Henrik Roed

Phase II study on stereotactic body radiotherapy of colorectal metastases

Surgical resection provides long term survival in approximately 30% of patients with colorectal carcinoma (CRC) liver metastases. However, only a limited number of patients with CRC-metastases are amendable for surgery. We have tested the effect of stereotactic body radiotherapy (SBRT) in the treatment of inoperable patients with CRC-metastases. Sixty-four patients with a total number of 141 CRC-metastases in the liver (n = 44), lung (n = 12), lymph nodes (n = 3), suprarenal gland (n = 1) or two organs (n = 4) were treated with SBRT with a central dose of 15 Gy×3 within 5–8 days. Median follow-up was 4.3 years. After 2 years, actuarial local control was 86% and 63% in tumor and patient based analysis, respectively. Nineteen percent were without local or distant progression after 2 years and overall survival was 67, 38, 22, 13, and 13% after 1, 2, 3, 4 and 5 years, respectively. One patient died due to hepatic failure, one patient was operated for a colonic perforation and two patients were conservatively treated for duodenal ulcerations. Beside these, only moderate toxicities such as nausea, diarrhoea and skin reactions were observed. SBRT in patients with inoperable CRC-metastases resulted in high probability of local control and promising survival rate. One toxic death and few severe reactions were observed. For the majority of patients, the treatment related toxicity was moderate.

Pulsed dose rate (PDR) brachytherapy of anal carcinoma

BACKGROUND AND PURPOSE With radiotherapy of anal carcinomas, sphincter preservation can be obtained at survival rates similar to those obtained with radical surgery. By combining external beam irradiation with interstitial irradiation, superiority over standard external irradiation has been obtained. With the introduction of pulsed dose rate equipment, where a single high activity source moves through catheters, a more individualized dose distribution and a further elimination of radiation exposure to the staff can be achieved. MATERIALS AND METHODS Between June 1993 and November 1994, 17 patients with anal carcinoma (T1:4, T2:4, T3:6, T4:3) have been treated at the Finsen Center. The treatment consisted of three-field external irradiation 46 Gy/23 fractions with five fractions a week to the anal canal and regional pelvic lymph nodes. Seven to 33 days after completion of external irradiation, the tumorspace was given 25.2 Gy PDR brachytherapy with 42 pulses of 0.6 Gy, one pulse every hour. RESULTS One isolated local recurrence has been noted 13 weeks after implantation. One additional local recurrence was seen in a patient with concomitant hepatic and inguinal recurrence. In three patients inguinal recurrence had occurred, two of these patients were irradiated without any further evidence of disease, and one patient with a primary advanced tumour, had local failure. So far necrosis has been observed in 13 patients within 1-49 weeks (median 16 weeks) after implantation. Eight of these patients required colostomy. No relation was observed between the number of implanted needles and the occurrence of necrosis. CONCLUSIONS The results indicate that the treatment is highly effective, but with substantial toxicity.

Influence of 2-(18F) fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography on recurrent ovarian cancer diagnosis and on selection of patients for secondary cytoreductive surgery.

The objective of this prospective study was to compare the sensitivities and the specificities of combined 2-(18F) fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (PET/CT), abdominal/transvaginal ultrasound (US), and CT for diagnosing recurrent ovarian cancer (OC) and to evaluate the influence of PET/CT on referral of patients with solitary recurrence to secondary cytoreductive surgery. From April 2005 to November 2007, 60 patients were consecutively included to PET/CT 68 times. The inclusion criteria were remission of 3 months or longer and recurrent OC suspected from physical examination, US, or increasing cancer antigen 125 (CA125) level (>50 U/mL or >15% above baseline level). Recurrent OC was diagnosed 58 times in 52 patients. The sensitivities of US, CT, and PET/CT for diagnosing recurrence were 66% (P = 0.003), 81% (P = 0.0001), and 97% (P < 0.0001), respectively. The specificity of US, CT, and PET/CT for diagnosing recurrence was 90%. Positron emission tomography/CT diagnosed recurrence in 19 (66%) of 29 patients without recurrence according to US and in 10 (50%) of 20 patients without recurrence after CT. Multiple recurrent tumors were found using PET/CT in 27 (69%) of 39 patients with solitary tumors on US and in 8 (42%) of 19 patients with solitary tumors on CT. We conclude that the diagnostic value of PET/CT for detecting recurrent OC was higher than those of US and CT and that PET/CT more accurately identified patients with solitary recurrence. However, prospective clinical trials are needed to specify the characteristics of patients most likely to undergo complete secondary surgery and to further clarify the role of PET/CT in selecting patients for secondary surgery.

Three-dimensional anal endosonography may improve staging of anal cancer compared with two-dimensional endosonography.

PURPOSEThree-dimensional (3-D) endosonography is a new method of staging anal carcinoma that has not yet been validated in comparison with two-dimensional (2-D) endosonography, the latter using only a single scan plane. The aim of this study was to investigate the differences between the two endosonographic techniques.METHODSThirty patients with an endosonographically detectable anal tumor were examined with a 10 MHz rotating endoprobe. Cross-sectional images of the anal sphincters were stored on a 3-D system during retraction of the endoprobe through the anal canal. Afterwards, any projection could be reconstructed. Cross-sectional images (2-D) were compared with reconstructed projections (3-D) according to five parameters concerning tumor spread and presence of regional lymph nodes. In this study, a scale of 0 to 5 points on critical issues was used; ideally, the results should be identical in 2-D and 3-D endosonography.RESULTSThe 3-D method detected a median of 5 diagnostic findings, compared with a median of 4 findings with the 2-D method (P = 0.001). In eight patients the lateral tumor margin was visualized only by 3-D endosonography. The median number of lymph nodes visualized in 3-D was 1 (range, 0-13), in 2-D the median number was 0 (range, 0-6), P = 0.002.CONCLUSIONSUse of 3-D endosonography in patients with anal carcinoma improves detection of perirectal lymph nodes and may improve that of tumor invasion, compared with 2-D endosonography. This may affect local tumor staging and thus planning of treatment. A study with histopathologic correlation is needed to verify this endosonographic study.

Inter-experiment variation and dependence on culture conditions in assaying the chemosensitivity of human small cell lung cancer cell lines☆

Sensitivity of five human small cell lung cancer cell lines to doxorubicin was assessed by a double layer agar technique using two different bottom-layers. Neither of the bottom-layers provided proportionality between numbers of cells plated and numbers of colonies, but they were correlated by a logarithmic function. Even after correction for lack of proportionality the two assay systems provided significantly different dose-response curves. The stability of the chemosensitivity was tested after 25-30 weeks continuous in vitro culture or prolonged storage in liquid nitrogen. One cell line underwent significant changes after continuous in vitro culture whereas the cell lines tested after prolonged storage in liquid nitrogen showed only minor changes. It is concluded that instead of considering the concentration necessary to achieve a certain degree of cell kill (e.g. ID50) in one experiment on one cell line, dose-response curves obtained on several cell lines in different assay systems should be used in the evaluation of new drugs.

The effect of the two epipodophyllotoxin derivatives etoposide (VP-16) and teniposide (VM-26) on cell lines established from patients with small cell carcinoma of the lung

SummaryTo determine whether there is any difference between the two epipodophyllotoxin derivatives etoposide and teniposide in their therapeutic effect in small cell carcinoma of the lung (SCCL), they were compared against five human SCCL cell lines in vitro. When the two were compared at equimolar concentrations teniposide was found to be 8–10 times more potent than etoposide, both with 1-h incubation and with continuous incubation in a clonogenic assay and in inducing cell cycle perturbations monitored by flow cytometry. Published pharmacokinetic data suggest that this potency difference is not accompanied by an equivalent increase in toxicity.The concentrations used for the 1-h incubation were about 100-fold the concentrations used in the experiments with continuous incubation to obtain the same degree of cell kill for both drugs. This suggests that they should be given according to a continuous rather than an intermittent schedule.

Pulsed dose rate (PDR) brachytherapy as salvage treatment of locally advanced or recurrent gynecologic cancer

PURPOSE Pulsed dose rate (PDR) brachytherapy is a new treatment option permitting dose distribution optimization in interstitial implants. It possesses the advantage of equipment simplification and radiation protection to the staff, compared to the manually afterloading technique. This study presents the first clinical results from The Finsen Center with PDR-brachytherapy in patients with locally advanced or recurrent gynecologic cancer. METHODS AND MATERIALS Between June 1993 and August 1996, 34 patients with gynecologic malignancies (22 pelvic recurrences, 12 primary locally advanced) have been treated with external irradiation, four-field box technique, to 46 Gy/23 fractions, 5 F/week and 192Ir-interstitial PDR-brachytherapy in pulses of 0.6 Gy, one pulse per hour to a total of 30 Gy. The Martinez Universal Perineal Interstitial Template applicator was used for all implantations. RESULTS The overall complete response rate was 74%. At median 14 months follow-up (range 3-40) 15 patients were alive with no evidence of disease. Seven of 14 patients with a second recurrence or progressive disease were still alive. The overall 1- and 2-year survival was 71% and 63%, respectively. There was no difference in survival probability when stratifying the patients by primary diagnosis (recurrent vs. primary advanced), relapse locations (central vs. central + pelvic wall mass) or treatment volume. Seventeen chronic grade III complications were observed in 10 patients. Large treatment volumes significantly correlated to severe gastrointestinal complications. Fifteen of 17 chronic grade III complications were observed in patients treated for recurrent disease. CONCLUSION PDR-brachytherapy in combination with external irradiation is an effective treatment option for patients with locally advanced or recurrent gynecologic cancer, although substantial toxicity is observed in patients with large treatment volumes and recurrent disease.

Complications following linear accelerator based stereotactic radiation for cerebral arteriovenous malformations.

PURPOSE Primarily, gamma knife centers are predominant in publishing results on arteriovenous malformations (AVM) treatments including reports on risk profile. However, many patients are treated using a linear accelerator-most of these at smaller centers. Because this setting is different from a large gamma knife center, the risk profile at Linac departments could be different from the reported experience. Prescribed radiation doses are dependent on AVM volume. This study details results from a medium sized Linac department center focusing on risk profiles. METHOD AND MATERIALS A database was searched for all patients with AVMs. We included 50 consecutive patients with a minimum of 24 months follow-up (24-51 months). RESULTS AVM occlusion was verified in 78% of patients (39/50). AVM occlusion without new deficits (excellent outcome) was obtained in 44%. Good or fair outcome (AVM occlusion with mild or moderate new deficits) was seen in 30%. Severe complications after AVM occlusion occurred in 4% with a median interval of 15 months after treatment (range, 1-26 months). CONCLUSIONS We applied an AVM grading score developed at the Mayo Clinic to predict probable outcome after radiosurgery in a large patient population treated with Gamma knife. A cutoff above and below a score of 1.5 could not discriminate between the likelihood of having an excellent outcome (approximately 45%). The chance of having an excellent or good outcome was slightly higher in patients with an AVM score below 1.5 (64% vs. 57%).

Local control and survival in patients with soft tissue sarcomas treated with limb sparing surgery in combination with interstitial brachytherapy and external radiation

PURPOSE The purpose of this study was to evaluate local control, survival and complication rate after treatment of soft tissue sarcoma (STS) with limb-sparing surgery combined with pulsed-dose rate (PDR) interstitial brachytherapy (BRT) and external beam radiotherapy (EBRT). PATIENTS AND METHODS A retrospective review of 39 adult patients (female/male=25/14, mean age 51(range 21-78) years) with STS who underwent primary limb-sparing surgery combined with PDR BRT (20Gy) and additional post-operative EBRT (50Gy) during the years 1995-2004. RESULTS Five patients developed local recurrence after a mean follow-up of 3.4 (1.5-5.9) years. The probability of local recurrence free 5 years survival was 83%. At the time of follow-up 10 patients had died (mean follow-up 2.3 (0.8-7.1) years) and 29 patients were still alive (mean follow-up 5.9 (2.1-11.2) years). The overall 5-year survival rate was 76%. Nineteen (49%) patients suffered from some degree of decreased force or function of the affected extremity, 16 (41%) suffered from oedema, 12 (31%) had persistent pain, 8 (21%) suffered from wound complications, and in 4 (10%) of these patients plastic surgery were required. CONCLUSION Limb sparing surgery, combined with PDR BRT and EBRT can result in good local control in patients with soft tissue sarcomas. BRT is an effective modality with good cosmetic results and acceptable toxicity.

In vitro circumvention of anthracycline-resistance in ehrlich ascites tumour by anthracycline analogues

In previously reported studies, acquired experimental resistance and cross resistance to anthracyclines are related to decreased drug accumulation and retention. The decreased accumulation seems to depend on a cellular mechanism for active drug efflux. N-Acetyl-daunorubicin (N-acetyl-DNR) has demonstrated the ability to increase drug accumulation and to overcome experimental resistance to daunorubicin (DNR) in resistant cells. In the present in vitro study 25 different anthracycline analogues were tested for their influence on [3H]DNR accumulation in resistant cells. At equimolar concentrations (5 microM) four of the analogues enhanced [3H]DNR accumulation more than 200%. Increasing the concentration of the analogues 3-20-fold, 12 of the compounds could enhance [3H]DNR accumulation above 200%. No specific structural changes separated those 12 compounds from the 13 analogues with no or minor effect. The lipid solubility of the 25 analogues was examined by measuring the partition coefficient in octanol/phosphate and pentanol/phosphate buffer (pH 7.45). A good correlation was demonstrated between increased lipid solubility of the analogues and their effect on [3H]DNR accumulation in resistant cells. Further studies demonstrated that N,N-dibenzyl-DNR was able to potentiate cytotoxicity of DNR in resistant cells. It is concluded that several anthracycline analogues are able to reverse resistance, but it is not possible from the chemical structure to predict which analogue results in enhanced [3H]DNR accumulation in resistant cells.