Mathias K. Fehr

Morbidity of Sentinel Lymph Node Biopsy (SLN) Alone Versus SLN and Completion Axillary Lymph Node Dissection After Breast Cancer Surgery A Prospective Swiss Multicenter Study on 659 Patients

Objective:To assess the morbidity after sentinel lymph node (SLN) biopsy compared with SLN and completion level I and II axillary lymph node dissection (ALND) in a prospective multicenter study. Summary Background Data:ALND after breast cancer surgery is associated with considerable morbidity. We hypothesized: 1) that the morbidity in patients undergoing SLN biopsy only is significantly lower compared with those after SLN and completion ALND level I and II; and 2) that SLN biopsy can be performed with similar intermediate term morbidity in academic and nonacademic centers. Methods:Patients with early stage breast cancer (pT1 and pT2 ≤ 3 cm, cN0) were included between January 2000 and December 2003 in this prospective Swiss multicenter study. All patients underwent SLN biopsy. In all patients with SLN macrometastases and most patients with SLN micrometastases (43 of 68) or isolated tumor cells (11 of 19), a completion ALND was performed. Postoperative morbidity was assessed based on a standardized protocol. Results:SLN biopsy alone was performed in 449 patients, whereas 210 patients underwent SLN and completion ALND. The median follow-ups were 31.0 and 29.5 months for the SLN and SLN and completion ALND groups, respectively. Intermediate-term follow-up information was available from 635 of 659 patients (96.4%) of enrolled patients. The following results were found in the SLN versus SLN and completion ALND group: presence of lymphedema (3.5% vs. 19.1%, P < 0.0001), impaired shoulder range of motion (3.5% vs. 11.3%, P < 0.0001), shoulder/arm pain (8.1% vs. 21.1%, P < 0.0001), and numbness (10.9% vs. 37.7%, P < 0.0001). No significant differences regarding postoperative morbidity after SLN biopsy were noticed between academic and nonacademic hospitals (P = 0.921). Conclusions:The morbidity after SLN biopsy alone is not negligible but significantly lower compared with level I and II ALND. SLN biopsy can be performed with similar short- and intermediate-term morbidity in academic and nonacademic centers.

[18F]-fluorodeoxyglucose positron emission tomography in patients with suspected recurrence of breast cancer

AimTo evaluate the role of [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients presenting with a suspicion of breast cancer relapse after primary treatment.Materials and methodsSixty consecutive female patients with clinical (n=35) or radiological (n=25) suspicion of breast cancer recurrence were evaluated by FDG-PET. Positive PET findings were further evaluated by histological examination or clinical and radiological follow-up. In 25 patients, the serum tumor marker (CA 15-3) status was compared to the PET results.ResultsDisease relapse was proven in 40 patients. Additionally, in three patients a second cancer was diagnosed with (n=1), and without (n=2) concomitant disease relapse. PET missed local recurrence in three patients, and was false positive in another four. In patient-based analysis, the overall sensitivity, specificity, and accuracy were 89%, 84%, and 87%, and 100%, 97%, and 98% for locoregional recurrence and distant metastases, respectively. FDG-PET was more sensitive than the serum tumor marker CA 15-3 in detecting relapsed breast cancer.ConclusionFDG-PET is a valuable tool in the follow-up of patients with breast cancer.

Selective photosensitizer distribution in vulvar condyloma acuminatum after topical application of 5-aminolevulinic acid

OBJECTIVE Our purpose was to determine the feasibility of selective photosensitization of vulvar condylomas by use of tropical application of 5-aminolevulinic acid. STUDY DESIGN In vivo fluorescence was assessed and biopsy specimens of condylomas were taken for fluorescence microscopy in 24 patients at different times after application of 2.5% 5-aminolevulinic acid ointment or 20% 5-aminolevulinic acid cream. RESULTS Both in vivo fluorescence imaging and fluorescence microscopy showed selective fluorescence of condylomas of the labia minora and vestibule only within short time intervals, because fluorescence of poorly keratinized normal epithelium was induced by both 5-aminolevulinic acid formulations. In non-hair-bearing skin, lesional fluorescence remained highly selective. Fluorescence microscopy showed that 90 minutes after drug application peak selectivity in epithelial lesional fluorescence was significantly higher with 2.5% 5-aminolevulinic acid ointment (4.5 +/- 0.9) than it was with 20% cream (2.1 +/- 0.2). CONCLUSION Selective fluorescence of vulvar condyloma acuminatum can be induced by nonselective topical 5-aminolevulinic acid application. Studies evaluating selective photodynamic destruction of condylomas are justified.

Photodynamic therapy of locoregional breast cancer recurrences using a chlorin‐type photosensitizer

Chest wall recurrences are a frequent problem in patients treated by mastectomy for breast cancer. Surgery and ionizing radiation are established treatment modalities in these cases. Photodynamic therapy (PDT) provides an alternative treatment modality using a photosensitizer and laser light to induce selective tumor necrosis. PDT was performed as compassionate use in 7 patients aged 57.6 years (±12.6 SD). A total of 89 metastatic skin nodes were treated in 11 PDT sessions. As photosensitizer meta‐tetra(hydroxyphenyl)chlorin (m‐THPC) was applied intravenously. Patients (n = 3) photosensitized with a drug dose of 0.10 mg/kg bodyweight were irradiated 48 hr after drug application at a lightdose of 5 J/cm2. Patients (n = 4) were illuminated by an optical dose of 10 J/cm2 96 hr after photosensitization with 0.15 mg/kg. Laser light at a wavelength of 652 nm was generated by a diode laser and applied by a front lens light diffuser using a fluence rate of 20–25 mW/cm2. PDT using m‐THPC resulted in complete response in all patients. Response to treatment did not differ when using the 2 different drugdose protocols. Healing time depended mainly on the size of the illumination field but not on the lightdose. Pain score usually raised 1 day after PDT and lasted at higher levels for about 10 days. Healing time usually ranged between 8–10 weeks. Photodynamic technique offers a minimal‐invasive, outpatient treatment modality for recurrent breast cancer on the chest wall with few side effects, high patients satisfaction and with possible repetitive application.

Axillary staging using positron emission tomography in breast cancer patients qualifying for sentinel lymph node biopsy.

Abstract:  Axillary lymph node dissection (ALND) is the standard of care for nodal staging of patients with invasive breast cancer. Due to significant somatic and psychological side effects, replacement of ALND with less invasive techniques is desirable. The goal of this study was to evaluate the clinical usefulness of axillary lymph node (ALN) staging by means of positron emission tomography (PET) with 18F‐fluorodeoxyglucose (FDG) in breast cancer patients qualifying for sentinel lymph node biopsy (SLNB). FDG‐PET was performed within 1 week before surgery in 24 clinically node‐negative breast cancer patients with tumors smaller than 3 cm. Sentinel lymph nodes (SLNs) were identified by preoperative lymphoscintigraphy following peritumoral technetium 99m‐labeled colloid albumin injection, and by intraoperative gamma detector and blue dye localization. Following SLNB, a standard ALND was performed. Serial sectioning and immunohistochemistry of the SLN as well as standard histologic examination of the non‐SLN was performed. FDG‐PET detected all primary breast cancers. Staging of ALNs by PET was accurate in 15 of 24 patients (62.5%), whereas PET staging was false negative in 8 of 10 node‐positive patients and false‐positive in 1 patient. The sensitivity, specificity, positive predictive value, and negative predictive value of FDG‐PET for nodal status was 20%, 93%, 67%, and 62%, respectively. The mean diameter of false‐negative ALN metastases was 7.5 mm (range 1–15 mm). Lymph node staging using FDG‐PET is not accurate enough in clinically node‐negative patients with breast cancer qualifying for SLNB and should not be used for this purpose. 

A mathematical model for light dosimetry in photodynamic destruction of human endometrium

We are involved in the development of photodynamic therapy (PDT) as a minimally invasive method for treating dysfunctional uterine bleeding, one of the primary clinical indications for hysterectomy. In this paper, we analyse light propagation through the uterus in order to specify the requirements for a light delivery system capable of effectively performing endometrial PDT. Our approach involves developing an analytical model based on diffusion theory to predict optical fluence rate distributions when cylindrical and spherical optical applicators are placed in the uterine cavity. We apply the results of our model calculations to estimate the thermal effects of optical irradiation and the effective photodynamic optical dose. Theoretical fluence rate calculations are compared to fluence rate measurements made in fresh, surgically removed human uteri. Our results show that a trifurcated cylindrical optical applicator inserted into the human uterus can provide a light dose that is sufficient to cause photodynamic destruction of the entire endometrium. When the optical power per unit length of each cylindrical applicator is 100 mW cm-1 (at 630 nm), a fluence rate of 40 mW cm-2 is delivered to the boundary layer between the endometrium and the myometrium (a depth of about 4-6 mm). The optical fluence delivered to the boundary layer after 20 min of exposure is 50 J cm-2, a level that is generally accepted to cause tissue damage throughout the endometrium in most patients.

Minimally-invasive debulking of ovarian cancer in the rat pelvis by means of photodynamic therapy using the pegylated photosensitizer PEG-m-THPC

Interstitial photodynamic therapy (PDT) using the pegylated photosensitizer PEG-m-THPC was evaluated as a minimally-invasive procedure to selectively debulk unrespectable pelvic ovarian cancer (NuTu-19) in immunocompetent rats. To assess tumour selectivity, PEG-m-THPC at dosages of 0.3, 3.0 and 30 mg kg–1 body weight was administered intravenously to 30 rats 4 weeks following tumour induction. Eight days later laser light at 652 nm and optical doses ranging from 100 to 900 J cm–1 diffuser-length was delivered by an interstitial cylindrical diffusing fibre inserted blindly into the pelvis. Three days following light application, the volume of necrosis was measured and the damage to pelvic organs was assessed histologically on cross sections. For analysis of survival, 20 tumour-bearing rats received PDT using drug doses of 3 or 9 mg kg–1 body weight and an optical dose of 900 J cm–1 diffuser-length, whereas ten untreated tumour-bearing rats served as controls. The histological assessment of PDT induced necrosis showed a non-linear dose–response for both the photosensitizer dose and the optical dose. The lowest drug dose activated with the highest optical dose did not induce more necrosis than seen in tumour-bearing control animals. The same optical dose induced necrosis of 17 mm in diameter using 30 mg kg–1 and 11 mm using 3 mg kg–1 photosensitizer. The optical threshold for induction of significant necrosis was between 100 and 300 J cm–1 diffuser-length for 30 mg kg–1 and between 300 and 500 J cm–1 for 3 mg kg–1 PEG-m-THPC. Significant damage to normal pelvic organs was only seen if 30 mg kg–1 photosensitizer was activated with optical doses of 700 J cm–1 or more. In the survival study, all treated animals survived PDT for at least 2 weeks and the intestinal and urinary tract remained functional. No clinical signs of blood vessel or nerve injury were observed. Mean overall survival of untreated tumour-bearing rats was 25.0 ± 4.5 days compared to 38.4 ± 3.8 days and 40.0 ± 3.6 days for rats treated with 3 mg kg–1 or 9 mg kg–1 PEG-m-THPC mediated PDT respectively (P < 0.05). We conclude that PEG-m-THPC mediated PDT has a favourable therapeutic window and that this minimally-invasive procedure can reduce pelvic cancer bulks effectively and selectively.

IGFBP2 and IGFBP3 protein expressions in human breast cancer : association with hormonal factors and obesity

Purpose: The insulin-like growth factor (IGF) signaling system is involved in breast cancer initiation and progression. The prognostic relevance of tumor expression patterns of IGFI-related proteins remains poorly understood. This study associates the expression of selected IGF proteins with breast tumor and patient characteristics. Experimental Design: IGFI, IGFI receptor, IGF-binding protein (IGFBP)2, and IGFBP3 expression was measured in 855 primary breast carcinomas by immunohistochemistry using tissue microarrays. We investigated the association of tumor and nodal stage, grade, hormone receptor status, HER2 gene amplification, menopausal status, body mass index, and survival with IGF protein expression. Results: In contrast to IGFI, the expression of IGFI receptor, IGFBP2, and IGFBP3 was associated with estrogen receptor status. In addition, IGFBP3 was positively correlated with body mass index and premenopausal status. Importantly, IGFBP2 was an independent and positive predictor of overall survival (hazard ratio, 0.48; 95% confidence interval, 0.24-0.95; P = 0.04). There was a weak suggestion for IGFBP2 and overweight to modify each others effect on survival. Conclusions: According to these results, which need confirmation in larger patient series, the prognostic relevance of IGFBP2 and IGFBP3 protein expressions in breast cancer may depend on the hormonal context and body weight. Clin Cancer Res; 16(3); 1025–32

Selective photosensitizer localization in the human endometrium after intrauterine application of 5-aminolevulinic acid

OBJECTIVE Our purpose was twofold: to determine the distribution of the endogenous photosensitizer protoporphyrin IX in the uterus and to ascertain the time interval leading to maximal endometrial fluorescence after intrauterine instillation of 5-aminolevulinic acid. STUDY DESIGN One milliliter of a 400 mg/ml 5-aminolevulinic acid-Hyskon solution was instilled into the uterine cavity of 27 women before hysterectomy. On frozen sections of uterine samples 5-aminolevulinic acid-induced fluorescence was measured with fluorescence microscopy. RESULTS 5-Aminolevulinic acid-induced fluorescence could first be detected in the superficial endometrial glands 75 minutes after drug injection. In the endometrial gland stumps fluorescence intensity peaked 4 to 8 hours after 5-aminolevulinic acid instillation and was > 48 times higher than in the underlying myometrium. CONCLUSIONS Fluorescence in the endometrial glands suggests that selective photodynamic destruction of the endometrium may be possible 4 to 8 hours after intrauterine 5-aminolevulinic acid instillation.

HIGHLY SELECTIVE TARGETING OF OVARIAN CANCER WITH THE PHOTOSENSITIZER PEG-M-THPC IN A RAT MODEL

Photodynamic therapy (PDT) uses light to activate a photosensitizer that has been absorbed or retained preferentially by cancer cells after systemic administration. The first pegylated photosensitizer, tetrakis‐(m‐methoxypo‐lyethylene glycol) derivative of 7,8‐dihydro‐5,10,15,20‐te‐trakis(3‐hydroxyphenyl)‐21,23‐[H]‐porphyrin (PEG‐m‐THPC), was evaluated to target selectively unresectable pelvic ovarian cancer bulks. Our goals were two‐fold: (1) to establish an ovarian cancer model suitable for the development of debulking techniques and (2) to characterize the pharmacokinetics and tumor selectivity of PEG‐m‐THPC by fluorescence microscopy. NuTu‐19 ovarian cancer cells were injected into the caudal part of the right psoas muscle of Fisher rats. Five weeks later, 30 mg/kg body weight of PEG‐m‐THPC was injected intravenously. Necropsy was performed between 4 and 10 days following drug application, and fluorescence of the tumor and various abdominal organs was measured. All rats developed bulky pelvic tumors with an average diameter of 2.6 cm (± 0.6 SD). Tumor masses were encompassing and infiltrating pelvic organs in a similar manner to ovarian cancers in humans. Fluorescence of cancer tissue was maximal 8–10 days following drug application. At 8 days, the tumor‐to‐tissue ratio was 40:1 (plusmn; 12 SE) for most abdominal organs. We conclude that this tumor model may be used for the study of new pelvic debulking techniques, and that the tumor selectivity of PEG‐m‐THPC is exceptionally high 8 days after drug application. Based on these data, we are currently developing a PDT‐based minimally invasive debulking technique for advanced ovarian cancer.