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PubMed2006

Prostate cancer-specific survival in men treated with hormonal therapy after failure of radical prostatectomy.

OBJECTIVES: We hypothesized that prostate cancer-specific survival (PCaSS) could be accurately predicted in men in whom radical prostatectomy (RP) failed and who received hormonal therapy (HT) after RP failure. METHODS: Between 1954 and 1994, 752 consecutive patients underwent RP without neoadjuvant therapy. Of those, 114 patients (15.2%) received HT at RP failure and represent the focus of this analysis. Cox regression models and a nomogram targeted PCaSS. The main predictor was timing of HT initiation: at prostate-specific antigen (PSA) versus local versus distant recurrence. Covariates included age at HT, pathologic T stage, surgical margin status and Gleason sum at RP, use of adjuvant or salvage radiation, and time from RP to HT. RESULTS: Mean and median follow-up periods were 5.1 and 3.9 yr; 70 deaths were recorded, of which 45 (39.8%) were due to PCa. At 1, 5, 10, and 15 yr, the estimates of PCaSS were, respectively, 97.1%, 68.3%, 49.3%, and 30.2% (median, 9.8 yr). Younger men and those with HT initiated at the time of distant recurrence had lower PCaSS. A nomogram predicting PCaSS at 2, 3, 4, and 5 yr after RP was developed and demonstrated 66% accuracy after 200-bootstrap internal validation. CONCLUSION: Despite RP failure, half the patients can expect to survive for 10 yr. The nomogram can help in discriminating between those with better versus worse PCaSS, better than relying on most educated guesses.

Aged↗

PubMed2004

[Combination therapy of a novel oral fluorouracil derivative TS-1 with low-dose cisplatin for recurrent and very advanced gastric cancer].

The case reports and clinical trials on combination therapy of a novel oral 5-fluorouracil derivative TS-1 with low-dose cisplatin for gastric cancer were reviewed. In the majority of the case reports, TS-1 was administered at 80-120 mg/body per day for 4 weeks followed by a rest of 2 weeks. However, in several case reports, TS-1 administration was slightly shortened such as 3 weeks administration followed by a rest of 2 weeks. The administration of cisplatin (CDDP) varied: every day, weekly, bi-weekly, and so on; the doses were from 1 to 25 mg/m2. CDDP was mostly given at 5-10 mg/body 5 days per week, mimicking the low-dose FP (5-fluorouracil+ CDDP). In most case reports, combination therapies were undertaken on an inpatient basis due to frequent administration of CDDP, while the weekly or bi-weekly CDDP administration regimens were done on an outpatient basis. The case reports demonstrated high efficacies and few adverse effects of the combination therapy. Several case reports showed unresectable cases could be operated curatively after the combination therapy. There have been three phase I clinical trials, two of which were regimens on an outpatient basis. JFMC 27-9902, an inpatient-basis phase I clinical trial, consisted of TS-1 at 80 mg/m2 every day and CDDP at low-dose for 5 days per a week: the regimen consisted of 4 weeks administration and 2 weeks' rest. The recommended dose of CDDP was determined to be 4 mg/m2 in the JFMC27-9902 regimen. In the modified JFMC27-9902 regimen, CDDP was given twice a week on an outpatient basis. This new phase I/II clinical trial has been under way since 2003 December. In conclusion, TS-1 + low-dose CDDP combination therapy will be done on an outpatient basis in future, and may be examined as a neoadjuvant therapy as well as a conventional form of chemotherapy.

Administration, Oral↗

PubMed2004

Anastrozole demonstrates clinical and biological effectiveness in oestrogen receptor-positive breast cancers, irrespective of the erbB2 status.

Overexpression of erbB2 in breast tumours can predict resistance to tamoxifen therapy. We conducted a small trial to determine if erbB2 status correlates with tumour response and biochemical changes in postmenopausal women receiving neoadjuvant therapy with the aromatase inhibitor, anastrozole. Twenty-four postmenopausal women with oestrogen receptor (ER)-rich, large, operable breast tumours received three months of neoadjuvant anastrozole, 1 or 10 mg daily, then surgery, followed by another five years of anastrozole 1 mg daily. Response to the treatment was based on changes in clinical and ultrasound measurements of tumour volume and changes in tumour proliferation and progesterone receptor (PgR) status. After follow-up for a median duration of four years therapy, there was no apparent difference between erbB2 0/1+ and erbB2 3+ tumours in clinical response or changes in proliferation and PgR expression. In conclusion, anastrozole appears to be an effective endocrine option in this patient population, irrespective of the erbB2 status.

Aged↗

PubMed2006

Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone.

BACKGROUND: Health-related quality of life (HRQL) outcomes are important in assessing new approaches to the treatment of cancer. Neoadjuvant therapy is being used increasingly before surgery in patients with localized oesophageal cancer. This prospective non-randomized study evaluated HRQL in patients treated by preoperative chemotherapy and radiation therapy followed by surgery (multimodal therapy) or by surgery alone. METHODS: Data from European Organization for Research and Treatment of Cancer quality of life questionnaires QLQ-30 and QLQ-OES24 were collected prospectively. Questionnaires were completed at diagnosis, after chemoradiotherapy where applicable, and at 3, 6 and 12 months after surgery. RESULTS: The study included 202 consecutive patients with oesophageal cancer considered suitable for curative (R0) resection at the time of staging. Eighty-seven patients received chemotherapy combined with external-beam radiotherapy before surgery. At baseline, 75 (86 percent) of 87 patients in the multimodal group completed questionnaires, compared with 72 (62.6 percent) of 115 in the surgery-alone group. There were no significant differences in baseline global HRQL scores between groups. Preoperative chemoradiotherapy significantly reduced physical (P=0.004) and role (P=0.007) functioning before surgery, despite a significant (P=0.043) improvement in the dysphagia score. Oesophageal resection had a negative impact on global, functional and symptom HRQL scores at 3 months in both groups. Most variables had recovered by 6 months in the two groups, but at 12 months physical and role functioning remained impaired in the surgery-alone group, and social functioning and financial worries in the multimodal group. CONCLUSION: Although the multimodal regimen had a negative impact on HRQL before surgery, postoperative quality of life in patients who had multimodal therapy was similar to that in those who had surgery alone.

Adult↗

PubMed2001

Aromatase and aromatase inhibitors.

Aromatase inhibition provides both paracrine/intracrine and endocrine treatment. Recent accumulated data clarified that 3rd generation aromatase inhibitors potently suppress intratumoral estrogen synthesis particularly in postmenopausal patients. In the 2nd-line treatment for metastatic breast cancer patients, aromatase inhibitors achieved results antitumor activity at least equal to and sometimes better than that of tamoxifen. In the first-line treatment for metastatic breast cancer patients, a recent pivotal study clearly demonstrated that aromatase inhibitor was superior to tamoxifen. Based upon these results, various adjuvant trials which compare aromatase inhibitors with tamoxifen and attempt to determine optimal combination therapies and treatment periods with aromatase inhibitors are currently being conducted. In addition, preliminary studies conducted in neoadjuvant setting indicated that aromatase inhibitors showed an extremely high response rate, which predicts a future paradigm, that neoadjuvant therapy using aromatase inhibitors singly or in combination may become standard for hormone-responsive and post-menopausal breast cancer patients.

Anastrozole↗

PubMed2004

The optimum timing of radical cystectomy for patients with recurrent high-risk superficial bladder tumour.

OBJECTIVE: To establish the optimum time of radical cystectomy (RC) for patients with recurrent high-risk superficial bladder tumours after the failure of intravesical therapy. PATIENTS AND METHODS: Among 318 patients with transitional cell carcinoma treated with RC and with no neoadjuvant therapy, there were 46 with clinical stage Ta, T1 or Tis refractory to transurethral resection associated with intravesical therapy. These patients had at least one of: (i) high-risk superficial bladder tumours after failure of two consecutive induction courses of intravesical therapy; (ii) superficial bladder tumours with prostatic stromal invasion; (iii) superficial bladder tumours with mucosa/ducts involvement after failure of one course of intravesical therapy; (iv) uncontrolled superficial tumours with transurethral resection associated or not with intravesical therapy. Progression and cause-specific survival of these patients were compared to those with muscle-invasive tumours. Univariate and multivariate analyses of predictive factors for cause-specific survival were also used in patients with superficial tumours. The incidence of significant prognostic factors was compared in both superficial and muscle-invasive tumours, as were the progression pattern and survival. RESULTS: The progression-free and cause-specific survival of patients with superficial tumours was 54% and 67%, respectively, with no significant difference from those with muscle-invasive tumours. In multivariate analysis, positive lymph-nodes and prostatic stromal invasion were significant and independent variables for survival. The incidence of positive lymph nodes was 15% vs 30% (P < 0.05) and of stromal invasion was 32% vs 1.5% (P < 0.001) in patients with superficial and muscle-invasive tumours, respectively. Accounting for the progression pattern in patients with superficial tumours, extravesical urothelial recurrence prevailed over local or distant recurrences (30% vs 15%), whereas in patients with muscle-invasive tumours the opposite occurred (5% vs 33%, respectively). The cause-specific survival of patients with superficial tumour and prostatic stromal invasion was one of three, and in those who developed extravesical urothelial recurrence was 28.5%. CONCLUSION: In patients with recurrent high-risk superficial bladder cancer after intravesical therapy, our criteria for RC were inappropriate, and patients had a survival rate similar to those with muscle-invasive tumours. RC might have been used too late, as there was a high incidence of prostatic stromal invasion and extravesical urothelial recurrence after RC. Both events seem to be responsible of the low cause-specific survival. Predictive factors for progression are needed to indicate early RC in patients with recurrent high-risk superficial tumours. From a previous analysis the pathological pattern of the clinical lack of response (T1, G3, bladder carcinoma in situ and prostate involvement) to intravesical therapy evaluated at 3 months might be important for predicting progression, and an early RC at that time might be useful.

Aged↗

PubMed1997

[Treatment outcome of radical cystectomy during a 10-year period (June 1984-September 1994) at Department of Urology, Fukui Medical School].

The treatment outcome was evaluated in 63 patients with bladder cancer more than 2 years after cystectomy. Cisplatin-based combination chemotherapies were given to 40 patients after the operation as an adjuvant therapy and two patients with T4 or N2 bladder cancer received chemotherapy before the operation as a neoadjuvant therapy. The extent of infiltration of the removed tumors was pTa in 5, pT1 in 18, pT2 in 8, pT3a in 6, pT3b in 17, and pT4 in 9 cases. Regional lymph node metastases were present in 10 cases (16%). Nineteen patients died of tumor recurrences. The 5-year acturial survival rates at each stage were 60% for stage pTa, 78% for stage pT1, 63% for stage pT2, 83% for stage pT3a, 33% for stage pT3b and 38% for stage pT4, respectively. A significant difference (p < 0.05) in survival curve was observed between pT3a and pT3b. The prognosis of patients with tumors extending beyond the bladder muscles is extremely unfavourable, with the exception of bladder cancers infiltrating the neighboring organ (pT4a), the removal of which may result in lasting survival in a part of the cases. Effective adjuvant treatment is required for patients with bladder tumors penetrating the bladder wall.

Adult↗

PubMed2001

The Twenty-third Annual San Antonio Breast Cancer Symposium.

This paper reviews the recent Twenty-third Annual San Antonio Breast Cancer Symposium. A total of 580 studies were presented either orally or as posters. Two phase III multi-centre clinical trials found that fulvestrant (Falsodex), given as a once-monthly intramuscular injection (250 mg), was well-tolerated and at least as good as anastrozole (1 mg) in postmenopausal women with advanced breast cancer that had progressed or recurred on prior endocrine therapy. Another phase III randomised trial found that letrozole (2.5 mg daily) was superior to tamoxifen as a neoadjuvant therapy in postmenopausal women with ER- and/or PgR-positive breast cancer unsuitable for breast-conserving surgery. In a phase III study, capecitabine (Xeloda) was found to be well-tolerated and able to improve survival by three months when added to Taxotere. Cutting edge data on microarray gene profiling in breast cancer were presented. The potential role of this new technology in predicting outcome and selecting therapy was discussed. Furthermore, its limitations and the need for validation were highlighted. The role of new diagnostic tools, such as fibre-optic ductoscopy (FDS) and microcatheters to obtain ductal cells, was discussed. Finally, the worldwide overview was presented.

Anastrozole↗

PubMed2001

Aromatase inhibitors.

The new non-steroidal and steroidal aromatase inhibitors are at least as effective as megestrol acetate (MA) as second-line hormonal agents in postmenopausal women with breast cancer. However, they are superior to MA in terms of tolerability and adverse effects. Letrozole and exemestane have been shown to be superior to MA in terms of efficacy. Furthermore, exemestane and anastrozole demonstrated a survival advantage over MA. These drugs are therefore considered established second-line hormonal agents. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors as first-line therapy for ER-and/or PgR-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor positive tumours unsuitable for breast conserving surgery. Studies comparing these drugs head-to-head and with adjuvant tamoxifen are currently in progress. The potential role of these drugs in breast cancer prevention is worth investigating.

Antineoplastic Agents, Hormonal↗

PubMed2006

HER-2 (c-erbB-2) test update: present status and problems.

HER-2 tests are routinely used for the identification of patients with metastatic breast cancer that is potentially responsive to trastuzumab (herceptin) therapy. Recently, convincing data have been published with regard to the efficacy of trastuzumab as a drug for neoadjuvant therapy or adjuvant therapy for operable primary breast cancer that overexpresses HER-2. It is also noteworthy that a the St. Gallen International Consensus Conference 2005, HER-2 protein overexpression or HER-2 gene amplification has been included as an indicator for higher risk of recurrence for both node-negative and node-positive breast cancers. To measure the HER-2 level, the worldwide consensus appears to be that immunohistochemistry (IHC) should be performed first and, if the results of IHC are uncertain, fluorescence in situ hybridization (FISH) should be performed later, although some investigators argue that FISH should be performed first. These tests should be performed in strict adherence to existing instructions. Quality control is of utmost importance when performing HER-2 tests, both internal and external, for routine diagnosis and in clinical protocol studies.

Breast Neoplasms↗

PubMed1996

Effects of neoadjuvant androgen deprivation therapy on prostatic cancer.

OBJECTIVES: In this study, we analyzed the involutive effects of androgen deprivation therapy on normal and neoplastic prostatic tissue, to investigate whether androgen deprivation prior to radical prostatectomy could reduce the incidence of extracapsular extension, positive margins, positive seminal vesicles and positive lymph nodes in patients with prostatic carcinoma. METHODS: We performed neoadjuvant androgen deprivation therapy (NADT) in 41 patients cT2N0M0 and in 21 patients cT3N0M0. Criteria to evaluate the effectiveness of NADT included prostate volume, tumor volume, serum prostate-specific antigen (PSA), staging, grading, histological modifications of the tumor, and evaluation of indices of cellular proliferation. RESULTS: We observed a decrease in prostate and tumor volume, as well as serum PSA; a down-staging effect was observed in 14.51% of cases. Evaluation of proliferating-cell nuclear antigen (PCNA) revealed a decrease of proliferative activity in treated prostatic carcinoma. The histological modifications after neoadjuvant therapy consisted of cellular necrosis with apoptotic phenomena, dense chromatin without nucleoli, absence of mitosis, inflammatory infiltrate, and interstitial fibrosis. Regressive aspects similar to those of neoplastic cells were observed in prostatic intraepithelial neoplasia. CONCLUSION: Our assessment of the biologic effects of NADT on tumoral activity of prostatic carcinoma led us to conclude that NADT can reduce the cellular proliferation of neoplastic cells.

Adenocarcinoma↗

PubMed1995

Staging concepts for gastrointestinal malignancies: the importance of preoperative locoregional T- and N-staging.

Preoperative locoregional staging of gastrointestinal tumors is of special significance for evaluation of resectability that means complete tumor removal without residual tumor (R0-resection). This is especially important within a multimodal therapeutic concept including neoadjuvant therapy of nonresectable tumors. In esophageal cancer above the bifurcation, tumors that are staged T3 or T4 should have neoadjuvant radiochemotherapy in order to achieve a down-staging and increase the chance for a complete tumor resection. Preoperative chemotherapy is further established in esophageal carcinomas below the bifurcation and gastric carcinomas in stage T4. As in pancreatic carcinoma, neoadjuvant treatment has no proven indication. Preoperative locoregional staging mainly concerns the infiltration of retroperitoneal veins, which represents the crucial point for resectability. Concerning carcinomas of the lower GI tract the T- and N-staging is of special relevance for rectal cancer because preoperative radiochemotherapy in T4-stage is an accepted indication. The T- and N-staging of gastrointestinal tumors has important clinical consequences; the demands for accuracy of endosonographic examinations are therefore very high.

Combined Modality Therapy↗

PubMed2001

Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer.

BACKGROUND: Neoadjuvant chemotherapy before resection is the standard of care for stage IIIA non-small cell lung cancer in many institutions. Further, neoadjuvant therapy is being studied in earlier stage lung cancer and may be applied more broadly in the future. There is little information about the effect of preoperative chemotherapy on the perioperative complications and mortality after lung resection. METHODS: All patients undergoing anatomic resection after neoadjuvant chemotherapy by a single surgeon at a single institution were compared with patients undergoing similar resections without preoperative chemotherapy. Complications were analyzed as life-threatening (pneumonia, emergency surgery, transfer to the intensive care unit, or intubation), major (prolonging hospital stay but not necessarily dangerous), and minor. The incidence of life-threatening complications, major complications, reintubation, tracheostomy, and mortality were analyzed to determine whether neoadjuvant chemotherapy might have an effect on these complications. Mortality was defined as hospital mortality. Two-tailed Student's t test was used to analyze differences in means and chi2 to determine differences in proportions. Differences less than 0.05 were considered significant. RESULTS: Thirty-four patients underwent resection after neoadjuvant chemotherapy, and 67 patients underwent resection without preoperative therapy. No differences between the two groups in age, pulmonary function, or comorbid diseases were found. The patients receiving chemotherapy did have a more advanced stage (2.52 versus 1.55, p < 0.0001). Striking increases were found in incidence of life-threatening complications (6.0% versus 26.5%, p = 0.0036), major complications (19.4% versus 47.1%, p = 0.0037), reintubation (3.0% versus 17.6%, p = 0.0093), and tracheostomy (0% versus 11.8%, p = 0.0042) in those patients who received preoperative chemotherapy. There was no hospital mortality. However, 2 (neoadjuvant) patients died within 90 days after discharge from the hospital of pneumonia and pulmonary embolus. This difference was also significant (0% versus 5.89%, p = 0.045). CONCLUSIONS: Neoadjuvant carboplatin and Taxol increased the perioperative life-threatening complications in this cohort of patients compared with a similar cohort undergoing operations by the same surgeon in the same institution. The most common life-threatening complication in patients receiving induction chemotherapy was the failure to respond to antibiotics given for pneumonia. Strategies to prevent these complications will be important, especially if chemotherapy before resection becomes the standard for earlier stages of non-small cell lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

The evolving role of aromatase inhibitors in breast cancer.

Anti-aromatase agents inhibit the cytochrome p-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues. These drugs can be classified into first-generation (e.g., aminoglutethimide), second-generation (e.g., formestane and fadrazole), and third-generation (e.g., anastrozole, letrozole, and exemestane) agents. Anti-aromatase agents can also be divided into type I and type II inhibitors. Type I inhibitors have a steroidal structure similar to androgens and inactivate the enzyme irreversibly by blocking the substrate-binding site, and are therefore known as aromatase inactivators. Type II inhibitors are nonsteroidal and their action is reversible. This article reviews the recent evidence regarding the role of third-generation aromatase inhibitors in the management of breast cancer. Relevant PubMed listed articles and presentations at recent international symposia were reviewed. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) as first-line and second-line therapy for estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor-positive invasive breast cancer unsuitable for breast-conserving surgery. Furthermore, the preliminary results of the ATAC (Arimidex, Tamoxifen, Alone and in Combination) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), adverse effects, and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. However, longer follow-up is required to assess the long-term effects of these agents on bone mineral density, cognitive function, and overall survival prior to considering their routine use in the adjuvant setting instead of tamoxifen. The potential role of these drugs in the management of ductal carcinoma in situ (DCIS), premenopausal breast cancer, and breast cancer prevention is worth investigating.

Anastrozole↗

PubMed2000

The role of multimodality therapy for resectable esophageal cancer.

BACKGROUND: There is an increasing interest in the role of combined therapy to achieve long-term survival for patients with resectable esophageal neoplasms. Surgery provides excellent palliation with relatively low morbidity and mortality rates, but cure remains elusive. MATERIAL AND METHODS: From January 1988 to January 1998, a total of 137 patients met eligibility criteria for a combined multimodal therapy, prospective, nonrandomized protocol of induction chemoradiation therapy followed by surgical resection, based on radiological and endoscopic assessment of the extension (all patients were initially considered to be at clinical stages I to III, locoregional). Consequently, patients with high grade Barrett's dysplasia or any squamous carcinoma in situ (stage 0) and those with distant metastatic disease (stage IV) were excluded. Among this group, 48 operable patients with biopsy-proven esophageal cancer finally entered and completed the protocol and are the sample of the present study. Multivariate logistic regression models were used to identify risk factors for death or recurrence. Actuarial survival was calculated since the beginning of the induction protocol by the Kaplan-Meier method, and comparisons between groups were made by the log-rank test. RESULTS: Mean age was 61.6 (range 45 to 71), and 72.9% were male. The majority of the tumors (70.8%) were located at the lower third/cardia and as many as 18.8% were adenocarcinoma. After a mean of 7.5 weeks (range 5 to 12) after the completion of the induction phase, 68.7% underwent a transthoracic esophagectomy and 31.3% a transhiatal esophagectomy. The in-hospital mortality rate was 10.4% (5 patients). A complete response (no evidence of tumor within the specimen: pT0) was achieved in 25% (12 patients). After a mean follow-up of 20.2 months, mean survival for the entire group was 18.2 months (95% confidence interval 14 to 22). At the end of the study, 25% (12) remained alive. Actuarial survival rates at 12, 23, and 37 months were 56.2%, 36.9%, and 21.9%, respectively. CONCLUSIONS: Esophageal resection after induction therapy seems to be related to a slightly higher mortality rate compared with historical series, and for this reason, neoadjuvant therapy must be considered still experimental. However, no statistical significant difference in survival is showed in those cases with complete pathological response (pT0). Factors influencing survival are recurrence and age. Surgery alone remains the standard therapy for esophageal cancer.

Aged↗

PubMed1999

Multidisciplinary Management of Locally Advanced Breast Cancer.

The treatment of locally advanced breast cancer is aimed at achieving long-term local control with local surgery and/or radiation therapy and at improving disease-free and overall survival through the application of systemic cytotoxic chemotherapy and hormonal therapy. Studies of local therapy alone with surgery or radiotherapy have demonstrated high rates of local recurrence and low rates of long-term survival. The application of anthracycline-based neoadjuvant chemotherapy has resulted in rates of response ranging from 72% to 97%, clinical complete responses of 12-52%, and pathologic complete responses of 4-33%. Multidisciplinary treatment with neoadjuvant therapy, followed by local surgery and/or radiation therapy, followed by additional chemotherapy, has resulted in rates of local control that exceed 80%, and 5-year survival rates exceeding 50% are not unusual. The use of anthracycline-based neoadjuvant chemotherapy in the treatment of locally advanced breast cancer is thus now firmly established. Research in the treatment of locally advanced breast cancer is needed to further define the optimal method of local therapy and the role of new agents such as the taxanes.

Journal Article↗

PubMed2004

Pilot trial evaluating an 123I-labeled 80-kilodalton engineered anticarcinoembryonic antigen antibody fragment (cT84.66 minibody) in patients with colorectal cancer.

PURPOSE: The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (V(L)-linker-V(H)-C(H)3; 80 kDa) that demonstrates bivalent and high affinity (4 x 10(10) m(-1)) binding to carcinoembryonic antigen (CEA). The variable regions (V(L) and V(H)) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the C(H)3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab')(2) fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether (123)I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer. EXPERIMENTAL DESIGN: Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5-10 mCi (1 mg) of (123)I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48-72 h. Surgery was performed immediately after the last nuclear scan. RESULTS: Tumor imaging was observed with (123)I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. (123)I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9-65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed. CONCLUSION: This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as (111)In.

Adult↗

PubMed1997

Therapeutic effects of leuprorelin microspheres in prostate cancer.

Leuprorelin has demonstrated effectiveness comparable to orchiectomy and oral diethylstilboestrol for the palliation of advanced prostate cancer. Unlike orchiectomy, leuprorelin's effects are reversible; also leuprorelin is not associated with the cardiovascular or thromboembolic adverse effects of oestrogens. For these reasons, leuprorelin has been widely used as an alternative to surgical castration or to oestrogens in the treatment of metastatic prostate cancer. Sustained-release leuprorelin microsphere formulations have been developed which exhibit zero order release of active drug from the injection site, such that in the United States the 7.5 mg dosage strength is recommended to be administered once a month and the 22.5 mg dosage strength once every three months. Although most patients will have suppressed release of pituitary luteinizing hormone by the third or fourth week after the first dose of depot leuprorelin, 4-5% of treated patients have been reported to have delayed responses, taking many more weeks or months to respond. A transient biochemical hormone escape has also been reported, although worsening of clinical symptoms has not accompanied the elevation of serum testosterone levels during treatment. Usually, leuprorelin is initiated as monotherapy when patients with advanced prostate cancer become symptomatic. However, newer studies of combination therapy of luteinizing hormone releasing hormone analogs with antiandrogens suggest that early initiation of therapy, at the time of diagnosis of advanced disease, may be beneficial, particularly in a subgroup of patients with small volume disease and good performance status. Leuprorelin is also undergoing evaluation as neoadjuvant therapy prior to radical prostatectomy for localized prostate cancer. Preliminary studies suggest that neoadjuvant leuprorelin in combination with an antiandrogen may be effective in downstaging prostate tumours. Leuprorelin commonly produces several adverse effects: hot flashes, decreased libido and impotence, and tumour flare.

Journal Article↗