Masataka Sawaki

The Feasibility Study of Docetaxel in Patients with Anaplastic Thyroid Cancer

There is no established chemotherapy for anaplastic thyroid cancer. We conducted a prospective feasibility study at a single center to explore the antitumor activity of docetaxel against anaplastic thyroid cancer. Docetaxel was administered intravenously at a dose of 60 mg/m(2) over the course of 1 h every 3 weeks in patients with anaplastic thyroid cancer who had received no prior chemotherapy. A total of seven patients with anaplastic thyroid cancer were enrolled over the course of 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response plus stable disease) was 43%. The median time to progression was 6 weeks (range, 1-50). Toxicity was tolerable. Docetaxel could be an effective drug for the treatment of anaplastic thyroid cancer, with tolerable toxicity.

Neuroendocrine tumor in the breast

A 34-year-old woman with a past history of a carcinoid tumor in the right ovary presented with a right breast mass found on contrast-enhanced computed tomography (CT) of the chest. She was asymptomatic, and her blood tests were normal. The mass measured about 2 cm. Mammography showed a lobular, circumscribed, high-density mass without microcalcifications in the upper outer quadrant of the right breast. Ultrasonography showed an irregular mass with both hypoechoic and hyperechoic components with increased vascularity. The mass was well enhanced on contrast-enhanced CT and dynamic magnetic resonance imaging. At the same time, a well-enhanced small nodule was detected in the pouch of Douglas. Both of the tumors were resected, and a primary breast neuroendocrine tumor (solid neuroendocrine carcinoma) and peritoneal dissemination of the ovarian carcinoid tumor were diagnosed.

PACLITAXEL ADMINISTERED WEEKLY IN PATIENTS WITH DOCETAXEL- RESISTANT METASTATIC BREAST CANCER: A SINGLE-CENTER STUDY

Aims and background We evaluated retrospectively the efficacy and toxicity of paclitaxel in patients with docetaxel-resistant metastatic breast cancer. Study design Paclitaxel (80 mg/m2) was administered weekly to 44 patients who had previously received chemotherapy regimens for metastatic breast cancer. All patients had progressive disease in spite of having received docetaxel therapy. Results Treatment was repeated until there was evidence of disease progression. Objective responses were obtained in 14 of 44 assessable patients (31.8%; 95% confidence interval, 17.5–46.1). Fourteen patients had partial responses; none responded completely. Seven of 14 responders had primary resistance to docetaxel therapy. The median duration of response was 6.1 months (range, 2.1–12.7). The median time to progression was 5.0 months. Clinically severe adverse events (grade 3 or 4) included neutropenia (27.2%), leukopenia (25.0%), neuropathy-sensory (13.6%), febrile neutropenia (6.8%), anemia (2.2%), constipation (2.2%), and edema (2.2%). Treatment was generally well tolerated and could be continued on an out-patient basis. Conclusions Weekly paclitaxel is effective in patients with docetaxel-resistant metastatic breast cancer. This observation suggests partial cross-resistance between paclitaxel and docetaxel. There was no evidence for additive cumulative toxic effects of the two taxanes.

Efficacy and safety of trastuzumab as a single agent in heavily pretreated patients with HER-2/neu-overexpressing metastatic breast cancer.

Aims and background The human epidermal growth factor receptor 2 (HER2) protein is a unique and useful target for antibody therapy against breast cancers that overexpress the HER-2/neu gene. The recombinant humanized anti-HER2 monoclonal antibody, trastuzumab, was approved for clinical use in the United States in 1998. It became available in Japan in June 2001. This study focuses on the efficacy and safety of trastuzumab as a single agent in second-third line treatment of HER2/neu-overexpressing metastatic breast cancer. Study design Between June 2001 and May 2002, we treated 62 patients with trastuzumab, as a single agent or in combination chemotherapy, for second-third line treatment of HER2-overexpressing metastatic breast cancer. Twenty-seven of 62 patients were treated with trastuzumab as a single agent. We reviewed retrospectively the efficacy and safety of the drug given as a single agent. The expression of HER2 was determined by immunohistochemical staining. All patients received a standard loading dose of 4 mg/kg followed by 2 mg/kg weekly. Results Patients received a median of 16.7 weekly infusions (range, 1–66 infusions). Trastuzumab therapy was generally well tolerated. Clinically severe adverse events (grade 3 or 4) included hypotension (7.4%), and hypoxia (3.7%). Grade 1 to 2 toxicity included fever (11.1%) and diarrhea (3.7%). Infusion-related reactions were infrequent, as were serious hematologic complications. Cardiotoxicity did not occur in the study. Three patients had a complete and 3 a partial response, 3 had no change, 17 had progressive disease, and one was not evaluated. The overall response rate in the 26 patients with available data was 23.1% (95% confidence interval, 5.7–40.4). The median duration of response was 6.4 months (range, 2.5–14.0). The median time to progression was 3.1 months (range, 0.2–16.7). Response rates differed by metastatic site as follows: lung 0% (0/12), bone 10.0% (1/10), liver 0% (0/8), skin 50.0% (4/8), lymph nodes 42.9% (3/7), brain 0% (0/2). Conclusions Molecular target therapy with trastuzumab appears safe and is generally well tolerated. For treatment of metastatic breast cancer, single agent therapy produces a durable response in some patients but lacks sufficient efficacy. Single agent use of trastuzumab is a viable option for treatment in cases with non-life-threatening disease without visceral metastasis.

Adrenal Incidentaloma: Review of 197 Patients and Report of a Drug-Related False-Positive Urinary Normetanephrine Result

PurposeTo determine the incidence and importance of functioning tumors among incidentally discovered adrenal masses in the era of laparoscopic surgery.MethodsWe defined adrenal incidentaloma as a tumor detected during abdominal imaging for adrenal-unrelated reasons, and we reviewed 197 consecutive patients with adrenal incidentaloma diagnosed since we started laparoscopic adrenalectomy.ResultsIncidentaloma was discovered initially in 91 (46%) patients and pheochromocytoma was detected as an incidentaloma in 21 (39%) of 54 patients. One patient, a 21-year-old woman taking mesalamine for ulcerative colitis, had a remarkably elevated urinary normetanephrine level, which resulted in the initial misdiagnosis of a 10-cm right adrenal incidentaloma as a pheochromocytoma. Laparoscopic right adrenalectomy resulted in a pathological diagnosis of ganglioneuroma. A series of urinary normetanephrine measurements were taken in parallel with the mesalamine doses. We found that other patients medicated with mesalamine, without adrenal tumors, had elevated urinary normetanephrine levels, confirming that mesalamine metabolites interfere with urinary normetanephrine measurements.ConclusionsIt is essential to diagnose the functional potential of adrenal incidentaloma preoperatively, and not to perform laparoscopic adrenalectomy for adrenal incidentaloma without careful evaluation first.

Patterns of Lymph Node Metastases in Papillary Thyroid Carcinoma: Results from Consecutive Bilateral Cervical Lymph Node Dissection

BackgroundIn patients with papillary thyroid carcinoma (PTC), the appropriate extent of lymph node dissection has not yet been established due to lack of accurate patterns of lymph node metastases (LNM). The aim of this study was to clarify the LNM pattern in PTC patients based on our institution’s experience with a consistent technique of bilateral neck dissection, and to consider the rational extent of lymph node dissection.MethodsBetween 1990 and 1999, 152 consecutive patients with PTC who underwent curative total thyroidectomy and bilateral neck dissection as initial treatment were analyzed. The patterns of LNM according to clinicopathological classification were analyzed using the lymph node ratio (LNR; number of metastatic lymph nodes/number of dissected nodes) and frequency (FLNM; number of patients with LNM/number of dissected patients) in cervical compartments.ResultsRegardless of clinicopathological classification, LNR in the central compartment was consistently higher than in other compartments, and FLNM in the ipsilateral lateral compartment was consistently higher than in other compartments except for multifocal tumors. The LNR and FLNM in the contralateral lateral compartment were significantly higher in advanced (≥T3) cases than in cases with smaller tumors (T1) and were comparable to those in the ipsilateral lateral compartment in advanced (≥T3) cases.ConclusionsThe pattern of LNR provided a better reflection of the patterns of LNM. In terms of the LNR, central neck dissection is the basic extent of lymph node dissection for all clinically apparent PTC. In advanced patients, it is also advisable to include bilateral lateral neck dissection.

Evaluation of Trastuzumab Without Chemotherapy as a Post-operative Adjuvant Therapy in HER2-positive Elderly Breast Cancer Patients: Randomized Controlled Trial [RESPECT (N-SAS BC07)]†

OBJECTIVE This trial is conducted to investigate the benefit of trastuzumab monotherapy compared with a combination therapy of trastuzumab and chemotherapy in women over 70 years with human epidermal growth factor receptor type-2-positive primary breast cancer. METHODS Inclusion criteria are the following: histologically diagnosed as invasive breast cancer and received curative operation for primary breast cancer; Stage I, IIA, IIB or IIIA/M0; and baseline left ventricular ejection fraction is ≥55%. Patients are randomized to receive either trastuzumab (8 mg/kg loading dose, 6 mg/kg every 3 weeks for 1 year) plus chemotherapy selected from regimens specified on the protocol or trastuzumab monotherapy. The primary endpoint is disease-free survival. Secondary endpoints are overall survival, relapse-free survival, safety, health-related quality of life, comprehensive geriatric assessment and cost effectiveness. RESULTS Patients recruitment has been commenced in October 2009. Enrollment of 300 patients is planned during the 4-year recruitment period. CONCLUSIONS We hereby report the study concept.

Prospective evaluation of corrected QT intervals and arrhythmias after exposure to epirubicin, cyclophosphamide, and 5-fluorouracil in women with breast cancer

BACKGROUND Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. PATIENTS AND METHODS To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. RESULTS A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. CONCLUSION This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.BACKGROUND Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. PATIENTS AND METHODS To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. RESULTS A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. CONCLUSION This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.

Comprehensive geriatric assessment in elderly breast cancer patients

Treatment of elderly patients with breast cancer is limited by the lack of evidence-based medicine due to exclusion of elderly persons from clinical studies and the difficulty of decision-making in an elderly population comprising subjects with heterogeneous health backgrounds. Individual variation of health conditions is larger in elderly patients than in young people. Since the risk–benefit balance of treatment depends on the health background, judgment of the vulnerability of individual patients is required in treatment planning. The comprehensive geriatric assessment (CGA) is a tool for acquisition of information for design of a cancer treatment plan based on evaluation of the vulnerability of elderly patients from various perspectives. The domains of the CGA include physical function, comorbidity, cognitive function, psychological status, social support system, nutrition, and medication. The CGA can be used to predict survival and adverse events; to identify health problems that cannot be detected based on medical history or examination; to recognize new problems that emerge during course observation; and to improve psychological conditions. However, application of the CGA in routine clinical practice requires establishment of a consensus regarding the survey method, evaluation scale, and use of results in decision-making. A prospective investigation of the CGA as an outcome index in elderly breast cancer patients is required to address these issues.

Prognostic importance of neuroendocrine differentiation in Japanese breast cancer patients

PurposeTo evaluate the frequency and prognostic importance of neuroendocrine differentiation (NED) in Japanese breast cancer patients.MethodsWe used standard immunohistochemical techniques to examine 50 patients who underwent resection of breast cancer between 1988 and 1993 at the Department of Surgery II, Nagoya University Hospital, for NED, defined as positive reactivity for four markers: neuron-specific enolase (NSE), synaptophysin, CD57, and chromogranin A (CGA). Neuroendocrine differentiation was defined by the presence of at least one marker including CGA, CD57, and synaptophysin, or at least two markers when one was positive for NSE.ResultsNeuroendocrine differentiation was found in 13 (26%) of the 50 patients examined. There were no significant differences in the distribution of patients with positive or negative NED in terms of age, menopausal status, tumor size, lymph node metastasis, histological grade, ER, PgR, and HER2. We calculated the cumulative survival rates of patient groups according to NED status, and found no significant difference in overall or disease-free survival between patients with and those without NED.ConclusionNeuroendocrine differentiation was identified in a subset (26%) of Japanese breast cancer patients, but this appeared to have no relationship with established prognostic factors or patient outcome.