Ebrahim Delpassand

Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial

BACKGROUND Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate. METHODS 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks. FINDINGS Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29). INTERPRETATION Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.

Sentinel lymph node biopsy is accurate after neoadjuvant chemotherapy for breast cancer.

PURPOSE Sentinel lymph node (SLN) biopsy has proved to be an accurate method for detecting nodal micrometastases in previously untreated patients with early-stage breast cancer. We investigated the accuracy of this technique for patients with more advanced breast cancer after neoadjuvant chemotherapy. PATIENTS AND METHODS Patients with stage II or III breast cancer who had undergone doxorubicin-based neoadjuvant chemotherapy before breast surgery were eligible. Intraoperative lymphatic mapping was performed with peritumoral injections of blue dye alone or in combination with technetium-labeled sulfur colloid. All patients were offered axillary lymph node dissection. Negative sentinel and axillary nodes were subjected to additional processing with serial step sectioning and immunohistochemical staining with an anticytokeratin antibody to detect micrometastases. RESULTS Fifty-one patients underwent SLN biopsy after neoadjuvant chemotherapy from 1994 to 1999. The SLN identification rate improved from 64.7% to 94.1%. Twenty-two (51.2%) of the 43 successfully mapped patients had positive SLNs, and in 10 of those 22 patients (45.5%), the SLN was the only positive node. Three patients had false-negative SLN biopsy; that is, the sentinel node was negative, but at least one nonsentinel node contained metastases. Additional processing revealed occult micrometastases in four patients (three in sentinel nodes and one in a nonsentinel node). CONCLUSION SLN biopsy is accurate after neoadjuvant chemotherapy. The SLN identification improved with experience. False-negative findings occurred at a low rate throughout the series. This technique is a potential way to guide the axillary treatment of patients who are clinically node negative after neoadjuvant chemotherapy.

The Safety of Lymphatic Mapping in Pregnant Breast Cancer Patients Using Tc‐99m Sulfur Colloid

Abstract:  This investigation was undertaken to assess the risk to the embryo/fetus associated with sentinel lymph node biopsy and lymphoscintigraphy of the breast performed in pregnant patients. Approximately 92.5 MBq (2.5 mCi) of filtered Tc‐99m sulfur colloid was injected peritumorally the day before surgery in two nonpregnant women with breast cancer. The whole‐body distribution of the radiopharmaceutical was evaluated using a gamma camera 1 hour after injection. We then calculated the absorbed dose to the embryo/fetus for three theoretical extreme scenarios of biodistribution and pharmacokinetics: 1) all of the injected radiopharmaceutical remains in the breast and is eliminated only by physical decay; 2) all of the injected radiopharmaceutical is instantaneously transported to the urinary bladder, where it remains and is eliminated only by physical decay; and 3) the injected radiopharmaceutical behaves as though it were administered intravenously, that is, it has the biodistribution and pharmacokinetics of Tc‐99m sulfur colloid injected for a liver/spleen or bone marrow scan. The fetal radiation absorbed dose was then estimated for two Tc‐99m dosages: 18.5 MBq (0.5 mCi) and 92.5 MBq (2.5 mCi). The Medical Internal Radiation Dosimetry (MIRD) program was used to estimate the absorbed doses to the embryo/fetus for the first two scenarios. Published data were used to calculate the doses for the third scenario. A single breast is not among the source organs in the MIRD program, so the heart was used as a surrogate in the first scenario. In the two breast cancer patients, whole‐body gamma‐camera images obtained 1 hour after radiopharmaceutical injection revealed no radioactivity except in the vicinity of the injection site. In the theoretical scenarios, with 92.5 MBq, the highest absorbed doses to the embryo/fetus were as follows: scenario 1, 7.74 × 10−2 mGy at 9 months of pregnancy; scenario 2, 4.26 mGy during early pregnancy; and scenario 3, 0.342 mGy at 9 months of pregnancy. The maximum absorbed dose to the fetus of 4.3 mGy calculated for the worst‐case scenario is well below the 50 mGy that is believed to be the threshold absorbed dose for adverse effects. Thus breast lymphoscintigraphy during pregnancy appears to present a very low risk to the embryo/fetus. 

Feasibility of preoperative lymphoscintigraphy for identification of sentinel lymph nodes in patients with conjunctival and periocular skin malignancies

Purpose To determine the feasibility of preoperative lymphoscintigraphy for identification of sentinel lymph nodes (SLNs) in patients with conjunctival and periocular skin tumors and to determine the patterns of lymphatic drainage from such tumors. Methods We retrospectively reviewed the records of all patients with biopsy-confirmed conjunctival and periocular skin malignancies who underwent lymphoscintigraphy with or without SLN biopsy between January 1999 and June 2000. Patients underwent lymphoscintigraphy with 0.3 to 1 mCi of technetium Tc-99m sulfur colloid in a volume of either 0.2 mL or 1 mL. Images were taken as soon as the first SLNs were detected through the camera and every 15 minutes thereafter. Intraoperative mapping and SLN biopsy was performed 1 to 2 days after lymphoscintigraphy unless the patient refused or there were medical contraindications to the procedure. Results The study included 7 patients with malignant melanoma of the conjunctiva or periocular skin and 1 patient with Merkel cell carcinoma of the eyelid. On lymphoscintigraphy, at least 1 SLN was identified in 7 of the 8 patients. Although all lesions located in the lateral half of the ocular adnexa drained to at least one SLN in the parotid (preauricular) area, there was some variability in the drainage patterns of lesions located in the medial half of the ocular adnexa. A smaller injection volume (0.2 mL) was adequate for detecting the nodes draining the area of injection and led to less spread of technetium to the surrounding areas. Six patients underwent SLN biopsy. In all but one, the nodes identified during surgery corresponded with those visualized on lymphoscintigraphy. Conclusions Preoperative lymphoscintigraphy successfully identifies SLNs in most patients with conjunctival and periocular skin malignancies. Smaller injection volumes (0.2 mL) appear to be adequate for identification of the sentinel nodes and lead to less spread to surrounding tissues.

Validation of Several SUV-Based Parameters Derived from 18F-FDG PET for Prediction of Survival After SIRT of Hepatic Metastases from Colorectal Cancer

90Y radioembolization (selective internal radiation therapy [SIRT]) is a valuable therapeutic option for unresectable hepatic metastases arising from primary colorectal cancer. The present study evaluated the prognostic value of 18F-FDG PET/CT metabolic parameters for predicting survival after SIRT. Methods: Eighty patients with hepatic metastases of colorectal cancer were treated with SIRT. 18F-FDG PET/CT was performed at baseline and 3 mo after the treatment. Metabolic volume, total lesion glycolysis, and maximum and peak standardized uptake value (SUVmax and SUVpeak, respectively) according to PET Response Criteria in Solid Tumors (PERCIST 1.0) were obtained from 3 liver lesions in each patient, and the corresponding percentage changes from baseline to follow-up were calculated. Tumor response was defined as more than a 30% decrease in these parameters. Furthermore, response was evaluated in accordance with Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Toxicity events and survival were recorded. Results: Overall median survival after SIRT was 60 wk. Responders who had a change in metabolic volume or total lesion glycolysis had significantly longer survival (92 vs. 49 wk [P = 0.006] and 91 vs. 48 wk [P = 0.025], respectively). However, neither RECIST 1.1 criteria nor changes in SUVpeak or SUVmax after treatment predicted outcome (P = 0.086 for RECIST; P = 0.310 for change in SUVpeak; P = 0.155 for change in SUVmax). Conclusion: Changes in metabolic volume and total lesion glycolytic rate as measured by 18F-FDG PET predicted survival in patients with hepatic metastases from colorectal cancer, whereas changes in SUVpeak or SUVmax and RECIST 1.1 criteria did not predict survival.

Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience.

Objective Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a novel method of treatment in patients with metastatic neuroendocrine tumors (NETs). For the first time in the United States, we present preliminary results of the treatment with Lutetium 177 (177Lu) DOTATATE in patients with progressive NETs. Methods Thirty-seven patients with grade 1 and grade 2 disseminated and progressive gastroenteropancreatic NET were enrolled in a nonrandomized, phase 2 clinical trial. Repeated cycles of 200 mCi (7.4 GBq; ±10%) were administered up to the cumulative dose of 800 mCi (29.6 GBq; ±10%). Results Among 32 evaluable patients, partial response and minimal response to treatment were seen in 28% and 3%, respectively, and stable disease was seen in 41% of patients. A total of 28% had progressive disease. A response to treatment was significantly associated with lower burden of disease in the liver. No significant acute or delayed hematologic or kidney toxicity was observed. An impressive improvement of performance status and quality of life were seen after 177Lu-DOTATATE therapy. Conclusions Treatment with multiple cycles of 177Lu-DOTATATE peptide receptor radionuclide therapy is well tolerated. This treatment results in control of the disease in most patients, whereas systemic toxicities are limited and reversible. Quality of life is also improved.

Sentinel lymph node biopsy for conjunctival melanoma.

Objective To investigate the feasibility and safety of preoperative lymphoscintigraphy and sentinel lymph node (SLN) biopsy for conjunctival melanoma. Methods A 49-year-old man with a biopsy-proven malignant melanoma of the conjunctiva (caruncle) underwent preoperative lymphoscintigraphy and SLN biopsy using a technique in which both isosulfan blue dye and technetium Tc 99 m sulfur colloid were injected in the subconjunctival space around the primary lesion. The conjunctival melanoma was excised just before identification and removal of the SLNs. The SLNs were excised along with concomitant dissection of their associated lymph node basins. The SLNs were evaluated histologically using serial sectioning and immunohistochemical staining with antisera against the S-100 protein and the melanoma antigen HMB-45. Results Three SLNs were identified in the left submandibular and the left upper and middle jugular lymph node basins during the preoperative lymphoscintigraphy. The same three SLNs were successfully identified in the operating room. The SLNs were histologically negative, and the immunohistochemical staining against S-100 and HMB-45 was also negative. We did not observe any immediate adverse effects on the globe or the periocular structures from lymphatic mapping and SLN biopsy. By 24 hours after injection of blue dye, only a faint trace of blue was visible on the ocular surface. Conclusions Preoperative lymphoscintigraphy and SLN biopsy can be performed safely in patients with conjunctival melanoma. A larger study is planned to determine the sensitivity of this technique for the detection of occult regional nodal disease in patients with conjunctival melanoma.

Safety and efficacy of radionuclide therapy with high-activity in-111 pentetreotide in patients with progressive neuroendocrine tumors

The intent of this study was to evaluate the safety and efficacy of high-activity 111In-pentetreotide in patients with neuroendocrine tumors. Thirty-two patients with pentetreotide-avid neuroendocrine tumors received therapy from August 2005 to November 2006. Fourteen (14) patients received 1 treatment and 18 patients received 2 treatments. Patients were followed an average of 12.73 months (range 1.2-24.5). Seventeen (17) patients (53%) had grade I or II hematologic toxicities, and 1 patient had grade III thrombocytopenia. One patient had grade II liver toxicity, which appeared 4 weeks after therapy and resolved on week 5. No patient had renal toxicity. Of the patients who completed 2 treatment cycles, 2 of 18 patients had partial disease regression, and 16 of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. A decrease in serum tumor markers was observed in 14 of 18 patients given 2 therapies. A clinical response was achieved in 84% of the patients. Upon interim analysis, median survival was approximately 13 months (range 1.2-24.5). These results show that high-activity 111In-pentetreotide therapy is effective in patients with progressive disseminated neuroendocrine tumors.

Canalicular stenosis secondary to weekly versus every-3-weeks docetaxel in patients with metastatic breast cancer

PURPOSE To compare the frequency of canalicular stenosis as a side effect of weekly versus every-3-weeks docetaxel in patients with metastatic breast cancer. DESIGN Retrospective nonrandomized comparative trial. PATIENTS AND METHODS Eighteen patients enrolled in a phase II study of weekly docetaxel plus trastuzumab and 18 patients enrolled in a phase II study of every-3-weeks docetaxel plus doxorubicin were evaluated. Each patient underwent a comprehensive ophthalmologic examination, probing and irrigation of the nasolacrimal duct, and, in some instances, a nuclear lacrimal scan. MAIN OUTCOME MEASURES If epiphora (excessive tearing) was reported by the patient, its time of onset was documented. In patients with epiphora, presence or absence of canalicular stenosis was evaluated on the basis of the findings on probing and irrigation. The duration of treatment with docetaxel, the dose frequency, and the cumulative dose of docetaxel were recorded in each case. RESULTS Fourteen patients (77%) receiving weekly docetaxel plus trastuzumab had epiphora. Nine of these patients had significant anatomic narrowing of the canaliculi. Bicanalicular silicone intubation or dacryocystorhinostomy was recommended in all nine patients. Eight patients underwent surgery and experienced complete or near complete resolution of epiphora. Although two patients (11%) receiving every-3-weeks docetaxel plus doxorubicin reported transient symptoms of epiphora, neither patient was found to have narrowing of the canaliculi, and the epiphora was not severe enough to justify surgical intervention. The mean duration of docetaxel therapy for the patients in this study was 19 weeks. The mean cumulative dose of docetaxel was higher in patients with canalicular stenosis than in patients without this side effect. CONCLUSIONS Canalicular stenosis was more common in patients receiving weekly docetaxel than in those receiving every-3-weeks docetaxel for metastatic breast cancer. Bicanalicular silicone intubation early in the course of weekly docetaxel therapy should be considered, because this intervention can prevent complete closure of the canaliculi. Once complete or near complete stenosis of the canaliculi occurs, placement of a permanent Pyrex glass tube may become necessary to overcome the blockage of tear outflow.

Lymphatic drainage patterns on early versus delayed breast lymphoscintigraphy performed after injection of filtered Tc-99m sulfur colloid in breast cancer patients undergoing sentinel lymph node biopsy

The axillary lymph node status is the most important predictor of prognosis and aids in breast cancer treatment planning. Patients with breast cancer now frequently undergo sentinel lymph node (SLN) biopsy rather than axillary lymph node dissection to determine the status of the regional lymph nodes. However, the optimal timing of radionuclide injection relative to the timing of SLN biopsy remains controversial. The objective of this study was to compare the lymphatic drainage patterns on lymphoscintigraphy performed at 15 minutes to 4 hours and at 18 to 24 hours after injection of filtered Tc-99m sulfur colloid, and to determine whether, over time, radiocolloid migrates to second-echelon nodes that are not the SLNs. Fifteen women with breast cancer (mean age, 55 years; range, 38–78 years) were scheduled to undergo SLN biopsy after each received an injection of 18.5 MBq (0.5 mCi) filtered Tc-99m sulfur colloid into the breast parenchyma surrounding the tumor or biopsy cavity. Both early (15 minutes to 4 hours after radionuclide injection) and delayed (18–24 hours after radionuclide injection) lymphoscintigraphy was performed in each patient. SLN biopsy was performed, followed by completion axillary lymph node dissection and planned breast surgery. In each patient the patterns of distribution of the radionuclide in the lymph nodes were the same on early and delayed lymphoscintigrams. These findings, that the distributions of radionuclide in lymph nodes are identical on early and delayed images obtained after injection of filtered Tc-99m sulfur colloid, suggest that performing SLN biopsy on the day after injection does not diminish the accuracy of the technique in predicting the potential site of metastasis in the regional lymph nodes in patients undergoing this procedure for breast cancer.