Karl-Mikael Kälkner

Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma

The 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 small fraction of patients the progression occurs slowly and in rare cases spontaneous regression are known to occur [1]. These have been reported in virtually all types of human cancer, although the greatest numbers of cases are reported in neuroblastoma, renal cell carcinoma, melanoma and lymphomas/leukemias. Spontaneous regression of cancer is an interesting phenomenon and elucidating the mechanisms by which it occurs offers the hope that more effective methods of treating and preventing cancer could be developed. In renal cell carcinomas spontaneous regression predominate in males by a ratio of 3:1. In over 90% of cases, pulmonary metastases are the site of regression. Regression of other sites such as skin, liver, intestine, bone and nodal areas have also been reported [2]. Most frequently spontaneous regression occurs after nephrectomy but the phenomenon has been reported in the absence of surgery or after vascular embolisation, radiofrequency ablation and radiotherapy [1]. Stereotactic radiotherapy (SRT) has been used in our center for almost 15 years for treating inoperable primary tumors of renal cell carcinoma and metastatic lesions in various malignant diseases [3 6]. In 28 renal cell carcinoma patients with treated and untreated metastatic lesions, we have four cases where non-irradiated metastases have regressed temporarily or seemingly permanently after treatment with SRT of either the primary tumor or other metastatic lesions. The frequency of such responses observed in our patient cohort is comparable to the response rates for conventional treatments like interferon and interleukin-2 and is strikingly high compared to the literature, where spontaneous regression of metastasis in renal cell cancer is reported to occur in 0.3 7% of cases [1]. The findings are in agreement with data indicating that local radiation treatment may induce systemic effects, a phenomenon referred to in the literature as the ‘‘abscopal effect’’ [7 12]. The phenomenon has been reported in various tumor forms but mainly as singular events [7,9,10,13,14]. The term ‘‘abscopal effect’’ caused by radiotherapy was first coined by R. H. Mole in 1953 (abscopal /distant target). This was originally defined as an action at a distance from the irradiated volume but within the same organism [15]. Recently the definition of the abscopal effect has been broadened to include other forms of local therapy that have systemic effects, i.e., a distant bystander effect [16,17]. The following cases illustrate both the possible induction of an anti-tumoral response against untreated metastases after SRTas well as the efficacy of this therapeutic option in slowly progressing renal

A prospective Phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma

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.

Zoledronic acid induces caspase-dependent apoptosis in renal cancer cell lines

Objective. To study and characterize the potential antitumoral effects of zoledronic acid (ZA) on renal cancer cell lines in vitro. Material and methods. Three different and well-characterized renal cancer cell lines were studied, namely ACHN, A-498 and CAKI-2. The cytotoxic potential of ZA was evaluated using a fluorometric microculture cytotoxic assay. The degree of M30 induction following ZA treatment was measured using an M30 enzyme-linked immunosorbent assay (ELISA), and the blockage of this effect was studied using a pan-caspase inhibitor. Immunofluorescence of the M30 neoepitope was performed to visualize the M30-inducing properties of ZA. Results. A significant reduction in viable cells was seen for all three cell lines following treatment with ZA, compared with untreated controls. This effect was most pronounced for the ACHN cells, as only 4% were viable following incubation with ZA for 72 h. A concomitant increase in the apoptosis significant caspase-dependent M30 antigen was demonstrated. This effect could be blocked by the pan-caspase inhibitor Z-VAD. Conclusions. ZA exerts cytotoxic effects on renal cancer cell lines in vitro. These include caspase-dependent induction of apoptosis, which can be quantified and visualized using M30 ELISA and immunofluorescence, respectively. The clinical relevance of this finding needs to be further investigated, but these results indicate that ZA may be a treatment alternative for selected patients with skeletal metastasized renal cell cancer, particularly for those with impaired performance status without other treatment options.

Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: Single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy

The aim of this study was to investigate the role of 70 Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48 months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA >0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p<0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8-10 in the prostatectomy specimens 17/40 (43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA >1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT) <10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3-4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in >50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.

Estramustine-Binding Protein (EMBP) in Renal Cell Carcinoma Immunohistochemistry, Immunoscintigraphy and in Vitro Estramustine Effects

The present report shows that the human renal cell carcinoma (RCC) cell lines, A498 and CAKI-2, express the estramustine-binding protein (EMBP). The RCC cell lines investigated were highly sensitive for estramustine, with cell arrest in atypical metaphase. In vitro experiments using a fluorimetric cytotoxicity assay (FMCA) showed a pronounced cytotoxic effect mediated by estramustine. Immunohistochemical analysis of tumour specimens from patients with RCC showed positive staining for EMBP in 12/16 cases. Immunoscintigraphy was performed in an experimental system in nude mice, heterotransplanted with the CAKI-2 cell line. A radiolabelled monoclonal anti-EMBP antibody was used. The results show a specific uptake of the antibody in the RCC tumour, expressed as a percentage of the injected dose per gram tissue, which ranged from 4.03 to 6.9. The results obtained form the basis for clinical studies on the feasibility of utilizing estramustine in the management of RCC. Immunoscintigraphy using the monoclonal anti-EMBP antibody is of potential use for in vivo characterization of the malignancy and in the selection patients suitable for treatment with estramustine.