Multicenter Phase 2 Trial of Gemcitabine,Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma

Background

Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma.

Effective clearance of Ara-U the major metabolite of cytosine arabinoside (Ara-C) by hemodialysis in a patient with lymphoma and end-stage renal failure

Purpose

We report that hemodialysis clears Ara-U from the blood after high-dose Ara-C treatment in a patient with lymphoma and end-stage renal failure.

Methods

The patient received two doses of Ara-C 1?g/m² 24?h apart and was hemodialyzed at about 6?h after each dose and subsequently as per her usual dialysis schedule. Multiple blood samples were collected after dosing. Blood and dialyzate were also collected from the dialysis circuit during a second identical treatment cycle. Ara-C and its metabolite Ara-U in plasma and dialyzate were measured chromatographically, and the data subjected to pharmacokinetic analysis.

Results

The distribution and elimination half-lives, steady-state volume of distribution and clearance values were 0.5?h, 7?h, 181 L and 307?l/h for Ara-C and 4.1?h, 34?h, 118 L and 2.64?l/h for Ara-U, respectively. The dialysis sessions immediately after the first and second doses cleared 39 and 52% (as Ara-U) of the respective Ara-C doses. Some 63% of Ara-U in plasma was extracted by dialysis. The patient showed no signs of neurotoxicity or other drug-related adverse effects.

Conclusion

Hemodialysis is very effective in clearing Ara-U from the plasma in renal failure, and this maneuver could easily be used routinely to prevent Ara-U accumulation and minimize adverse effects in patients with renal failure.     

High-dose ifosfamide,carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity

An autologous bone marrow transplant regimen of ifosfamide, carboplatin, and etoposide (ICE) has been developed as treatment for certain malignancies. At maximum tolerated doses renal insufficiency precludes dose escalation. The objective was to examine whether measurement of plasma drug levels early during treatment would provide warning of renal failure. Nine patients received a 96-h continuous infusion of ifosfamide 16000 mg/m², carboplatin 1600 mg/m², and etoposide 1200 mg/m². Pharmacokinetics, including drug levels and plasma concentration-time curves, of ifosfamide, ultrafiltrable platinum (uPt) and etoposide were analyzed and correlated with renal function. One of the nine patients developed anuric renal failure requiring hemodialysis. By 17 h from the start of infusion, this patient showed substantially higher drug levels of ifosfamide (200 vs mean 217 M) and uPt (19 vs mean 10M) than those patients with preserved renal function. The 95% confidence intervals suggested that a 16–22 h ifosfamide level >153 M and an uPt level >M predict the development of significant renal dysfunction. Although drug levels were substantially higher at 56 h, the serum creatinine did not yet reflect kidney injury. This study suggests that high plasma ifosfamide and uPt levels, analyzed early in the course of a 96-h infusion of high-dose ICE, provide warning of severe and potentially fatal renal injury. Since ICE has substantial activity in a number of malignancies, but significant renal morbidity, real-time pharmacokineticguided dosing may reduce treatment-related toxicity.Supported in part by US. Public Health Service Grants PO1-CA-38493 and CA-06516 and a grant from the Mathers Foundation. Drs. Ayash and Schwartz are recipients of a Career Development Award from the American Cancer Society     

Phase II Trial of Carboplatin and Paclitaxel in Papillary Renal Cell Carcinoma

Background

Cytotoxic chemotherapy has not been well investigated in non-clear-cell renal cell carcinoma (RCC). A phase II study was thus conducted to assess the efficacy of carboplatin and paclitaxel in such patients.

Patients and Methods

Patients were treated with carboplatin (area under the curve of 6) and paclitaxel 225 mg/m² every 21 days and assessed for measurable disease response every 2 cycles. An initial 20 patients were planned to be enrolled to rule out a null hypothesized 15% response rate.

Results

Seventeen patients were enrolled, of which 16 patients had papillary and 1 had collecting duct histology. The patient with collecting duct histology had a complete response, but no responses were observed in patients with papillary histology and the trial was thus terminated early. Toxicities were as expected for the carboplatin and paclitaxel regimen.

Conclusion

Carboplatin and paclitaxel is not an active regimen in patients with metastatic papillary RCC. Future studies should explore the role of this or similar regimens in collecting duct carcinoma.     

Prognostic factors in urothelial renal pelvis and ureter tumours: a multicentre Rare Cancer Network study

To assess the prognostic factors in patients with transitional-cell carcinoma of the renal pelvis and/or ureter, a series of 138 patients with transitional-cell carcinoma of the renal pelvis and/or ureter was collected in a retrospective multicentre study. 12 patients with distant metastases were excluded from the statistical evaluation. All but 3 patients underwent radical surgery: nephroureterectomy (n=71), nephroureterectomy and lymphadenectomy (n=20), nephroureterectomy and partial bladder resection or transurethral resection (n=20), nephrectomy (n=10), and ureterectomy (n=5). Sixty-one per cent (n=77) of the tumours were located in the renal pelvis, and 21% (n=27) in the ureter (both in 22 [17%]). Following surgery, residual tumour was still present in 33 patients (16 microscopic and 17 macroscopic). Postoperative radiotherapy was given to 45 (36%) patients. The median follow-up period was 39 months. In a median period of 9 months, 66% of the patients relapsed (34 local, 7 locoregional, 16 regional, and 24 distant). The 5- and 10-year survival were 29% and 19%, respectively, in all patients. In univariate analyses, statistically significant factors influencing the outcome were Karnofsky index, pT-classification, pN-classification, tumour localisation, grade, and residual tumour after surgery. Multivariate analysis revealed that independent prognostic factors influencing outcome were pT-classification, the existence of residual tumour, and tumour localisation. In patients with urothelial renal pelvis and/or ureter tumours, a radical surgical attitude is mandatory; and the presence of tumour in the ureter is associated with a poorer prognosis.     

Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study

Purpose

To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.

Patients and Methods

Sixty-two adult cancer patients received intravenous bortezomib at 0.7?C1.5?mg/m² on days 1, 4, 8, and 11 every 3?weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73?m² into five cohorts: normal renal function (??60?ml/min/1.73?m²); mild dysfunction (40?C59?ml/min/1.73?m²); moderate dysfunction (20?C39?ml/min/1.73?m²); severe dysfunction (<20?ml/min/1.73?m²); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.

Results

Bortezomib escalation to the standard 1.3?mg/m² dose was well tolerated in all patients with CrCl ??20?ml/min/1.73?m²; 0.7?mg/m² was tolerated in three patients with severe renal dysfunction (<20?ml/min/1.73?m²). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3?mg/m² in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.

Conclusion

Bortezomib 1.3?mg/m² is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.     

Neoadjuvant chemotherapy with docetaxel and carboplatin followed by radical hysterectomy for stage IB2, IIA2, and IIB patients with non-squamous cell carcinoma of the uterine cervix

Background

We conducted a phase II study to evaluate the efficacy of neoadjuvant chemotherapy with docetaxel and carboplatin followed by radical hysterectomy for patients with non-squamous cell carcinoma of the uterine cervix.

Methods

Sixty-one patients with International Federation of Gynecology and Obstetrics stage IB2, IIA2, or IIB non-squamous cell carcinoma of the uterine cervix were enrolled. The patients were administered docetaxel at a dose of 60 mg/m², followed by carboplatin at a dose based on an area under the curve of 6. The treatments were repeated every 21 days for one to three cycles. Fifty-two patients were eligible to evaluate the efficacy of neoadjuvant chemotherapy followed by radical hysterectomy. Adverse events were evaluated in 59 patients.

Results

The response rate was 69 % (95 % CI, 57–82 %), with 5 patients achieving complete response, 31 partial response, 15 stable disease, and 1 progressive disease. Median follow-up duration was 1913 days with a range of 145–2632 days. Of 52 patients, 50 underwent radical hysterectomy after neoadjuvant chemotherapy. The 2-year overall survival rate was 81.8 % for stage IB2, 85.7 % for stage IIA2, and 92.6 % for stage IIB. The most frequent grade 3 and 4 hematological toxicity was neutropenia, with 43 patients experiencing grade 4 and 11 with grade 3. The nonhematological toxicities were mainly grade 1 or 2 in severity.

Conclusion

Neoadjuvant chemotherapy with docetaxel and carboplatin followed by radical hysterectomy may be a useful strategy for patients with non-squamous cell carcinoma of uterine cervix.

     

Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients

Background

The objective of this study was to evaluate the efficacy and safety of pemetrexed plus cisplatin/carboplatin in locally advanced or metastatic non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy.

Methods

Fifty-three locally advanced or metastatic non-small cell lung cancer patients previously treated with platinum-based chemotherapy received pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve (AUC) 5 every 21 days, with dexamethasone, folic acid and vitamin B12 being administered.

Results

Median age was 52 years. Eastern Cooperative Oncology Group (ECOG) performance status was 0-2. Thirty-eight patients had stage IV tumors. Thirty-seven patients had adenocarcinoma (including 6 alveolar carcinoma patients), and fourteen patients had squamous cell carcinoma. Thirty-four patients were treated in second line, 15 in third line, and 4 in fourth line. Seven patients (13.2%) showed partial response; Thirty-six (67.9%) had stable disease. The median progression free survival time was 6.0 months and the median overall survival time was 10.0 months. The 1-year survival rate was 40.9%. Five (9.4%) and four (7.5%) patients experienced grade 3 or 4 leukopenia and thrombocytopenia, respectively. Nonhematological toxicities included grade 3 nausea/vomiting in 1 patient (1.9%), grade 3 rash in 1 patient, grade 4 diarrhea in 1 patient (1.9%) and grade 4 creatinine increase in 1 patient (1.9%).

Conclusion

Locally advanced or metastatic NSCLC patients previously treated with platinum-based chemotherapy could benefit from pemetrexed plus cisplatin/carboplatin chemotherapy with tolerable adverse events.     

Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma

Background

Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma.

Methods

Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin.

Results

Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 μM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone.

Conclusions

Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin. Administering taurolidine in combination with 30 mg/m² doxorubicin in dogs is not recommended but taurolidine in combination with carboplatin (300 mg/m²) appears safe.     

Template-based lymphadenectomy reduces the risk of regional lymph node recurrence among patients with upper/middle ureteral cancer

Background

Our previous nonrandomized prospective study showed that template-based lymphadenectomy improved survival among patients with renal pelvic cancer but not among patients with ureteral cancer. However, regional node sites vary according to the tumor’s location in relation to the ureter. Therefore, this retrospective study examined the therapeutic role of lymphadenectomy for ureteral cancer according to tumor location.

Methods

Between January 1988 and September 2015, we performed nephroureterectomy for 154 patients with nonmetastatic urothelial carcinoma of the ureter at two Japanese institutions. The tumors’ locations were classified as the lower ureter or the upper/middle ureter (before the cranial crossing of the common iliac artery). The appropriate regional nodes were identified based on our previous mapping study. Dissection was classified as complete lymphadenectomy (all regional sites were dissected), incomplete lymphadenectomy (not all sites were dissected), or no lymphadenectomy. We focused the analyses on patients with ≥pT2 disease to clarify the effect of the lymphadenectomy.

Results

Among the 48 patients with upper/middle ureteral cancer, recurrence-free and cancer-specific survival were significantly higher in the complete lymphadenectomy group (vs. the incomplete or no lymphadenectomy groups). However, there were no differences in recurrence-free and cancer-specific survivals among the 56 patients with lower ureteral cancer. In the patients with upper/middle ureteral cancer, multivariate analysis revealed that template-based lymphadenectomy was independently associated with a reduced risk of cancer-specific mortality.

Conclusions

Template-based lymphadenectomy has a therapeutic benefit for treating patients with upper/middle ureteral cancer but not for treating patients with lower ureteral cancer.

     

Pharmacokinetic analysis of carboplatin in patients with cancer who are undergoing hemodialysis

Purpose

To examine the safety of carboplatin-based chemotherapy and the applicability of the Calvert formula in patients with cancer who are undergoing hemodialysis.

Methods

We treated two patients who were undergoing hemodialysis and received carboplatin-based chemotherapy to treat non-small-cell lung cancer or ovarian cancer. The dose of carboplatin was calculated by the Calvert formula. Glomerular filtration rate was considered to be 0, and the target area under the plasma concentration versus time curve (AUC) was 4 (carboplatin dose, 100 mg) for patient 1 and 5 (125 mg) for patient 2. Carboplatin was administered as a 1-h intravenous infusion on day 1. Hemodialysis was performed for 3 or 4 h, starting 24 h after the infusion of carboplatin had begun. Heparinized blood samples were collected during the first cycle of chemotherapy.

Results

The AUCs in patients 1 and 2 were 4.7 and 6.1 (mg/ml min), which were about 20% higher than the target values (4 and 5 mg/ml min, respectively). In the absence of hemodialysis, the hypothetical AUCs were 6.2 and 7.6 (mg/ml min), respectively. The pre-dialysis body clearances of carboplatin were 16.1 and 16.5 ml/min, with elimination half-lives of 17.5 and 13.8 h, respectively.

Conclusion

By performing hemodialysis 24 h after the start of chemotherapy, we obtained reproducible and robust AUC data. Use of the Calvert formula allowed carboplatin-based chemotherapy to be performed safely. Our results suggest that the non-renal clearance of carboplatin is lower in Japanese patients than in non-Asian patients.     

A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors

Purpose

To determine the maximum tolerated doses and dose-limiting toxicities of oral panobinostat in combination with paclitaxel and carboplatin when administered to patients with advanced solid tumors.

Patients and methods

Patients initially received panobinostat twice weekly. Following amendment #1, patients received panobinostat three times weekly. Paclitaxel and carboplatin were administered intravenously on day 1 of each 21-day treatment cycle. Dose escalation continued until the maximum tolerated dose was determined. A total of 10 patients were treated at the recommended phase II dose to further assess safety.

Results

Twenty-one patients were enrolled across four different dose levels. The dose-limiting toxicity of the combination regimen was myelosuppression (neutropenia and thrombocytopenia), which often warranted panobinostat dose omissions or reductions. Nearly two-thirds of the patients experienced grade 4 neutropenia or grade 3 or 4 thrombocytopenia. Non-hematologic toxicities consisted primarily of diarrhea, fatigue, and vomiting, which were mild to moderate in intensity. No QTc prolongation was reported. Three partial responses were confirmed in patients with carcinoma of unknown primary (two patients) and non-small-cell lung cancer (one patient). Eleven additional patients reported stable disease as their best response to treatment.

Conclusions

The recommended phase II dose is panobinostat 10?mg orally three times weekly in combination with paclitaxel 175?mg/m² and carboplatin AUC 5 administered intravenously on day 1 of every 21-day cycle.     

A phase II trial of concurrent chemoradiotherapy with weekly paclitaxel and carboplatin in advanced oesophageal carcinoma

Background

This study was performed to assess the efficacy and feasibility of definitive chemoradiotherapy consisting of weekly doses of combined paclitaxel and carboplatin concurrent with radiation therapy, followed by 2 cycles of consolidation chemotherapy for advanced esophageal carcinoma.

Methods

Eligibility criteria included local, advanced, newly diagnosed and postoperative local regional lymph node metastasis; Eastern Cooperative Oncology Group (ECOG) score ≤ 2; and adequate organ function. Patients received concurrent chemoradiation therapy consisting of radiotherapy (50.4 Gy/28 Fx or 61.2 Gy/34 Fx) and concurrent paclitaxel (50 mg/m²) and carboplatin (area under the curve, AUC = 2) on days 1, 8, 15, 22 and 29. The two-cycle consolidation chemotherapy protocol was paclitaxel (175 mg/m²) plus carboplatin (AUC = 5) administered on days 57 and 85, after concurrent chemoradiotherapy.

Results

Between August 2013 and February 2015, 65 patients with oesophageal carcinoma were enrolled in the study; 34 (52.3%) were newly diagnosed and 31 (47.6%) had postoperative local regional lymph node metastasis. The median overall survival time was 21.7 months (95% confidence interval [CI] 16.7–26.6), and the median progression-free survival time was 12.1 months (95% CI 9.0–15.3). A total of 96.9% (63/65) and 67.6% (44/65) patients completed ≥5 cycles and all 7 cycles of chemotherapy, respectively. A total of 93.8% (61/65) patients completed radiation therapy. The 1- and 2-year overall survival rates were 73.7 and 42.0%, respectively. The 1- and 2-year progression-free survival rates were 50.6 and 31.1%, respectively. Grade 3–4 toxicity during chemoradiotherapy included neutropenia (24.5%), thrombocytopenia (4.6%), fatigue (1.5%), anaemia (1.5%), radiation dermatitis (1.5%), pneumonitis (1.5%), oesophagitis (4.6%) and vomiting (1.5%).

Conclusions

In patients with locally advanced oesophageal cancer, the combination of weekly doses of paclitaxel and carboplatin was well tolerated and produced comparable results. A three-arm randomised phase III trial (NCT02459457) comparing paclitaxel in combination with cisplatin, carboplatin or 5-fluorouracil with concurrent radiotherapy is on-going at our hospital.

     

Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women with newly diagnosed, untreated, gynaecologic tumours: a phase I/II trial of the AGO study group

Introduction:

Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non-overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin.

Methods:

This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m^–2 plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib.

Results:

Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m^–2 plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m^–2 plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients.

Conclusion:

Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option.     

Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001

Background

This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II–IIIA non-small-cell lung cancer (NSCLC).

Methods

Patients received four cycles of S-1 (80 mg/m²/day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m²/day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was ≥50%.

Results

Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4–71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%.

Conclusions

We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC.

Clinical registration number

UMIN000005041.

     

Pharmacokinetics of carboplatin administered with lobradimil to pediatric patients with brain tumors

Purpose To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors.Methods Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mgmin/ml per dose ×2 (2.5 mgmin/ml per dose ×2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m²)=target AUC (mgmin/ml) × [0.93 × GFR (ml/min/m²)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min lobradimil infusion (100–600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity.Results The median GFR was 65 ml/min/m² (range 38–95 ml/min/m²) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m²/day (124–235 and 179–360 mg/m²/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2–131%). The median carboplatin AUCs at the 2.5 and 3.5 mgmin/ml target AUCs were 3.4 and 4.8 mgmin/ml (2.51–5.8 and 3.9–7.7 mgmin/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r²=0.14).Conclusions Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.     

High dose melphalan in children with advanced malignant disease

Summary Nine children with poor-prognosis malignancies — seven with advanced neuroblastoma and two with metastatic Ewing's sarcoma — were give high doses of melphalan (HDM), 150 mg/m² (3 patients) and 180 mg/m² (6 patients), as a late intensification agent combined with noncryopreserved autologous bone marrow transplants. Melphalan levels in the plasma decreased biphasically, with mean half-lives of 6.6 min and 3.0 h. At the time of marrow reinfusion (12–21 h after HDM) the melphalan plasma level was generally below 0.1 g/ml. The renal contribution to melphalan clearance was low, a mean of 5.8% of the injected dose being found in patients' urine over the 12 h following HDM administration. No significant difference was seen in pharmacokinetic parameters between patients undergoing and not undergoing forced diuresis.     

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease

Introduction

This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC).

Induction chemotherapy with carboplatin and taxol followed by radiotherapy and concurrent weekly carboplatin?+?taxol in locally advanced nasopharyngeal carcinoma

Purpose

Aim of this study was the clinical evaluation of carboplatin?Ctaxol combination in a neoadjuvant and concomitant setting with conventional radiotherapy in loco-regionally advanced nasopharyngeal carcinoma (A-NPC).

Methods

Thirty patients were treated with three cycles of carboplatin (AUC6) plus taxol (175?mg/m²) on day 1 every 3?weeks, followed by weekly carboplatin (AUC1) plus Taxol (60?mg/m2) and concomitant radiotherapy (70?Gy).

Results

We observed the objective complete response rates of 33% (after chemotherapy) and 87% (after chemo-radiotherapy). Treatment tolerability and toxicity were controllable. Three- and five-year progression-free survival were 80 and 75%, respectively, and 3- and 5-year overall survival were 85 and 80% (follow-up 49.5?months). Five-year loco-regional control was 90.3%, and five-year distant metastases?Cfree survival was 85%.

Conclusions

Neoadjuvant chemotherapy with such protocol represents a feasible, efficient treatment for patients with A-NPC, ensuring excellent loco-regional disease control and overall survival with low incidence of distant metastases.     

Phase II study of docetaxel,cisplatin, and concurrent radiation followed by platinum-based adjuvant chemotherapy for technically unresectable,locally advanced head and neck squamous cell carcinoma

Background

Phase I study of weekly administration of low-dose docetaxel/cisplatin concurrent with conventionally fractionated radiotherapy for locally advanced head and neck squamous cell carcinoma suggested the recommended dose of docetaxel at 10 mg/m² and cisplatin at 20 mg/m². Phase II study of the concurrent chemoradiotherapy for technically resectable disease showed satisfactory results.

Methods

This phase II study was designed to address efficacy and safety when patients with technically unresectable disease were treated with concurrent chemoradiotherapy, followed by two cycles of moderate-dose platinum-based adjuvant chemotherapy: docetaxel, cisplatin, and fluorouracil (modified TPF). Modified TPF was replaced with docetaxel/carboplatin when renal impairment became evident. Surgical salvage was considered when residual or recurrent locoregional disease was technically resectable and free of distant metastasis.

Results

Of 33 enrolled patients, 31 were analyzable: 24 (78 %) and 18 (58 %) patients completed chemoradiotherapy and adjuvant chemotherapy, respectively; 15 (48 %) patients completed study treatment per protocol, and overall complete response rate was 45 %. Seven patients underwent surgical salvage, which was successful in 4 patients. At a median follow-up of 60.8 months for surviving patients, median progression-free survival and median overall survival were 16.2 and 39.9 months, respectively. Grade 3 or 4 toxicity included mucositis (77 %) and dysphagia (45 %) during the chemoradiotherapy period and neutropenia (100 %) and febrile neutropenia (35 %) during the adjuvant period. No patient died of toxicity.

Conclusion

The tested regimen seems effective, although there is room for improvement in adjuvant chemotherapy because of the high toxicity and low compliance of modified TPF.