherapy was stopped well before irradiation. No hospitalizations were needed because side effects, regional pain and nausea, were mild. All patients have now survived 5-14 years without recurrences. Two verified and one suspected secondary cancers occurred in organs close to the irradiated targets, and two of them could be resected for cure. Precision irradiation can thus cure selected liver malignancies. It is the first non-invasive method to achieve this, and the present patients are its first long-term survivors. A prolonged follow-up period is, however, necessary, because we have in other patients seen local tumor regrowth as late as four years after irradiation. The approach may cure some tumors, which are technically unsuited for other treatment modalities, and can be used for patients at high surgical risk. The success rate for local control seems good, but has to be defined by formal studies after optimization of radiation doses.

To the EditorThe treatment options in renal cancer are few and the response rates are low. It is also a cancer form that has a diverse biology-the vast majority of cases progress rapidly but in a s...

A retrospective study has indicated that stereotactic radiotherapy (SRT) has a value in treating both primary tumors and singular metastatic lesions that cause local symptoms. Here we present the results of a prospective study evaluating the safety and local efficacy of SRT in metastatic or inoperable primary renal cancer. Thirty patients with metastatic renal cell carcinoma (RCC) or inoperable primary RCC received high-dose fraction SRT. In total, 82 lesions were treated. Dose/fractionation schedules varied depending on target location and size. The most frequently used fractionations were 8 Gy×4, 10 Gy×4, 15 Gy×2 or 15 Gy×3 prescribed to the periphery of the PTV. Local control, defined as radiologically stable disease (SD) or partial/complete response (PR/CR) was obtained in 98% of treated lesions but 19% of lesions were in patients with a follow time of less than 6 months. CR was observed in 21% of the patients and 58% of the patients had a partial volume reduction or local stable disease after a median follow-up of 52 months (range 11–66) for patients alive and 18 months (range 4–57) for deceased patients. Local progression was seen in two lesions. Side effects were grade I–II in 90% of cases. The overall survival was 32 months. SRT for patients with primary and metastatic RCC resulted in high local control rate with generally low toxicity. The method can thus be considered a therapeutic option to surgery in patients with a limited number of metastases, as local treatment in RCC with an indolent presentation or as a method of reducing tumor burden prior to medical treatment.

PURPOSE:The level of thymidylate synthase (TS) in primary colorectal cancer (CRC) has been reported as a prognostic marker. The purpose of this study was to determine whether TS expression in lymph node metastases of Dukes' C CRC is a prognostic marker.PATIENTS AND METHODS:TS expression in the primary tumor and lymph node metastases from 348 patients with Dukes' C CRC was retrospectively assessed using immunohistochemistry and the monoclonal antibody TS 106. The patients had all been enrolled onto our previous study of 862 CRC patients who were included in Nordic trials that randomly assigned the patients to either surgery alone or surgery plus adjuvant chemotherapy.RESULTS:TS expression in lymph node metastases was a distinct prognostic marker in the entire study group for overall survival (OS; P = .02) and disease-free survival (DFS; P = .04). A low TS expression in the lymph node metastases correlated with a better clinical outcome. In the subgroup of patients treated with surgery alone, the expression of TS in lymph node metastases also had a prognostic value for OS (P = .04) and DFS (P = .03), but this was not the case for the other subgroup who received adjuvant fluorouracil-based chemotherapy (OS, P = .5; DFS, P = .2). The expression of TS in the primary tumor only had a significant prognostic value among patients who were treated with surgery alone (OS, P = .03; DFS, P = .03) and not among the entire patient population.CONCLUSION:These data show that TS expression in lymph node metastases is a prognostic marker for patients with Dukes' C CRC.

BACKGROUND AND PURPOSE:We investigated the results of using stereotactic radiotherapy (SRT) for 58 patients with renal cell carcinomas (RCC) who were evaluated restrospectively for response rates, local control rates and side effects. PATIENTS AND METHODS:From October 1997 to January 2003, 50 patients suffering from metastatic RCC and eight patients with inoperable primary RCC received high-dose fraction SRT while placed in a stereotactic body-frame. The most common dose/fractionation schedules used were 8 Gyx4, 10 Gyx4 and 15 Gyx3 during approximately 1 week. RESULTS:SRT-treated tumor lesions regressed totally in 30% of the patients at 3-36 months, whereas 60% of the patients had a partial volume reduction or no change after a median follow-up of 37 months (SD 17.4) for censored and 13 months (SD 12.9) for uncensored patients. Side effects were generally mild. Of 162 treated tumors, only three recurred, yielding a local control rate of 90-98%, considering the 8% non-evaluable sites as defined here. For patients with one to three metastases, the time to new spread was 9 months. CONCLUSIONS:Our use of SRT for patients with primary and metastatic RCC yielded a high local control rate with low toxicity. Patients with one to three metastases, local recurrences after nephrectomy or inoperable primary tumors benefited the most, i.e. had fewer distant recurrences (13/23) and longer survival times compared to patients with >3 metastases (24/27 recurrences).

The possible relation between the site of primary intracranial tumors and mitogenic responses of blood lymphocytes was analyzed in 115 patients who had not undergone surgery or received any radiation or chemotherapy. Some of the patients had however received corticosteroid treatment. PHA responses were impaired in nonsteroid treated patients with tumors affecting the left cerebral hemisphere. They were normal in patients with tumors affecting the right cerebral hemisphere or central structures of the brain or tumors growing in the posterior fossa of the skull. Lymphocyte responses to PPD were normal in patients with hemispheric or posterior fossa tumors. However, the PPD response was sharply reduced in patients with central tumors. The results could not be explained by different histological tumor types or anticonvulsant medication in the various patient groups. In addition, the capacity of sera to promote mitogen stimulation of lymphocytes did not differ significantly between the patient groups. It is speculated that intracranial tumors may interfere with the function of certain centers in the brain which are involved in the regulation of lymphocyte responses.

BACKGROUND/AIMS:Most resected liver metastases from colorectal cancer recur. A minority of liver recurrences have been re-resected, but most re-resections fail and they decrease the postoperative performance status for a longer time than the initial resections, so that less demanding potentially curative treatments need evaluation.METHODOLOGY:Four out of 5 liver-only recurrences after 18 consecutive liver resections were limited and suitable for radiosurgery. The patients were fixed in a frame and stereotactic irradiation with 20 Gy twice or 15 Gy three times was delivered to the tumors.RESULTS:Limited side effects were seen, without medical need for hospital admission. Thirteen--101 months later, all treated tumors were locally controlled with complete radiologic remission of two of them. Only one patient recurred in the liver, with bilobar lesions preceded by extrahepatic spread. Neither recurrence would have been prevented by a rehepatectomy instead of irradiation. One patient died later tumor-free from stroke, two died from generalized tumors, and one remains in remission 101 months after radiosurgery.CONCLUSIONS:Radiosurgery of liver tumors merits further study, and may offer a less demanding alternative to resection for selected liver tumors with the prospect of long-term survival.

BACKGROUND:Levels of the enzyme thymidylate synthase (TS) are of prognostic significance in colorectal cancer. It may be argued that the levels of TS merely reflect the proliferative activity and could be replaced by markers of proliferation.MATERIALS AND METHODS:We used immunohistochemical approaches to examine the expression of TS, Cyclin A and Ki-67 in morphologically well-defined tumor areas in consecutive slices of rectal cancer, using the antibodies TS 106, NCL-Cyclin A and Mib-1.RESULTS:There was a linear relationship between Cyclin A- and Ki-67-positive cells (p < 0.0001). There did not seem to be any significant relationship between TS-expression and the frequency of Cyclin A-positive cells (p = 0.1) but a significant correlation was observed between TS-expression and the frequency of Ki-67-positive cells (p = 0.02).CONCLUSION:TS, immunohistochemically-detected in rectal cancer cells, is not associated with an accurate assessment of the proliferative stage. The prognostic value of TS determination can only partly be explained by the proliferative activity.

PURPOSE:We studied the prognostic value of thymidylate synthase (TS) expression in primary colorectal cancer (CRC) and the role of TS expression as a predictor of chemotherapeutic benefit in patients treated with adjuvant chemotherapy.PATIENTS AND METHODS:TS expression was immunohistochemically assessed on tumor sections from 862 patients with CRC Dukes' stages B and C enrolled onto randomized trials evaluating fluorouracil (5-FU)-based adjuvant chemotherapy.RESULTS:TS expression was an independent prognostic factor for disease-free (P =.05) and overall survival (P =.05). In the subgroup treated with surgery alone, TS was an independent prognostic factor for disease-free (P <.001) and overall survival (P =.001), whereas this was not the case in the subgroup of adjuvantly treated patients. Patients whose tumors expressed high TS levels had a tendency to improved outcome after adjuvant therapy (not significant). The group whose tumors expressed the highest TS grade, grade 3 (34% of the patients), had a significantly longer disease-free survival if they were treated with adjuvant therapy compared with surgery alone (multivariate analyses, P =.02), whereas patients whose tumors expressed low TS levels (28% of the patients) had an impaired outcome after adjuvant therapy (multivariate analyses: disease-free survival, P =.01; overall survival, P =.01).CONCLUSION:TS expression predicts for survival independent of Dukes' stage in patients with CRC treated with surgery alone. The study indicates that patients with high TS levels may benefit from adjuvant 5-FU-based chemotherapy. However, patients with low TS levels seem to have a worse outcome when treated with adjuvant chemotherapy.

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.

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.

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.

A method for extracranial stereotactic radiosurgery (ESRS) is described. For this treatment method a stereotactic body frame was developed and is described here. The ESRS method uses a hypofractionation schedule with 2–3 fractions with 10–20 Gy/fraction to the periphery of the target volume, at the 65% isodose. The heterogeneous target dose is used as a means to increase the probability of killing the hypoxic tumor cells. It is argued from in vitro cell survival data that the dose increase used will give a reasonable probability to eradicate at least moderate concentrations of hypoxic cells. A high reproducibility of the target position with the ESRS method is based on the definition of the patient reference system to the stereotactic system and not to the bony anatomical reference points as used in conventional radiotherapy. Important to the ESRS method is that the target position is verified by computed tomography (CT) examinations. The positional accuracy of the target in the stereotactic system is 3.1 mm (mean deviation) in the transversal plane and 5.5 mm (mean deviation) in the longitudinal direction. The setup accuracy, i.e., the correct alignment of the stereotactic system to the isocenter of the treatment unit, is within 1 mm. Other aspects of the ESRS method that are discussed are the treatment technique including collimation methods and dose distributions used, as well as target margins. ESRS has been in clinical use for several years at Radiumhemmet, Karolinska Hospital.

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 of4S 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.