A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial.

BACKGROUND: Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles. RESULTS: A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. CONCLUSION: Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. CLINICAL TRIAL NUMBER: UMIN000000608.

Feasibility trial for adjuvant chemotherapy with docetaxel plus cisplatin followed by single agent long-term administration of S-1 chemotherapy in patients with completely resected non-small cell lung cancer: Thoracic Oncology Research Group Study 0809.

BACKGROUND: We conducted a multicentre feasibility study for single agent long-term S-1 chemotherapy following docetaxel plus cisplatin in patients with curatively resected stage II-IIIA non-small cell lung cancer. METHODS: Patients received three cycles of docetaxel (60 mg m(-2)) plus cisplatin (80 mg m(-2)) and then received S-1 (40 mg m(-2) twice daily) for 14 consecutive days with a 1-week rest for >6 months (maximum, 1 year). The primary end point was feasibility, which was defined as the proportion of patients who completed eight or more cycles of S-1 chemotherapy. If the lower 95% confidence interval (CI) of this proportion was 50% or more, then the treatment was considered as feasible. The sample size was set at 125 patients. RESULTS: One hundred and thirty-one patients were enrolled, of whom 129 patients were eligible and assessable. In all, 109 patients (84.5%) completed 3 cycles of docetaxel plus cisplatin and 66 patients (51.2%, 95% CI: 42.5-59.8) completed 8 or more cycles of S-1 treatment. Grade 3/4 toxicities during the S-1 chemotherapy included anaemia (7.3%), neutropaenia (3.7%), and anorexia (3.7%). CONCLUSION: The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule for S-1 chemotherapy might improve the treatment compliance.

A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606).

BACKGROUND: This study aimed to evaluate the safety and efficacy of dose-dense weekly chemotherapy, followed by resection and/or thoracic radiotherapy. METHODS: Patients with histologically documented thymoma with unresectable stage III disease received 9 weeks of chemotherapy: cisplatin 25 mg m(-2) on weeks 1-9; vincristine 1 mg m(-2) on weeks 1, 2, 4, 6 and 8; and doxorubicin 40 mg m(-2) and etoposide 80 mg m(-2) on days 1-3 of weeks 1, 3, 5, 7 and 9. Patients went on to surgery and post-operative radiotherapy of 48 Gy; those with unresectable disease received 60 Gy radiotherapy. RESULTS: total of 23 patients were entered. The main toxicities of the chemotherapy regimen were neutropenia and anaemia, and 57% of patients completed the planned 9 weeks of therapy. There were no toxic deaths. Of the 21 eligible patients, 13 (62%) achieved a partial response (95% confidence interval: 38-82%). Thirteen patients underwent a thoracotomy and nine (39%) underwent complete resection. Progression-free survival at 2 and 5 years was 80 and 43%, respectively. Overall survival at 5 and 8 years was 85 and 69%, respectively. Survival did not seem to be affected by resection. CONCLUSION: In thymoma patients, weekly dose-dense chemotherapy has activity similar to that of conventional regimens. Although some patients could achieve complete resection, the role of surgery remains unclear.

A randomised trial of intrapericardial bleomycin for malignant pericardial effusion with lung cancer (JCOG9811).

Safety and efficacy of intrapericardial (i.p.c.) instillation of bleomycin (BLM) following pericardial drainage in patients with malignant pericardial effusion (MPE) remain unclear. Patients with pathologically documented lung cancer, who had undergone pericardial drainage for MPE within 72 h of enrolment, were randomised to either arm A (observation alone after drainage) or arm B (i.p.c. BLM at 15 mg, followed by additional i.p.c. BLM 10 mg every 48 h). The drainage tube was removed when daily drainage was 20 ml or less. The primary end point was survival with MPE control (effusion failure-free survival, EFFS) at 2 months. Eighty patients were enrolled, and 79 were eligible. Effusion failure-free survival at 2 months was 29% in arm A and 46% in arm B (one-sided P=0.086 by Fisher's exact test). Arm B tended to favour EFFS, with a hazard ratio of 0.64 (95% confidence interval: 0.40-1.03, one-sided P=0.030 by log-rank test). No significant differences in the acute toxicities or complications were observed. The median survival was 79 days and 119 days in arm A and arm B, respectively. This medium-sized trial failed to show statistical significance in the primary end point. Although ipc BLM appeared safe and effective in the management of MPE, the therapeutic advantage seems modest.

Characteristics and outcomes of patients with advanced non-small-cell lung cancer who declined to participate in randomised clinical chemotherapy trials.

There are inadequate data on the outcomes of patients who declined to participate in randomised clinical trials as compared with those of participants. We retrospectively reviewed the patient characteristics and treatment outcomes of both participants and non-participants in the two randomised trials for chemotherapy-naive advanced non-small-cell lung cancer. Trial 1 compared four platinum-based combination regimens. Trial 2 compared two sequences of carboplatin plus paclitaxel and gefitinib therapies. Nineteen of 119 (16%) and 153 (37%) patients declined to participate in Trials 1 and 2, respectively. Among the background patient characteristics, the only variable associated with trial participation or declining was the patients' attending physicians (P<0.001). Important differences were not observed in the clinical outcomes between participants and non-participants, for whom the response rates were 30.6 vs 34.2% and the median survival times were 489 vs 461 days, respectively. The hazard ratio for overall survival, adjusted for other confounding variables, was 0.965 (95% confidence interval: 0.73-1.28). In conclusion, there was no evidence to suggest any difference in the characteristics and clinical outcomes between participants and non-participants. Trial designs and the doctor-patient relationship may have an impact on the patient accrual to randomised trials.

A phase-II trial of dose-dense chemotherapy in patients with disseminated thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9605).

BACKGROUND: To evaluate the safety and efficacy of dose-dense weekly chemotherapy in the treatment of advanced thymoma. METHODS: Subjects comprised patients with histologically documented chemotherapy-naïve thymoma with stage-IVa or IVb disease. Thymic carcinoma, carcinoid or lymphoma cases were excluded. Patients received 9 weeks of chemotherapy: cisplatin (25 mg m(-2)) on weeks 1-9; vincristine (1 mg m(-2)) on weeks 1, 2, 4, 6 and 8; and doxorubicin (40 mg m(-2)) and etoposide (80 mg m(-2)) on days 1-3 of weeks 1, 3, 5, 7 and 9. Chemotherapy courses were supported by granulocyte colony-stimulating factor. Post-protocol local therapy was allowed. RESULTS: From July 1997 to March 2004, 30 patients were entered. Three were ineligible due to different histology. Chemotherapy-associated toxicity was mainly haematological and was well tolerated, with no deaths due to toxicity, and 87% of patients completed the planned 9-week regimen. Overall response rate was 59%, with 16 of the 27 eligible patients achieving partial response. Median progression-fee survival (PFS) was 0.79 years (95% confidence interval: 0.52-1.40 years), and PFS at 1 and 2 years was 37 and 15%, respectively. Overall survival rates at 2 and 5 years were 89 and 65%, respectively. CONCLUSION: In stage-IV thymoma patients, weekly dose-dense chemotherapy offers similar activity to conventional regimens.

Phase I/II and pharmacologic study of long-term continuous infusion etoposide combined with cisplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: The primary objective of this study was to determine the pharmacodynamics of prolonged administration of low-dose etoposide by continuous infusion (CI). We investigated the hypothesis that maintenance of an etoposide concentration of 1 microgram/mL would be cytotoxic in non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty patients with advanced NSCLC without prior chemotherapy or radiotherapy were treated with etoposide at 20, 25, or 30 mg/m2/d infused continuously for 14 days (336 hours), following a 10-mg/m2 bolus. They also received cisplatin 30 mg/m2 on chemotherapy days 1, 2, and 3. Plasma concentrations of etoposide were measured by high-performance liquid chromatography at 0, 2, 4, 24, 48, 120, 336, and 342 hours after initiation of CI etoposide. RESULTS: The maximum-tolerated dose (MTD) of etoposide was 25 mg/m2/d with leukocytopenia as the dose-limiting toxicity. Plasma concentrations of etoposide at steady-state (Css) showed approximately twofold interpatient variability at each dose level, and were greater than 1 microgram/mL in most patients at higher dose levels. The severity of neutropenia was dependent on performance status (PS), age, and the Css of etoposide. The overall response rate for the 29 assessable cases was 28%. Five of 11 patients with a Css greater than 1.2 micrograms/mL responded to the therapy, whereas only one of 10 patients with a Css less than 1 microgram/mL responded. CONCLUSION: With long-term CI of etoposide, a Css greater than 1 or 1.2 micrograms/mL appeared necessary, but not sufficient, to achieve a major response against NSCLC.

Phase II trial of docetaxel in previously untreated advanced non-small-cell lung cancer: a Japanese cooperative study.

PURPOSE: This phase II study was conducted to evaluate the efficacy and toxicity of moderate-dose (60 mg/m2) docetaxel in Japanese patients with previously untreated advanced (stage IIIB or IV) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Docetaxel 60 mg/m2 was administered intravenously over 1 to 2 hours to patients with previously untreated stage IIIB or IV NSCLC. Treatment was repeated every 3 weeks. No routine premedication was given. The patients' median age was 67 years (range, 40 to 80). Forty-four patients (59%) had adenocarcinoma and 55 (73%) had stage IV disease. The median Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 1. RESULTS: Seventy-five patients were eligible and treated with docetaxel. Fourteen patients (19%) achieved a partial response (PR); response was not significantly affected by histology or clinical stage. The median survival time for all patients was 297 days. The predominant toxicity was neutropenia, with 87% of patients experiencing grade 3 or 4. Febrile neutropenia was seen in eight patients. Hypersensitivity and edema each occurred in only 4% of patients and were easily manageable. There was no possible treatment-related death of acute exacerbation of pneumonitis. CONCLUSION: Docetaxel 60 mg/m2 showed significant activity in advanced NSCLC, with a low incidence of hypersensitivity or peripheral edema. Further investigation of this agent in NSCLC is warranted, especially in combination with other active drugs.

Correlation between docetaxel clearance and estimated cytochrome P450 activity by urinary metabolite of exogenous cortisol.

PURPOSE: There is no simple and practical method for the estimation of the interpatient variability of cytochrome P450 (CYP3A4) enzyme activity. Cortisol is metabolized by this enzyme and excreted as 6-beta-hydroxycortisol (6beta-OHF) and free-cortisol (FC) in urine, and docetaxel is also metabolized by hepatic CYP3A4 enzyme. We developed a new method for the estimation of CYP3A4 activity by measuring urinary cortisol metabolite after administration of exogenous cortisol. This study was aimed at assessing the predictability of the individual activity of CYP3A4 estimated by this method. PATIENTS AND METHODS: Thirty patients with advanced non-small-cell lung cancer were entered onto this study. Hydrocortisone 300 mg was administered intravenously, and urinary 6beta-OHF and FC were measured. More than 2 days later, 60 mg/m(2) of docetaxel was administered intravenously with pharmacokinetic sampling. The correlation between docetaxel pharmacokinetics and estimated interpatient variability of CYP3A4 activity with the application of our method was assessed. RESULTS: After cortisol administration, the total amount of 24-hour urinary 6beta-OHF (T6beta-OHF) increased about 60-fold compared with pretreatment levels, averaging 12,273 +/- 4,076 microg/d (mean +/- SD). Docetaxel clearance (CL) and area under the concentration-time curve averaged 24.5 +/- 6.4 L/h/m(2) and 2.66 +/- 0.91 mg/L 8729. h, respectively. An excellent correlation between docetaxel CL and T6beta-OHF was observed (r =.867). In multivariate analysis, T6beta-OHF (P <.001), alpha-1-acid glycoprotein (P <.004), AST (P =.007), and age (P =. 022) significantly correlated with docetaxel CL. CONCLUSION: The interpatient variability of CYP3A4 activity and docetaxel CL could be predicted by measuring T6beta-OHF after cortisol administration.

Lower incidence of Bronchiolitis obliterans in allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning compared with myeloablative conditioning.

Bronchiolitis obliterans (BO) is one of the most devastating complications after allogeneic stem cell transplantation (HSCT). However, its true pathogenesis is still to be elucidated. We conducted this study to find whether tissue damage due to high-dose chemo-radiotherapy is related to its pathogenesis. In all, 144 patients who received allogeneic HSCT between May 1999 and October 2001, and survived more than 80 days after transplant, were analyzed. Clinical course, pulmonary function tests, imaging studies including CT scan, and pathology results were reviewed. The overall incidence of BO was 9.7% (14/144). The cumulative incidence of BO at 2 years after transplant was 17% with myeloablative conditioning, and 2.3% with reduced intensity conditioning (P=0.024). Multivariate analysis showed that myeloablative conditioning was the only factor which affected the incidence of BO. Development of BO did not significantly affect the overall survival of patients. However, if they developed BO earlier than 200 days post transplant, the prognosis was significantly worse than if they developed it later than 200 days post transplant (P=0.003) or if they did not develop BO (P=0.002). Our results imply that tissue damage secondary to intensive chemo-radiotherapy may contribute to the pathogenesis of BO.

Concurrent daily carboplatin and accelerated hyperfractionated thoracic radiotherapy in locally advanced nonsmall cell lung cancer.

PURPOSE: This study was designed to evaluate the feasibility and efficacy of accelerated hyperfractionated thoracic radiotherapy concurrently combined with daily carboplatin in patients with locally advanced, unresectable nonsmall cell lung cancer. METHODS AND MATERIALS: Thirty-one patients with locally advanced nonsmall cell lung cancer were treated with continuous course, twice daily thoracic radiotherapy (1.5 Gy each) to a total of 60 Gy over 4 weeks. Carboplatin (25 mg/m2) i.v. was given immediately before each morning thoracic radiotherapy. Blood samples were taken to measure the blood free platinum pharmacokinetics on day 1. RESULTS: All 31 patients completed the protocol treatment without delay. The median age was 73 years, and the majority had Stage IIIA (32%) or IIIB (48%) disease. Major acute toxicity (> or = Grade 3) included 17 patients (55%) with leukopenia, 5 patients (16%) with thrombocytopenia, and 7 patients (23%) with esophagitis. One possible treatment-related death due to diffuse pneumonitis was observed. There were three complete responses (CRs) and 23 partial responses (PRs) in the radiation field, for a response rate of 84%. The relapse pattern was predominantly loco-regional, and the median survival time was 9.8 months. The area under the plasma level-time curve (AUC) of free platinum correlated significantly (r = -0.41, p = 0.04) with the surviving fraction of leukocytes, but not with the severity of the esophagitis. Responders had significantly (p = 0.04 by Welch's t-test) higher AUCs than nonresponders. CONCLUSIONS: This combination therapy was feasible and efficacious against locally advanced nonsmall cell lung cancer. Although long-term local control still remains unsatisfactory, pharmacokinetic data are suggestive of a role for platinum in enhancing the radiation effect.

Radiation pneumonitis in lung cancer patients: a retrospective study of risk factors and the long-term prognosis.

PURPOSE: To retrospectively evaluate the risk factors for acute radiation pneumonitis (RP) and long-term prognosis of patients with lung cancer treated by thoracic radiotherapy. METHODS AND MATERIALS: Of the 256 lung cancer patients who underwent definitive thoracic radiotherapy between June 1988 and May 1998, the 191 patients who were capable of being evaluated were divided into three groups according to the grade of RP. RP was defined as "severe," when it caused severe clinical symptoms, such as intractable cough, dyspnea at rest, and the need for oxygen or steroid therapy. The definition was made by using a modification of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer acute radiation morbidity scoring criteria. Factors that influenced the incidence of severe RP were assessed by using the Mantel-Haenszel chi(2) test in the univariate analysis and the logistic regression test in the multivariate analysis. Survival rates was calculated by using the Kaplan-Meier method, and the p values indicating the significance of differences between the RP groups were calculated by the log-rank test. RESULTS: Of the 94 patients (49%) who experienced clinical RP in this study, the RP was mild in 69 (36%) and severe in 25 (13%) patients. The 3-year survival rates of the patients who experienced no, mild, and severe RP were 33.4%, 38.2%, and and 0%, respectively, and the survival rate of the patients who experienced severe RP was significantly poorer than the other two groups combined (p = 0.0028). The incidence of severe RP did not correlate with any of the baseline patient characteristics, radiotherapeutic factors, or chemotherapeutic variables. Two clinical risk factors were identified from medical records before radiotherapy: low PaO2 (< 80 torr) and high C-reactive protein (CRP) (> 1.0 ng/mL). Both of them were significantly related to the development of severe RP in the univariate analysis (p = 0.004 and 0.013, respectively), and low PaO2 remained a significant risk factor in the multivariate analysis (p = 0.034). Multivariate analysis also revealed the occurrence of severe RP to be the most important factor determining poor survival (p = 0.0065). There was no significant difference in survival rate according to whether the patients had been treated with corticosteroids. CONCLUSION: Mild and severe RP occurred in 69 (36%) and 25 (13%), respectively, of 191 lung cancer patients who had undergone irradiation of the chest. Only severe RP was an adverse prognostic factor. Low PaO2 (< 80 torr) before radiotherapy was a significant risk factor predictive of severe RP. The role of corticosteroids in RP could not be accurately determined.

A randomized controlled trial of sulfamethoxazole/trimethoprim plus norfloxacin versus sulfamethoxazole/trimethoprim alone for the prophylaxis of bacteria infection during chemotherapy for lung cancer.

The efficacy of the prophylactic administration of sulfamethoxazole/trimethoprim (ST) plus norfloxacin (NFLX) versus ST alone to prevent the development of bacterial infection during chemotherapy-induced leukopenia was compared in patients with lung cancer. Patients who underwent systemic chemotherapy were randomized into one of the prophylactic regimens when grade 3 or 4 leukopenia occurred. Prophylactic treatment was performed on 133 courses of leukopenia in 75 patients and the efficacy was evaluated on 127 of those courses after excluding those patients who demonstrated a fever within 24 h from the start of the prophylaxis. The number of patients who had leukopenia associated fever was two out of 63 (3.2%) with the ST plus NFLX regimen and 10 out of 64 (15.6%) with ST alone; the difference was statistically significant. The prophylactic use of ST plus NFLX was thus found to be more useful than ST alone for the treatment of chemotherapy-induced leukopenia in patients with lung cancer.

A phase I/II trial of cisplatin, docetaxel and ifosfamide in advanced or recurrent non-small cell lung cancer.

This trial was initiated to evaluate the toxicity and activity of combination chemotherapy employing cisplatin (CDDP), docetaxel (DCT) and ifosfamide (IFX) in non-small cell lung cancer (NSCLC), and to determine the maximum tolerated dose (MTD) of IFX. Chemotherapy-naive patients with advanced or recurrent NSCLC received 60 mg/m(2) DCT followed after a 3-h interval by 60 mg/m(2) CDDP on chemotherapy day 1, and IFX at an escalating dose with mesna protection on days 2-4. The chemotherapy was repeated every 3 weeks. Granulocyte colony-stimulating factor (GCSF) was administered in the event of grade 3 leukopenia/neutropenia. The patients tolerated the treatment well up to level 4 of IFX dosing 1.5 g/day, but not the IFX dose at level 6 (2.0 g/day). Additional patients were enrolled in level 5 (IFX 1.7 g/day) to evaluate the toxicity of the drugs around the MTD. Level 5 was also judged as having exceeded the MTD, with febrile neutropenia and hepatic toxicity being observed as the dose-limiting toxicities. No toxicity-related deaths occurred. The majority of the chemotherapy courses were supported by GCSF administration. A total of 33 eligible patients were entered into the trial; the overall response rate was 10/33 or 30% among all eligible cases, and the rate for patients treated with the MTD or higher (levels 4-6) was 8/24, or 33% (90% confidence limit: 18-52%). The MTD of IFX was 1.5 g/m(2) administered for 3 days in this triplet combination. The clinical activity does not seem to justify the toxicity profile.

Suspected delayed immune recovery against cytomegalovirus after reduced-intensity stem cell transplantation using anti-thymocyte globulin.

A reduced-intensity hematopoietic stem cell transplantation (RIST) regimen was developed to induce immunosuppression to facilitate the engraftment of donor cells. However, there have been concerns that the incidence of opportunistic infection may increase after this procedure. To address this problem, we retrospectively analyzed the medical records of 24 RIST recipients who were treated over a recent 16-month period for comparison with 31 recipients of conventional allogeneic transplantation (CST). The RIST regimen consisted of cladribine (0.66 mg/kg), busulfan (8 mg/kg), and rabbit anti-thymocyte globulin (ATG; 5-10 mg/kg). All of the patients received allogeneic peripheral blood stem cells from an HLA-identical or one-locus mismatched related donor. Although the incidence of positive CMV antigenemia was comparable between the two groups (58% vs 68%), RIST patients developed positive antigenemia significantly sooner than did CST patients (P = 0.01) and showed higher initial and maximum antigenemia values (P = 0.026 and P = 0.003, respectively). These findings may suggest that immune recovery against CMV was delayed after our RIST procedure, but this did not directly translate into an increase in clinically significant CMV disease. Early therapeutic intervention with ganciclovir might play a role in preventing the progression of early CMV infection to CMV disease.

Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan.

From April 1998 to March 2000, a cytomegalovirus (CMV) antigenemia-guided pre-emptive approach for CMV disease was evaluated in 77 adult patients who received allogeneic hematopoietic stem cell transplantation at the National Cancer Center Hospital. A CMV antigenemia assay was performed at least once a week after engraftment. High-level antigenemia was defined as a positive result with 10 or more positive cells per 50 000 cells and low-level antigenemia was defined as less than 10 positive cells. Among the 74 patients with initial engraftment, 51 developed positive antigenemia. Transplantation from alternative donors and the development of grade II-IV GVHD were independent risk factors for positive antigenemia. Ganciclovir was administered as pre-emptive therapy in 39 patients in a risk-adapted manner. None of the nine low-risk patients with low-level antigenemia as their initial positive result developed high-level antigenemia even though ganciclovir was withheld. Only one patient developed early CMV disease (hepatitis) during the study period. CMV antigenemia resolved in all but two cases, in whom ganciclovir was replaced with foscarnet. In eight patients, however, the neutrophil count decreased to 0.5 x 10(9)/l or less after starting ganciclovir, including three with documented infections and two with subsequent secondary graft failure. The total amount of ganciclovir and possibly the duration of high-dose ganciclovir might affect the incidence of neutropenia. We concluded that antigenemia-guided pre-emptive therapy with a decreased dose of ganciclovir and response-oriented dose adjustment might be appropriate to decrease the toxicity of ganciclovir without increasing the risk of CMV disease.

Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae.

PURPOSE: Carboplatin doses can be individualized using the formula of Calvert et al. (Calvert formula) dose (mg) = area under the plasma concentration versus time curve (AUC) x [glomerular filtration rate (GFR) + 25]. Creatinine clearance (Ccr), either measured by the 24-h method or calculated by the formula of Cockcroft and Gault [Cockcroft-Gault (CG) formula], is often substituted for the GFR. The CG formula is based on patient weight, age and sex, and the serum creatinine (Cr) concentration. Another method for predicting carboplatin clearance (CL) using patient characteristics has also been proposed by Chatelut et al. (Chatelut formula). This study was undertaken to evaluate the performance of the three formulae in predicting standard- and low-dose carboplatin pharmacokinetics. METHODS: A total of 52 patients with advanced lung cancer were enrolled in this pharmacokinetic study; 37 received standard-dose carboplatin and 25 received low-dose carboplatin. The Cr concentration was measured using an enzymatic assay. The three formulae were used to predict carboplatin CL. The median absolute percent error (MAPE) for each formula was evaluated by comparing the calculated and observed CL. For comparison of AUCs, free platinum plasma concentrations were measured at intervals up to 24 h after carboplatin administration. AUCs were determined and compared with predicted values. RESULTS: In the standard-dose carboplatin group, the MAPEs for the prediction of carboplatin CL from the 24-h Calvert, CG-Calvert and Chatelut formulae were 13%, 12% and 23%, respectively. In the low-dose carboplatin group, the corresponding MAPEs were 27%, 18% and 44%, respectively. Observed standard-dose carboplatin AUCs after aiming for target AUCs of 5 and 6 mg x min/ml using the Calvert formula based upon the 24-h Ccr were 5.3+/-0.8 and 5.9+/-0.8, respectively, indicating a small and acceptable bias compared with that predicted from the dosing formula. CONCLUSIONS: The pharmacokinetics of standard-dose carboplatin were accurately predicted by the Calvert formula based upon either 24-h or CG-calculated Ccr, but not by the Chatelut formula. Either CG-calculated or 24-h Ccr can be substituted for the GFR in the Calvert formula for the determination of individual doses. The poor predictability of the Chatelut formula found in this study might be the result of a differences in either the Cr assay or the patient population. Therefore, formulae which attempt to estimate GFR are not necessarily valid if either the Cr assay or the patient population is changed.

[Pulmonary leiomyoma: a case report].

A case of pulmonary leiomyoma is presented. A 61-year-old asymptomatic woman underwent surgical resection of the lung for definite diagnosis of abnormal shadow on chest X-ray. Her history was hysterectomy and bilateral salpingo-oophorectomy performed 25 years previously because of uterine myoma. Histologic findings of pulmonary lesion was leiomyoma, and nuclear atypia and mitotic figures were not found. Pulmonary smooth muscle neoplasms are exceptionally rare. We review pulmonary leiomyoma reported in the Japanese literature, and also discuss the diagnostic problems in relation to metastasizing leiomyoma of the uterus.