Risk factors for joint symptoms in postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Endocrine treatment-related adverse events have a strong impact on patients' quality of life and sometimes result in treatment discontinuation. Since joint symptoms are the most frequently recognized side effect of aromatase inhibitors, evaluation of associated risk factors may yield significant findings. PATIENTS AND METHODS: A total of 391 postmenopausal Japanese women with estrogen receptor-positive breast cancer and treated with adjuvant anastrozole were enrolled from 28 centers for assessment of patient-reported outcomes (PROs) in this prospective cohort study (SAVS-JP, UMIN000002455). Patients completed the self-report questionnaire at baseline and after 3, 6, 9, and 12 months of treatment for evaluation of frequency of treatment-related joint symptoms (arthralgia, decrease in range of joint motion, and joint stiffness). RESULTS: We obtained PROs from 362 patients (92.6 %) at baseline and at one or more subsequent points. New or worsening from baseline of joint symptoms were reported by 260 patients (71.8 %). More than 90 % of the symptoms were mild or moderate and nearly 80 % had occurred by 6 months. Multivariate analysis showed that a short time span after menopause [odds ratio (OR) 0.95, 95 % confidence interval (CI) 0.90-0.99; P = 0.02] and adjuvant chemotherapy (OR 2.29, 95 % CI 1.06-4.95; P = 0.03) were significant independent risk factors for joint symptoms. No significant relationships between body mass index (BMI) and joint symptoms were identified. Eighteen patients discontinued treatment during the 1st year and eight of them reported joint symptoms. CONCLUSION: Taking into consideration that PROs may yield higher prevalence rates than physician ratings for symptoms published in pivotal clinical trials, we found that a short time span after menopause and use of adjuvant chemotherapy, but not high BMI, were significantly associated with joint symptoms. These findings might prove useful for counseling before initiating treatment with adjuvant aromatase inhibitors in postmenopausal Japanese women.

Body mass index and menopausal disorders during menopause affect vasomotor symptoms of postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Adverse events related to endocrine therapies have a major impact not only on patients' quality of life but also on treatment discontinuation. Although vasomotor symptoms induced by aromatase inhibitors are frequently recognized, risk factors, especially for Japanese women, are not well reported. To identify risk factors for vasomotor symptoms of Japanese breast cancer patients treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs). PATIENTS AND METHODS: For this prospective cohort study (SAVS-JP, UMIN000002455), 391 postmenopausal Japanese estrogen receptor-positive breast cancer patients who were treated with adjuvant anastrozole were recruited from 28 centers. The PRO assessment was obtained from a self-reported questionnaire at baseline, 3, 6, 9 and 12 months between August 2009 and April 2012. Vasomotor symptoms, comprising hot flashes, night sweats, and cold sweats, were categorized into four grades (none, Grade 1: mild, Grade 2: moderate, Grade 3: severe). Pre-existing symptoms were only included if they had become worse than at baseline. RESULTS: Hot flashes, night sweats, and cold sweats at baseline were reported by 20.5, 15.1, and 8.2 % of the patients, respectively, and new appearance or worsening of symptoms in comparison with baseline by 38.4, 29.3, and 28.7 %, respectively. About 80 % of newly occurring symptoms were Grade 1, and less than 5 % were Grade 3. Vasomotor symptoms were reported by 201 out of 362 patients (55.5 %) during the first year and the mean time to onset was 5.6 months. Patients with vasomotor symptoms were significantly younger (mean 62.8 years, range 38-86 vs 64.7 years, range 37-84; p = 0.02), had higher body mass index (BMI) (23.4 kg/m2, range 15.8-39.9 vs 22.4 kg/m2, range 15.8-34.9; p = 0.01), had vasomotor symptoms sooner after menopause (12.4 years, range 0-51 vs 15.1 years, range 1-37; p = 0.002), and had more menopausal disorders during menopause (63.3 vs 36.7 %; p = 0.002). Multivariate analysis showed that BMI [odds ratio (OR) 1.09 per unit of increase, 95 % confidence interval (CI) 1.02-1.16; p = 0.009] and experiencing menopausal disorders (OR 2.11, 95 % CI 1.35-3.30; p = 0.001) were significantly associated with vasomotor symptoms. CONCLUSION: High BMI and experiencing menopausal disorders at menopause were found to be significantly associated with the occurrence of vasomotor symptoms. These findings are expected to prove useful for the management of postmenopausal Japanese women treated with aromatase inhibitors.

Prevention of bone metastases from breast cancer by adjuvant bisphosphonate therapy.

There is increasing evidence regarding the importance of osteoclast activation in the pathogenesis of bone metastases. Cancer cells produce osteoclast-activating factors which play an important role in the development of bone metastases. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. In patients with bone metastases from breast cancer, the effectiveness of bisphosphonate is well established for reducing skeletal complications, such as bone pain, pathological fracture, bone surgery and hypercalcemia. Recent attention has focused on a possible preventive effect on bisphosphonates of bone metastases. Animal models have supported the prevention of bone metastasis by bishosphonate therapy, but three major adjuvant clinical trials of the oral bisphosphonate clodronate have yielded conflicting results. However, our preliminary trial of intravenous bisphosphonate with pamidronate showed effective inhibition of bone metastases. Use of bisphosphonates as adjuvant therapy is still investigational yet promising. Several more randomized trials are underway to further investigate adjuvant therapy with bisphosphonates.

[A case of effective weekly paclitaxel administration for metastatic gastric cancer].

We report a case of effective weekly paclitaxel (TXL) administration for metastatic gastric cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. A 74-year-old man was diagnosed with recurrence 49 months after surgery for gastric cancer. He was treated with 5-fluorouracil and cisplatin, and thrombocytopenia (grade 3) and creatinin elevation (grade 1) were observed and assessed as progressive disease 2 months after the treatment. We attempted weekly TXL administration and after 5 courses assessed the patient as having a partial response. The treatment is ongoing. The toxic event was leukopenia (grade 2), with no episode of thrombocytopenia. The patient did not complain of nausea or vomiting, and his quality of life was fair during the treatment. Weekly TXL administration is a useful treatment for metastatic gastric cancer.

[Weekly paclitaxel therapy for metastatic breast cancer].

We treated 12 patients with metastatic breast cancer with weekly paclitaxel therapy. Paclitaxel was administrated by 1 hour infusion at a dose of 80 mg/m2 after short premedication every week on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. All patients had received prior metastatic chemotherapy, and prior anthracycline therapy was done in 66.7% of the patients. Partial responses were observed in 66.7% of the patients and progressive disease in 33.3%. The response rate was 66.7%. Responses were observed in 62.5% of the patients with prior anthracycline therapy. Grade 3/4 leukopenia and neutropenia occurred in 25% of the patients, respectively, and no grade 3/4 peripheral neuropathy was observed. Dyspnea occurred in 25% of the patients and was grade 3 in 16.7%. Dyspnea is thought to be one of the adverse events requiring caution with weekly paclitaxel administration. Weekly paclitaxel therapy is effective and well tolerated in patients with metastatic breast cancer.

[A case of effective paclitaxel therapy for adriamycin resistant metastatic breast cancer with brain metastases].

A 36-year-old woman was referred to our hospital because of a right breast lump. Chest computed tomography revealed pulmonary metastases with lymphangitis carcinomatosa. Additional examination revealed liver metastases and axillary and cervical lymph node metastases. The patient was started on CA therapy (cyclophosphamide 900 mg, adriamycin 90 mg). A minor response was observed in the pulmonary metastases after two courses but new brain metastases were detected. We then tried paclitaxel administration (260 mg). A partial response was observed in the brain and pulmonary metastases. Thus, paclitaxel administration was continued on a weekly basis (120 mg) and the brain and pulmonary metastases continued to diminish. The primary breast cancer, liver metastases and axillary and cervical lymph node metastases were disappeared. Whole brain radiation was done with weekly paclitaxel administration and the brain metastases were diminished even more. Paclitaxel is as a radiosensitizer and seems to have a strong antineoplastic effect with concurrent radiation.

[A case of effective weekly paclitaxel administration for metastatic gastric cancer].

We report a case of long-term effectiveness of weekly paclitaxel (TXL) administration for metastatic gastric cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. A 61-year-old man was diagnosed as having gastric cancer with multiple liver metastases. He was treated with FP therapy and irinotecan/cisplatin administration and both therapies were assessed to result in progressive disease. We attempted weekly TXL administration and assessed a long period of no change after 6 courses. The treatment is ongoing. The toxic events were peripheral neuropathy and alopecia (grade 2), with no episodes of leukopenia, nausea and vomiting. The patient's quality of life was fair during the treatment. Weekly TXL administration is a useful treatment for metastatic gastric cancer.

[Two cases of effective weekly paclitaxel administration and concurrent radiation for metastatic breast cancer].

We report two cases in which weekly paclitaxel (TXL) administration and concurrent radiation was effective for metastatic breast cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication. Case 1: A 50-year-old woman was found to have atelectasis of the middle lobe after treatment for brain metastasis. She was diagnosed with hilar, mediastinal and supraclavicular lymph nodes metastases. She received weekly TXL administration and concurrent radiation to the mediastinum and supraclavicular fossa. The metastatic lymph nodes had disappeared one month after the treatment. Case 2: A 31-year-old woman was diagnosed with advanced breast cancer with lung, pleural, bone and orbital metastases. She received weekly TXL administration and concurrent radiation to the orbit. The lung and pleural metastases had disappeared and the orbital metastasis was decreased by 75% one month after the treatment, and the case was assessed as a partial response. Leukopenia and other major adverse effects were not observed in either of the two cases.

[Management of patients with hepatic metastases from gastric carcinoma].

Many studies have reported the benefit of hepatic resection for metastatic tumors from colorectal cancer. However, the significance of hepatic resection for gastric metastasis has been controversial. Peritoneal metastases were recognized in 40% of gastric cancer patients with liver metastases, and metastatic lesions in both lobes of the liver were seen in 60% of patients. Resection with curability B was performed in only 10% of the all gastric cancer patients with liver metastases. However, the overall 5-year survival rate of curability B resection was more than 30%, suggesting that it is worth while treating metastases of gastric cancer to the liver. Both synchronous and metachronous metastases are indications for hepatectomy. If there is only one liver metastasis, with no peritoneal and paraaortic lymph node metastases, curability B resection can be performed. Although there is no consensus on the method of hepatectomy, wedge resection is satisfactory. As systemic chemotherapy, S-1 + cisplatin results in a response rate of 50% in patients with metastases to the liver. As arterial infusion chemotherapy, the 5-fluorouracil-doxorubicin-mitomycin (FAM) regimen yields a response rate of more than 70% including 15% complete response rate. FAM is thus a superior regimen, but care must be taken to prevent complications resulting from intraarterial infusion of outside the vas due to deviation of the catheter.

Adjuvant pamidronate therapy prevents the development of bone metastases in breast cancer patients with four or more positive nodes.

Bisphosphonates are strongly efficacious in inhibiting osteoclast bone resorption and have beneficial effects on bone metastasis. Due to their mechanism of action, bisphosphonates are expected to prevent the development of bone metastases in breast cancer patients. Pamidronate is a potent inhibitor of osteoclast activity. We examined whether pamidronate was able to prevent the development of bone metastases in breast cancer patients at high risk for bone metastasis. Between 1997 and 2001, 90 patients with primary breast cancer with ≥4 positive nodes were assigned to receive 45 mg pamidronate 4 times every 2 weeks (33 patients) or standard follow-up (57 patients) based on patient self-preference. Patients underwent surgery and adjuvant therapy. The characteristics of the patients in the two groups were well-balanced. The median follow-up period was 5 years. Bone metastases were detected in 12.1% of patients in the pamidronate group and 40.4% in the control group (p=0.005). Distant metastases (36.4 vs. 56.1%, p=0.071) and non-osseous metastases (33.3 vs. 52.6%, p=0.077) were detected at a lower frequency in the pamidronate group. Thus, the rate of bone metastasis-free survival was significantly higher in the pamidronate group (85.9 vs. 64.0% at 5 years, p=0.023). Overall and disease-free survival rates did not differ between the two groups. In the pamidronate group, the incidence of bone metastases was significantly reduced and bone metastasis-free survival was significantly higher. Adjuvant pamidronate therapy therefore prevents the development of bone metastases in breast cancer patients with ≥4 positive nodes.