Comparison of dose-volume histograms and dose-wall histograms of the rectum of patients treated with intracavitary brachytherapy.

The correlation between dose values from dose-volume histograms (DVHs) and dose values from dose-wall histograms (DWHs) of the rectum tissue of patient with uterine cervix cancer was determined. The minimum dose in 2 cm3 in the high-dose region of the DVH is a good estimate of the dose in the rectum wall.

Photodynamic therapy with meta-tetrahydroxyphenylchlorin for basal cell carcinoma: a phase I/II study.

BACKGROUND: Photodynamic therapy (PDT) is a convenient and effective method of treating small superficial tumours. New second-generation photosensitizers offer some advantages over first-generation sensitizers such as haematoporphyrin derivatives. OBJECTIVES: To define the optimal treatment parameters (drug dose, light dose and time interval) using meta-tetrahydroxyphenylchlorin (mTHPC) as a photosensitizer in patients with multiple basal cell carcinomas (BCCs). METHODS: Light of 652 nm (100 mW cm(-2)) was used for illuminating different tumours (n = 187) with light doses of 5--15 J cm(-2). Following an intravenous injection of 0.1 mg kg(-1) mTHPC each patient (n = 5) was illuminated on 4 consecutive days. Each day at least three BCCs per patient were treated with PDT. RESULTS: Response evaluation at 6, 12 and 18 months showed maximum responses for illumination with 10 or 15 J cm(-2) on days 1 or 2 after injection (86% complete responses). Normal tissue reactions (oedema and erythema) around the treatment site were more severe on day 1 than after longer intervals. CONCLUSIONS: mTHPC is a very effective photosensitizer; short illumination times can result in long-term cures with good cosmetic healing and with skin phototoxicity of short duration.

A method to improve the dose distribution of interstitial breast implants using geometrically optimized stepping source techniques and dose normalization.

BACKGROUND AND PURPOSE: The standard linear source breast implant of our institution was compared with alternative linear source implant geometries and a stepping source implant, to evaluate the possibility of minimizing the treated volume. Normalization to a higher isodose than the conventional 85% of the mean central dose (MCD) was investigated for the stepping source implant to reduce the thickness of the treated volume and to increase dose uniformity. The purpose of this study was to develop an implant geometry yielding a high conformity and a more uniform dose distribution over the target volume. MATERIALS AND METHODS: The dose distributions of four implant geometries were compared for a planning target volume (PTV) of 48 cm(3). Implants #1 (standard) and #2 had linear sources arranged in a triangular pattern of equal lengths and lengths adapted to the shape of the PTV. Implants #3 and #4 were squared pattern arranged implants with linear sources and a stepping source with geometric optimized dwell times. The active lengths were adapted to the shape of the PTV. Using implant #4 for PTVs of different volumes, the reference dose (RD) was normalized to 85 and 91% of the MCD. RESULTS: Comparing implants #2, #3, and #4 with #1, the treated volume (V(100)) encompassed by the reference isodose was reduced by 22, 35, and 37%, respectively. The volumes receiving a dose of at least 125% (V(125)) of the reference dose was reduced by 16, 30, and 30%, respectively. The conformation number increased being 0.30, 0.39, 0.47, and 0.48 for implants #1, #2, #3, and #4, respectively. The average reduction of V(125) when the dose was normalized to 91% compared with 85% of the MCD was 18%. CONCLUSIONS: A conformal treatment to a PTV could be best achieved with a geometrically optimized stepping source plan with needles arranged in a squared pattern. Reduction of high dose volumes within the implant was obtained by normalizing the RD to 91% instead of 85% of the MCD.

An improved technique for breast cancer irradiation including the locoregional lymph nodes.

PURPOSE: To find an irradiation technique for locoregional irradiation of breast cancer patients which, compared with a standard technique, improves the dose distribution to the internal mammary-medial supraclavicular (IM-MS) lymph nodes. The improved technique is intended to minimize the lung dose and reduce the dose to the heart. METHODS AND MATERIALS: The standard technique consists of an anterior mixed electron/photon IM-MS field. In the improved technique, an oblique electron and an oblique asymmetric photon field are combined to irradiate the IM lymph nodes. To irradiate the MS lymph nodes, a combination of an anterior electron and an anterior asymmetric photon field is used. For both the standard and the improved technique, tangential photon fields are used to irradiate the breast. Three-dimensional (3D) treatment planning was performed for 8 patients with various breast sizes for these two techniques. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) were compared for both techniques. The field dimensions and energy of the standard technique were determined at simulation, whereas for the improved technique the fields were designed by CT-based treatment planning. RESULTS: The dose in the breast planning target volume was essentially the same for both techniques. For the improved technique, combined with 3D localization information, an improvement in the IM-MS planning target coverage is seen. The volume within the 95% isodose surface was on average 25% (range, 0-64%) and 74% (range, 43-90%) for the standard and improved technique, respectively. The heart generally receives less dose with the improved technique. However, sometimes a small but acceptable increase in lung dose is found. CONCLUSION: The improved technique, combined with localization information of the IM-MS lymph nodes, greatly improves the dose distribution in the planning target volume for a large group of patients without significantly increasing the dose to organs at risk.

Inter-observer variation in delineation of bladder and rectum contours for brachytherapy of cervical cancer.

BACKGROUND AND PURPOSE: In 3D treatment planning of low dose rate brachytherapy of cervical carcinoma the dose in bladder and rectum can be estimated from dose-volume histograms (DVHs). In this study, the influence of inter-observer variation in delineation of bladder and rectum on DVHs and dose at specific bladder and rectum points was investigated. MATERIALS AND METHODS: Three observers delineated bladder and rectum on axial CT images of ten patients. The highest minimum dose in bladder and rectum was determined for, respectively, 2 cm(3) (D(2)) and 5 cm(3) (D(5)), as well as the dose at specific points placed on the bladder and rectum wall. RESULTS: The inter-observer variation in D(2) was 10% (1 average relative SD) in bladder and 11% (1 SD) in rectum. In D(5) the variation was 8% (1 SD) in bladder and 11% in rectum. The variation in the bladder point was 13% (1 SD) and in the rectum point 11% (1 SD). Differences in delineation among the observers were caused by unclear organ boundaries on the CT images. CONCLUSIONS: Taking the inter-observer variation caused by delineation differences into account, dose in bladder and rectum can be determined within an accuracy of about 10% (1 SD).

Biodistribution and bioactivity of tetra-pegylated meta-tetra(hydroxyphenyl)chlorin compared to native meta-tetra(hydroxyphenyl)chlorin in a rat liver tumor model.

It has been proposed that the construction of a photosensitizer-polymer conjugate would lead to an increased selective retention of the drug in tumor tissue resulting in an enhancement of selective tumor destruction by light in photodynamic therapy. In this study the kinetics of a tetra-pegylated derivative of meta-tetra(hydroxyphenyl)chlorin (mTHPC-PEG) were compared with those of native meta-tetra(hydroxyphenyl)chlorin (mTHPC) in a rat liver tumor model. In addition, the time course of bioactivity of both drugs was studied in normal liver tissue. Pegylation of mTHPC resulted in a two-fold increase in the plasma half-life time, a five-fold decrease in liver uptake and an increase in the tumor selectivity at early time intervals after drug administration. However, although mTHPC concentrations in liver decrease rapidly with time, mTHPC-PEG liver concentrations increased as a function of time. This led to a loss of tumor selectivity at all but the earliest time points, whereas with mTHPC tumor selectivity increased with time. For both drugs the time course of bioactivity in the liver parallels drug concentration levels with extensive necrosis after irradiation of mTHPC-PEG-sensitized liver tissue up to drug-light intervals of 120 h. It is concluded that on balance mTHPC-PEG does not appear to show any benefits over native mTHPC for the treatment of liver tumors, as normal liver tissue accumulates the compound. However, pegylation is a potentially promising strategy with an increase in tumor selectivity and reduced liver uptake if accumulation in the liver can be prevented.

Effective treatment of liver metastases with photodynamic therapy, using the second-generation photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC), in a rat model.

The only curative treatment for patients with liver metastases to date is surgery, but few patients are suitable candidates for hepatic resection. The majority of patients will have to rely on other treatment modalities for palliation. Photodynamic therapy (PDT) could be a selective, minimally invasive treatment for patients with liver metastases. We studied PDT in an implanted colon carcinoma in the liver of Wag/Rij rats, using the photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC). mTHPC tissue kinetics were studied using ex vivo extractions and in vivo fluorescence measurements. Both methods showed that mTHPC kinetics were different for liver and tumour tissue. After initial high levels at 4 h after administration (0.1 and 0.3 mg kg(-1)) mTHPC in liver tissue decreased rapidly in time. In tumour tissue no decrease in photosensitizer levels occurred, with mTHPC remaining high up to 48 h after administration. Both concentration data and fluorescence data showed an increase in tumour to liver ratios of up to 6.3 and 5.0 respectively. Illumination with 652 nm (15 J) resulted in extensive damage to tumour tissue, with necrosis of up to 13 mm in diameter. Damage to normal liver tissue was mild and transient as serum aspartate aminotransferase and alanine aminotransferase levels normalized within a week after PDT treatment. Long-term effects of mTHPC-PDT were studied on day 28 after treatment. Regardless of drug dose and drug-light interval, PDT with mTHPC resulted in complete tumour remission in 27 out of 31 treated animals (87%), with only four animals in which tumour regrowth was observed. Non-responding tumours proved to be significantly larger (P < 0.001) in size before PDT treatment. This study demonstrates that mTHPC is retained in an intrahepatic tumour and that mTHPC-PDT is capable of inducing complete tumour remission of liver tumours.

5-Aminolevulinic acid induced endogenous porphyrin fluorescence in 9L and C6 brain tumours and in the normal rat brain.

A new approach in photodynamic therapy is the use of endogenous porphyrins for sensitisation of tumours to light. The induction of endogenous porphyrins after intravenous injection of 5-aminolevulinic acid (ALA, 200 mg kg-1) was studied in 23 rats, bearing intracranial 9L or C6 tumours. After 0, 2, 4, 6, 8, and 22 hours the rats were sacrificed and the fluorescence distribution of endogenous porphyrins was studied in brain tissue sections with a standard fluorescence microscope and a confocal laser scanning microscope. The role of blood-brain barrier disruption on porphyrin production was studied in 2 rats with a cryo-lesion of the cortex. Additionally, 9L and C6 tumour cell cultures were incubated with ALA for 8 hours in vitro. Fluorescence was measured with a fluorescence spectrophotometer in cell cultures and in the brain sections. Porphyrins were detected in vitro in the tumour cells from 2 hours onwards and ex vivo in the tumour sections mainly from 2 to 8 hours, by 22 hours porphyrin fluorescence had almost disappeared. The contralateral brain showed low fluorescence levels between 2 and 6 hours after ALA administration. At the site of the cryo-lesions low fluorescence was measured 6 hours after ALA administration. The 9L tumours fluoresced homogeneously, with a sharp demarcation towards normal brain tissue. Fluorescence in the C6 tumours was patchy, with a poorly fluorescing edge. In both tumour models fluorescence was also detected in brain surrounding the tumour and sometimes in contralateral white matter and ventricle ependyma and pia mater. The slight increase of porphyrin fluorescence in the normal brain of tumour bearing rats, compared to the absence of this in rats without a tumour, was attributed to transport by bulk flow of porphyrins made in the tumours, and possibly also of circulating porphyrins or ALA leaking from the tumour vessels.

Evaluation of spectral correction techniques for fluorescence measurements on pigmented lesions in vivo.

Recently, the use of optical spectroscopy for non-invasive diagnosis of malignant melanoma has been suggested. The reliability of such optical measurements can be seriously compromised by spatial variations in the optical properties of the tissue that are not related to malignancy. In the present paper we report a novel approach to fluorescence spectroscopy which allows for elimination of spatial variations in the optical properties of the tissue investigated. To test this concept we performed fluorescence and color measurements on moles and unpigmented control skin in human volunteers before and after topical application of delta-aminolevulinic acid (ALA). Two types of fluorescence data analysis were investigated; a single ratio technique based on the ratio of the red to the yellow fluorescence (660-750 nm to 550-600 nm) at 405 nm excitation and a double-ratio technique, the red-to-yellow ratio at 405 nm excitation divided by the red-to-yellow ratio at 435 nm excitation. The two excitation wavelengths were selected to be located close to the maximum and at some distance from the Soret excitation band of the porphyrins. The single ratio showed a significant correlation between fluorescence and color. The double ratio was independent of the color of the lesion. These findings indicate that the double-ratio technique is suitable for in-vivo detection of local differences in concentration of fluorescent tumor-localizing drugs in pigmented lesions. This enables in-vivo studies of the pharmacokinetics of tumor-localizing agents in pigmented lesions and may significantly contribute to the development of a non-invasive diagnostic tool for malignant melanoma.