MTX intolerance in children and adolescents with juvenile idiopathic arthritis.

MTX is the medication most commonly used for antirheumatic treatment in juvenile idiopathic arthritis. It has high efficacy, is usually well tolerated and has an excellent safety profile. However, frequently intolerance symptoms develop that manifest as nausea, feelings of disgust or abdominal complaints prior to or directly after administration of the medication. No obvious toxicity is causing these intolerance symptoms, but symptoms are strictly limited to MTX and not transferred to other medications. MTX intolerance causes a significant reduction of quality of life in affected patients, frequently puts the treating physician in difficult situations regarding treatment choice, and may lead to uncomfortable decisions whether or not to stop an otherwise effective drug. Conventional countermeasures such as antiemetics, change of route from subcutaneous to oral or vice versa, or taste masking usually have only a limited effect. In this review, we present the current knowledge on MTX intolerance, its clinical picture and commonly employed strategies. We also consider newer behavioural treatment strategies that may offer a more effective symptom control.

Anticipatory Nausea, Risk Factors, and Its Impact on Chemotherapy-Induced Nausea and Vomiting: Results From the Pan European Emesis Registry Study.

CONTEXT: Anticipatory (prechemotherapy) nausea (AN) is a classic conditioned symptom not responding well to current antiemetics. Minimal work has been done to assess its risk factors and impact on chemotherapy-induced nausea and vomiting (CINV). OBJECTIVES: To evaluate risk factors for AN and assess its impact on CINV development. METHODS: We analyzed data (n = 991) from a prospective observational multisite study in eight European countries over three cycles of chemotherapy. Patient/treatment characteristics were collected before chemotherapy. History of nausea/vomiting (yes/no), patient expectation of CINV (0-100 mm visual analog scale, [VAS]), and prechemotherapy anxiety (0-100 mm VAS) also were collected before chemotherapy. A patient-completed diary during each chemotherapy cycle obtained information on AN in the 24 hours before chemotherapy administration and nausea and vomiting (episodes of vomiting and severity of nausea) daily for five days after administration of chemotherapy (0-100 mm VAS). RESULTS: AN was reported by 8.3%-13.8% of patients, increasing in frequency and intensity over each cycle. Every 1 mm increase in AN on the VAS was significantly associated with 2%-13% of increase in the likelihood of CINV (all P-values <0.05). Key predictors of AN in Cycle 1 included metastatic disease and prechemotherapy anxiety. However, predictors of AN in subsequent cycles included prechemotherapy anxiety and AN and CINV experience in the previous cycle, the latter being the strongest predictor (odds ratio = 3.30-4.09 for CINV outcomes over the cycles). CONCLUSION: AN is a challenging symptom, and its prevention needs to consider better CINV prevention in the previous cycles as well as managing prechemotherapy anxiety.

Overshadowing as prevention of anticipatory nausea and vomiting in pediatric cancer patients: study protocol for a randomized controlled trial.

BACKGROUND: Emesis and nausea are side effects induced by chemotherapy. These effects lead to enormous stress and strain on cancer patients. Further consequences may include restrictions in quality of life, cachexia or therapy avoidance. Evidence suggests that cancer patients develop the side effects of nausea and vomiting in anticipation of chemotherapy. Contextual cues such as smell, sounds or even the sight of the clinic may evoke anticipatory nausea and vomiting prior to infusion. Anticipatory nausea and vomiting are problems that cannot be solved by administration of antiemetica alone.The purpose of the proposed randomized placebo-controlled trial is to use an overshadowing technique to prevent anticipatory nausea and vomiting and to decrease the intensity and duration of post-treatment nausea and vomiting. Furthermore, the effect on anxiety, adherence and quality of life will be evaluated. METHODS/DESIGN: Fifty-two pediatric cancer patients will be evenly assigned to two groups: an experimental group and a control group. The participants, hospital staff and data analysts will be kept blinded towards group allocation. The experimental group will receive during three chemotherapy cycles a salient piece of candy prior to every infusion, whereas the control group will receive flavorless placebo tablets. DISCUSSION: If an effectiveness of the overshadowing technique is proven, implementation of this treatment into the hospitals' daily routine will follow. The use of this efficient and economic procedure should aid a reduced need for antiemetics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30242271/

Anticipatory nausea and vomiting.

A commonly reported consequence of post-treatment nausea or vomiting is the development of anticipatory nausea and vomiting (ANV). In most published work, nausea is reported to occur before chemotherapy drugs are administered by approximately 20% of patients at any one chemotherapy cycle and by 25-30% of patients by their fourth chemotherapy cycle. Most studies in adult patients strongly support the view that the development of ANV involves elements of classical conditioning. The best method to avoid development of ANV is to adequately prevent both vomiting and nausea from the first exposure to chemotherapy. If anticipatory side effects develop, behavioral treatment techniques, such as systematic desensitization, have been shown effective. Benzodiazepines used in combination with behavioral techniques or antiemetics may also be useful. The evidence on which these conclusions are based is reviewed in this article.

[Analysis of adverse events of amrubicin hydrochloride for pretreated lung cancer patients].

Although amrubicin hydrochloride (AMR) has promising activity against pretreated lung cancer, there are few reports on the adverse events of this agent in a clinical practice setting. We analyzed the adverse events experienced in 27 hospitalized patients who had received AMR monotherapy by collecting data from the pharmaceutical management records. Neutropenia was the main hematological toxicity, and 77.8% of patients developed grade 3/4 neutropenia. Neutrophil counts reached the nadir in 9 to 21 (median 14) days and recovered to normal in 14 to 27 (median 20) days. Seven cases experienced febrile neutropenia without any serious sequelae. Grade 2 or worse non-hematological toxicities were fatigue, constipation, nausea, vomiting, anorexia, and pneumonitis. In comparison with the data of pre-marketing clinical trials, constipation was more commonly observed, while nausea/vomiting was less frequent probably due to appropriate preventive antiemetics. Based on these findings, we have created a novel drug information chart for patients and utilized it in pharmaceutical care in our hospital.

[The second report from Sapporo Tsukisamu hospital--chemotherapy for patients with advanced colorectal cancer].

The remedy,especially recent chemotherapy,against colorectal cancer is improving median survival time (MST) of patients with Stage IV advanced colorectal cancer. According to other reports,however,it seems to be difficult to improve it longer than 20 months. In May 2002, we devised a new regimen by intermittent dosage of 5-FU (-->S-1), CDDP and paclitaxel utilizing the difference of cell cycle between normal and cancer cells, and thirteen patients with advanced colorectal cancer (Stage IV) were treated with this regimen. As a result, a satisfactory efficacy rate of 53.8%, 1-year survival rate of 69 .2%, 2-year survival rate of 53.9%, 3-year survival rate of 44.9%, 5-year survival rate of 17.9%, and MST 36 months were achieved. Five patients had hematological toxicities over grade 3 (38.5%) and most of them were anemia (3 cases) and neutropenia (5 cases). Thrombocytopenia and gastroenterological toxicity were all under grade 2. Adverse effects related to this regimen were clinically manageable. These results, although for a limited number of patients, indicated that this may contribute to the extension of survival time of patients with Stage IV advanced colorectal cancer.

[Nedaplatin (NDP)-combination therapy (NDP/5-FU,NDP/S-1) for oral cancer].

PURPOSE: The present study evaluated the efficacy and safety of nedaplatin-combination therapy (NDP/5-FU [5-FU arm] or NDP/S-1 [S-1 arm] ) for the treatment of oral squamous cell carcinoma. PATIENTS AND METHOD: Previously non-treated oral squamous cell carcinoma patients were eligible. Patients received 5-FU 600 mg/m(2)iv, as a 24-hour infusion (day 1 to 5) followed by NDP 80 to 100 mg/m(2) iv (day 1), or S-1 60 to 80 mg/m(2) orally twice a day (day 1 to 14) followed by NDP 80 mg/m(2) iv (day 8) every 28 days for one or two cycles. RESULTS: In total, 32 patients (18 in the 5-FU arm, 14 in the S-1 arm) were enrolled. Twenty patients were male and 12 were female. Median age was 57 years (range 20 years to 87 years). Thirty-one patients had a performance status (PS) oF 0, and 1 patient had a PS 1. Three patients were stage I, 12 stage III, and 12 were stage IV. The overall response rate was 69% (5-FU arm,72%;S-1 arm,64%). Two patients achieved a complete response, 20 patients a partial response, and 10 patients had no change. Grade 3 leucopenia, grade 3 and 4 thrombocytopenia and liver injury occurred in 6% (one in the 5-FU arm, and one in the S-1 arm), 9% (two in the 5-FU arm, and one in the S-1 arm), and 3% (one in the 5-FU arm), respectively. No other severe toxicities were observed. RESULTS: Response rate and toxicities were similar in both arms. However, the psychosocial stress on patients in the S-1 arm was reduced compared to that in the 5-FU arm, which required hospitalization for a longer period. The outcome in the present study needs further investigation.

[Chemotherapy for elderly patients with colorectal cancer].

The number of elderly patients with colorectal cancer is increasing in Japan. Until recently, chemotherapy was not adapted for older patients. Today, older patients have opportunity to receive new regimen with newly developed agents and improvement of supportive therapy. UFT/leucovorin therapy has been shown to be as effective and equally tolerated in elderly patients as in younger patients. There is no difference between older and younger patients in efficacy and toxicity of FOLFOX 4 (oxaliplatin plus 5-FU and leucovorin) Bevacizumab with 5-FU and leucovorin is also tolerable and effective for elderly patients. It is necessary to evaluate the possibility of new molecular target agents for treatment for super-elderly patients (>80 years). Increasing cost of the new agents will pose economical problem to resolve specially for older population.

Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer.

BACKGROUND: In this non-randomized study we aimed to assess the efficacy of the addition of low molecular weight heparin (LMWH) to gemcitabine (GEM) plus cisplatinum (CDDP) combination chemotherapy on survival by prevention of thromboembolic complications in patients with advanced pancreatic cancer (APC). PATIENTS AND METHODS: Between November 1999 and February 2004, 69 consecutive patients with APC were treated with GEM (800 mg/m2, day 1, day 8) plus CDDP (35 mg/m2, day 1, day 8) every 21 days +/-LMWH (nadroparine calcium, 2,850 IU/day until disease progression). Ten out of 35 patients in LMWH group and 10 out of 34 patients in chemotherapy alone group had primary inoperable locally advanced disease and the rest of the patients had metastatic disease. RESULTS: Total response rate was 58.8% (11.7% CR) for the patients treated with LMWH and 12.1% for those treated without LMWH (P = 0.0001). LMWH group had a better median time to progression (TTP) and survival when compared to control group (7.3 vs. 4.0 months, P = 0.0001; 13.0 vs. 5.5 months, P = 0.0001). The toxicity was similar and acceptable in both groups. CONCLUSION: Addition of LMWH to GEM plus CDDP combination significantly improved the response and survival in patients with APC and the current schedule deserves to be tested in phase III trials.

[A feasibility study of doxorubicin/cisplatin (AP) for postoperative chemotherapy in patients with advanced endometrial cancer].

OBJECTIVE: We evaluated the feasibility of doxorubicin/cisplatin (AP) for postoperative chemotherapy in patients with advanced endometrial cancer. METHODS: Patients with newly diagnosed advanced endometrial cancer received AP (doxorubicin 60 mg/m(2), cisplatin 50 mg/m(2)) every 3 weeks. Treatment was continued until disease progression or completion of 6 courses. Toxicities were evaluated every cycle according to NCI-CTCAE Ver.3.0. RESULTS: Fifteen patients were enrolled from April 2004 through December 2005. All patients successfully completed therapy. There were two patients who needed dose reduction and nine patients with prolongation of treatment interval. Patients with over Grade 3/4 toxicity were observed to have leucopenia (47%), neutropenia (67%), anemia (26%), and vomiting (13%). No grade 3/4 cardiac and renal failure were observed. CONCLUSIONS: The doxorubicin/cisplatin (AP) regimen is tolerated and can be safely given without severe toxicity.

[Adjuvant doxorubicin and cyclophosphamide followed by weekly paclitaxel for Japanese women with node-positive breast cancer: a multi-institutional feasibility study in a variety of practice settings in Kyushu].

We evaluated the feasibility of doxorubicin plus cyclophosphamide (AC) followed by weekly paclitaxel (wT) as adjuvant therapy for node-positive breast cancer in a variety of practice settings. Forty-seven patients received AC at either doses of 40 mg/m(2)+400 mg/m(2) (A(40)C(400), 33 patients) or 50 mg/m(2)+500 mg/m(2) (A(50)C(500), 14 patients) every 3 weeks for 4 cycles followed by wT at a dose of 80 mg/m(2)for 12 cycles with a week pause after 3 consecutive weekly administrations. Mean relative dose-intensities were 98.8% for A(40)C(400), 90.7% for wT after A(40)C(400), 91.3% for A(50)C(500), and 89.2% for wT after A(50)C(500). Grade 4 toxicity included neutropenia (3.0% for A(40)C(400), 14.3% for A(50)C(500)). Grade 3 toxicity included neutropenia (18.2% for A(40)C(400), 28.6% for A(50)C(500), 6.7% for wT), thrombocytopenia (2.2% for wT), nausea/vomiting (6.1% for A(40)C(400)), anorexia (3.0% for A(40)C(400), 2.2% for wT), fatigue (3.0% for A(40)C(400)), AST/ALT elevation (7.1% for A(50)C(500)), allergic reaction (4.4% for wT). There were six (12.8%) treatment discontinuations, including two allergic reactions to paclitaxel. AC followed by wT can be administered safely in the community at doses of 50 mg/m(2), 500 mg/m(2), and 80 mg/m(2), respectively,with minimal toxicity.

[A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting].

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.

[Two cases of advanced pancreatic cancer with cervical lymph node or liver metastasis responding well to S-1 monotherapy].

In two patients with advanced pancreatic cancer with cervical lymph node or liver metastasis and no indication of pancreatic resection and radiotherapy, oral treatment with S-1 (an anti-cancer agent of fluoropyrimidine derivative) exerted high anti-tumor activity on the metastatic lesions. Both cases responded well to this therapy in the late phase II study of S-1 in patients with advanced pancreatic cancer designed to evaluate efficacy and safety. In Case 1 (with cervical lymph node metastasis), the anti-tumor efficacy of this therapy was evaluated as a partial response (PR) after the first four courses of treatment. In Case 2 (with liver metastasis), the efficacy was evaluated as PR for overall response. Thus, the therapy indicated excellent efficacy in both cases. No grade 3 or severe adverse event was noted in either of the two cases. In Case 1, grade 2 anemia, stomatitis, vomiting and fatigue, and some other mild events were noted. When used as a systemic chemotherapy for metastatic pancreatic cancer, oral treatment of S-1 is highly effective, tolerable and convenient in an outpatient clinic. This drug is a promising way to improve and preserve the QOL essential to long-term home care.

[Combination chemotherapy with S-1 plus CPT-11 for patients with advanced or recurrent colorectal cancer].

Various kinds of combination chemotherapies with 5-FU as a base agent have been performed for patients with advanced or recurrent colorectal cancer. S-1 was a newly developed 5-FU derivative and was orally administered. One of the combination therapies with S-1 plus irinotecan (CPT-11) has also been expected to have a better therapeutic value. Recently this combination therapy has been undertaken by our department, and its clinical use and toxicities are described in this article.

Cochrane systematic reviews examine P6 acupuncture-point stimulation for nausea and vomiting.

BACKGROUND: In 1998, the National Institutes of Health Consensus Statement on Acupuncture concluded that promising results have emerged showing the efficacy of acupuncture in adult postoperative and chemotherapy induced nausea and vomiting. The acupuncture point, P6 had been the point used in most of the trials. OBJECTIVES: To summarize Cochrane systematic reviews assessing P6 stimulation for nausea and vomiting. RESULTS: Reviews were found on postoperative sickness, chemotherapy-induced nausea and vomiting, and pregnancy-related nausea and vomiting. Results for postoperative nausea and vomiting show the most consistent results with 26 trials and more than 3000 patients showing the superiority of real P6 stimulation over sham for both adults and children and for both nausea and vomiting. Pooled data of trials including different antiemetics showed that P6 stimulation seems to be superior to antiemetic medication for nausea and equivalent for vomiting. P6 stimulation was similarly effective across the different methods of stimulation, both invasive or noninvasive. Results for chemotherapy-induced nausea and vomiting showed 11 trials and over 1200 patients. Electroacupuncture, but not manual acupuncture, was beneficial for first-day vomiting. Acupressure was effective for first-day nausea but not vomiting. Wristwatch-like electrical devices were not effective for any outcome. Results for pregnancy-related nausea and vomiting comprised six trials and approximately 1150 patients. Results were mixed with some trials showing positive and other trials equivocal results with no favor to a certain kind of method. CONCLUSIONS: P6 stimulation may be beneficial for various conditions involving nausea and vomiting. The added value to modern antiemetics remains unclear. In patients on chemotherapy, future research should focus on patients for whom the problems are refractory. The next steps in research should include investigating whether acupuncture points added to P6 or individualizing treatment based on a Traditional Chinese Medicine diagnosis increases treatment effectiveness. It would also be worthwhile to identify predictors of response across the different conditions so that the individual patients can optimize acupuncture point therapy.

[Complete response to CPT-11 and UFT/LV combination therapy in a case with simultaneous multiple lung metastases from colon cancer].

We report the complete response for one year of a patient with simultaneous multiple lung metastases from colon cancer who was treated using a combination of irinotecan (CPT-11) and uracil/tegafur (UFT)/Leucovorin (LV) using a schedule reported overseas. A 61-year-old woman was admitted to our hospital and diagnosed with ascending colon cancer and simultaneous multiple lung metastases. The patient underwent a right hemicolectomy and was treated with CPT-11 (150 mg/m(2)) on day 1 and oral UFT and oral LV on days 1-14. This treatment cycle was repeated every 3 weeks. A CT examination after 4 cycles of chemotherapy revealed a partial response of multiple lung metastases, and the next examination after 6 cycles revealed a complete response. The adverse effects observed during this chemotherapy regimen were leucopenia (grade 1), neutropenia (grade 2), vomiting (grade 2) and hair loss (grade 1). The patient is now receiving her 22nd cycle of chemotherapy, and her multiple metastases have shown a complete response for one year. The CPT-11 and UFT/LV combination therapy was well tolerated and was covered by the national health insurance system in Japan. This treatment may enable prolonged survival and improve quality of life in patients with metastatic colorectal cancer.

[Clinical examination of safety and effectiveness of primary chemotherapy with CEF followed by docetaxel in preoperative breast cancer].

SUBJECTS: The subjects were patients with resectable breast cancer who visited our department between August 2003 and November 2004, did not have any other risk factors defined in the St. Gallen Consensus Conference,and were receptor-negative or had axillary lymph node metastasis. METHODS: The histological type, ER, PgR, HER2, and histological grade were evaluated by needle biopsy. Four courses of CEF (5-FU: 500 mg/m(2)+EPI: 75 mg/m(2)+CPA: 500 mg/m(2)) were performed at 3-week intervals, followed by 4 courses of Docetaxel (70 mg/m(2)). RESULTS: Treatment was performed in 14 patients including a male. Their age ranged from 37 to 69 years (mean, 55.3 years). Stage IIA was observed in 5 patients, IIB in 4, IIIA in 1, and IIIB in 4. In patients with Grade 3 or more, leukocytopenia was observed in 7 patients and diarrhea in 1 as adverse events. CR was obtained in 6 patients, PR in 5, and NC in 3 (response rate, 78.5%). Pathological examination showed pCR in 1 patient and pPR in 10 (response rate, 78.5%). Of the 10 patients with pPR, 2 showed a state near pCR. DISCUSSION: Our results showed the safety and effectiveness of preoperative chemotherapy with CEF followed by Docetaxel.

[Method of levofolinate.5-FU administration by hepatic arterial infusion therapy for hepatic metastasis from colorectal cancer].

Hepatic arterial infusion chemotherapy with levofolinate (l-leucovorin) and fluorouracil regimen was performed using an implanted port system on unresectable hepatic metastasis patients with colorectal cancer. A comparative study was performed on two groups in which the levofolinate was administered arterially or intravenously. Levofolinate 200-250 mg/m(2) was infused for two hours intra-arterially or intravenously, and 5-FU 400-600 mg/m(2) was administered as a bolus in midinfusion. The regimen was repeated weekly for six weeks, followed by no medication for two weeks. Six patients were administered intra-arterially and 7 patients intravenously. The response rate was higher in the group in which levofolinate was given intravenously. The adverse effect was lower in the former than in the latter group. When 5-FU and levofolinate was performed using an implanted port system, it seemed better to administer levofolinate intravenously.