Concurrent Administration Of Cisplatin Research Articles

Acute kidney injury in a child treated with cisplatin and amphotericin B

Cisplatin and amphotericin B are both known to be potentially nephrotoxic. We describe acute kidney injury due to the combination of Liposomal amphotericin B and cisplatin in an adolescent with osteosarcoma. Acute kidney injury (peak creatinine 431 µmol/L) consistent with drug-induced acute tubulointerstitial nephritis was observed a few days after concomitant administration of cisplatin and amphotericin B. Kidney function nearly normalised during follow-up. The timing of the concomitant administration of amphotericin B and cisplatin led us to presume that the combination was the cause of renal failure, and we conclude that concurrent administration of cisplatin and amphotericin B should be avoided.

Combination therapy of cisplatin and green silver nanoparticles enhances cytotoxicity and apoptosis in breast cancer cells

Cisplatin is one of the first-line drugs for the treatment of breast cancer and is known for its ability to disrupt cancer cell DNA. However, cisplatin chemotherapy carries side effects and the risk of drug resistance. A strategy to improve its anti-cancer efficacy while reducing its negative effects on health is to leverage the synergistic potential of natural molecules with cisplatin. In this study, we explored combination therapy using cisplatin along with biosynthesized silver nanoparticles (Ag NPs) to enhance apoptosis induction in MCF-7 breast cancer cells while reducing cisplatin resistance. The biosynthesized Ag NPs, derived from Acacia Luciana flower extracts, possess active molecules that effectively inhibit MCF-7 cells. Concurrent administration of cisplatin and Ag NPs resulted in a notable decrease in the IC50 value – approximately 22 – 26 times lower compared to individual treatments of free Ag NPs and cisplatin, respectively. Furthermore, the combination therapy significantly increased the BAK1/BCLX ratio by 162-fold compared to the control, while the cisplatin alone failed to activate intrinsic apoptosis pathway. In addition, the expression level of the CASP3 gene, indicative of the extrinsic pathway of apoptosis, increased approximately 273 times compared to free cisplatin (CASP3 expression = 3.5). Notably, the combination therapy also reduced the expression of the AKT1 gene, associated with cell survival and treatment resistance, when compared to free cisplatin (1.87 vs. 4.488). In conclusion, our findings proved that combination therapy effectively enhances apoptosis induction by cisplatin while reducing drug resistance.

A Comparative Study of Clinical Outcomes in Locally Advanced Cervical Cancer: External Beam Radiotherapy (EBRT) and Sequential High Dose Rate Intracavitary Brachytherapy (HDRICBT) with or without Concurrent Cisplatin on the Day of ICBT Insertion - A Tertiary Care Center Randomized Controlled Trial in India.

The current study aimed to delve into the comparative clinical outcomes between external beam radiation therapy (EBRT) and sequential High Dose Rate Intracavitary Brachytherapy (HDRICBT) with or without concurrent cisplatin administration on the day of intracavitary brachytherapy (ICBT) insertion in women with locally advanced cervical cancer. In this study, conducted between January 2017 and July 2018 at a leading institute in India, diagnosed and untreated patients of locally advanced carcinoma cervix were randomized into two groups. Arm 1 received concurrent cisplatin before each course of brachytherapy, while Arm 2 underwent brachytherapy alone. The outcomes were compared in terms of acute and late toxicities, treatment response, and follow-up. Data analysis was performed using SPSS 16, with statistical significance set at p < 0.05. Both study arms showed similar complete response (CR) rates of 73.3%, with no significant advantage of concurrent cisplatin before brachytherapy. However, a noteworthy trend emerged during follow-up. In the concurrent cisplatin group, the CR rate increased from 73.3% post 1 month of brachytherapy to 86.7% at 3 months and 83.3% at 6 months. Contrastingly, the control group showed CR rates of 73.3% post 1 month, 80% at 3 months, and 76.6% at 6 months. While not statistically significant, this observation suggests a possible enhancement in response rates with concurrent cisplatin and ICBT. Future studies focusing on the optimal drug, dosage, scheduling, and combining cisplatin with other agents are recommended to further explore the potential benefits observed in this study.

Effect of radiation dose rates and cisplatin on cytogenetic damage in rats receiving head–neck radiotherapy

ABSTRACT Background: We aimed to investigate effect of radiotherapy (RT) applications with different dose rates on cytogenetic damages, which focused on micronucleus (MN) formation, and evaluate how this damage varies by cisplatin in rats receiving head–neck RT. Material and Methods: Thirty-six Sprague Dawley rats were divided into five groups. The first and second groups were irradiated at a dose rate of 300 monitor unit/minute (MU/min) and 600 MU/min, respectively. The third group was irradiated at a dose rate of 300 MU/min and given cisplatin. The fourth group was irradiated at a dose rate of 600 MU/min and given cisplatin. The fifth group received neither irradiation nor cisplatin (control group). One thousand polychromatic erythrocytes were scored, and MN frequency in polychromatic erythrocytes was determined for each rat. Results: There was a significant difference among five groups in terms of the number of MN (p: 0.001). The number of MN was significantly higher in the 600 MU/min + cisplatin group (fourth group) compared to the control group [9.5 (1.0–23.0) vs. 1.5 (1.0–2.0), respectively]. It was also significantly higher in 600 MU/min + cisplatin group (fourth group) compared to 300 MU/min group (first group) [9.5 (1.0–23.0) vs. 2.0 (1.0–3.0), respectively]. On the other hand, there was no significant difference among other groups. Conclusions: Our findings suggest that RT given at a higher dose rate causes more cytogenetic damage, and this damage is increased by concurrent administration of cisplatin.

Protective effect of Rosinidin on Cisplatin-Induced Nephrotoxicity

Rosinidin is an O-methylated anthocyanidin derived from Cyanidin. It is a pigment found in the flowers of Catharanthus roseus and, in lower concentration, in Primula rosea. The molecular docking studies predicted that rosinidin has adequate structural competency, making it a viable medicinal candidate for the treatment of a wide range of disorders. The current study intends to assess rosinidin nephroprotective efficacy against nephrotoxicity induced by cisplatin in rats. nephrptoxicity is most serious side effect. This toxicity caused by free radicals. This free radicals damage Renal Tubule which is overcome by Rosinidin. Materials and Methods: Oral acute toxicity tests of rosinidin were conducted to assess potential toxicity in animals, and it was shown to be safe. The nephroprotective effect of rosinidin 10, and 20 mg/kg were tested in rats for 25 days with concurrent administration of cisplatin. Several biochemical parameters were measured to support enzymatic and non-enzymatic oxidative stress such as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH). Likewise, changes in several non-protein-nitrogenous components and blood chemistry parameters were made to support the theory linked with the pathogenesis of chemical-induced nephrotoxicity. Results: Cisplatin caused significant changes in biochemical, enzymatic, and blood chemistry, which rosinidin efficiently controlled. Conclusions: The present investigation linked rosinidin with nephroprotective efficacy in experimental models.

Rosinidin Protects against Cisplatin-Induced Nephrotoxicity via Subsiding Proinflammatory and Oxidative Stress Biomarkers in Rats.

Background: Rosinidin is a flavonoid anthocyanin pigmentation found in shrub flowers such as Catharanthus roseus and Primula rosea. The molecular docking studies predicted that rosinidin has adequate structural competency, making it a viable medicinal candidate for the treatment of a wide range of disorders. The current study intends to assess rosinidin nephroprotective efficacy against nephrotoxicity induced by cisplatin in rats. Materials and Methods: Oral acute toxicity tests of rosinidin were conducted to assess potential toxicity in animals, and it was shown to be safe. The nephroprotective effect of rosinidin 10, and 20 mg/kg were tested in rats for 25 days with concurrent administration of cisplatin. Several biochemical parameters were measured to support enzymatic and non-enzymatic oxidative stress such as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH). Likewise, changes in several non-protein-nitrogenous components and blood chemistry parameters were made to support the theory linked with the pathogenesis of chemical-induced nephrotoxicity. Results: Cisplatin caused significant changes in biochemical, enzymatic, and blood chemistry, which rosinidin efficiently controlled. Conclusions: The present investigation linked rosinidin with nephroprotective efficacy in experimental models.

Adaptive radiotherapy in locally advanced esophageal cancer with atelectasis: a case report

BackgroundTo the best of our knowledge, no study has reported mediastinal shift accompanied with obstructive atelectasis due to bulky primary esophageal tumor components treated with adaptive radiotherapy and concurrent chemotherapy.Case presentationHere we report the case of a 65-year-old male patient diagnosed with locally advanced thoracic esophageal squamous cell cancer, clinical T4bN1M0, stage IVA. Bronchoscopy and computed tomography (CT) revealed an almost complete obstruction of the lumen of the left bronchus due to compression by bulky primary esophageal tumor components. On admission, the patient presented with dyspnea and decreased arterial oxygen saturation. Chest radiography and CT on admission revealed mediastinal shift with left atelectasis, as opposed to findings from the chest radiography performed 26 days before admission. Because of the patient’s overall good condition, we recommended definitive chemoradiotherapy instead of palliative bronchial stent placement. After obtaining the patient’s consent, chemoradiotherapy was initiated on the following day and it comprised three-dimensional conformal radiotherapy with 60 Gy in 30 fractions with concurrent administration of cisplatin and 5-fluorouracil. During chemoradiotherapy, tumor location was monitored with cone-beam CT and chest radiography. Chemoradiotherapy on day 8 revealed no evidence of the mediastinal shift. CT simulation was reperformed to adjust the radiotherapy fields to account for geometrical changes induced by the absence of the mediastinal shift. Subsequently, the mediastinal shift and bronchial obstruction did not recur during the course of chemoradiotherapy. The patient completed the planned radiotherapy with concurrent and adjuvant chemotherapy, and no non-hematological grade ≥ 3 adverse events were observed. Complete response was confirmed 7 months after initiating chemoradiotherapy. Currently, no disease recurrence, dysphagia, or respiratory symptoms have been reported at 13 months after initiating chemoradiotherapy.ConclusionsIn this study, a bulky primary esophageal tumor caused mediastinal shift due to ipsilateral bronchial obstruction. The close follow-up for monitoring resolution of the mediastinal shift during the course of chemoradiotherapy enabled adequate dose delivery to targets, thus reflecting the geometrical changes induced by the absence of the mediastinal shift. Adaptive radiotherapy technique was crucial for favorable patient outcomes in this challenging clinical situation.

Concurrent gemcitabine (GEM) and radiotherapy (XRT) as organ-sparing treatment for muscle-infiltrating bladder cancer (MIBC): Preliminary results of a patient-based cumulative analysis of seven phase I-II trials.

306 Background: GEM is a highly effective radiosensitiser and has been combined with XRT in MIBC after transurethral resection (TUR) to achieve bladder preservation. Several phase I-II trials confirmed that concurrent GEM and XRT is a feasible treatment able to achieve good disease control and a high rate of organ preservation. We performed a patient-based cumulative analysis of the published trials with concurrent GEM/XRT in MIBC. Methods: Primary data for patients (pts) enrolled in all published studies on GEM/XRT were provided from the institutions. Results: A total of 190 pts were treated in seven phase I-II GEM/XRT trials. The median age was 70 yrs (range 42-87 yrs). The histology was pure transitional in 79% and mixed with squamous features in 21% of the cases. Clinical stage was T2 in 70%, T3 in 21%, and T4 in 8% of the cases, respectively. After TUR, pts received a median XRT dose of 55.5 Gy (range 45-64 Gy) with standard and hypo-fractionated regimes used in 68% and 32% of the cases, respectively. GEM was administered on a weekly or twice-weekly basis, with doses ranging from 10 mg/sqm to 500 mg/sqm; a concurrent administration of cisplatin was planned in 38 pts (20%). Grade ≥ 3 acute and late urinary toxicities were recorded in 7 (4%) and 5 (3%) pts, while grade ≥ 3 acute and late intestinal toxicities were recorded in 20 (10%) and 1 (0.5%) pts, respectively. The complete remission rate was 93.3%. Thirty-six pts (18.9%) experienced a bladder recurrence with 14 pts undergoing cystectomy. The 3- and 5-year survival rates calculated by Kaplan-Meier methods are reported in the table. Conclusions: From this pooled analysis of the clinical outcomes of the pts enrolled in phase I-II studies it appears that GEM/XRT is a treatment with mild toxicity profile, able to achieve a high rate of bladder preservation and producing favorable outcomes compared to other published series for organ-sparing therapy for MIBC. Prospective studies are ongoing to confirm these findings. [Table: see text]

Concurrent chemoradiotherapy with cisplatin and fluorouracil for locally advanced hypopharyngeal carcinoma

Conclusions. The concurrent administration of cisplatin and fluorouracil (CCRT) during radiotherapy after induction chemotherapy had better results than induction chemotherapy followed by radiotherapy alone (CT+RT) for overall survival, laryngeal preservation, and locoregional control in patients with locally advanced hyopharyngeal cancer. Objectives. To report treatment results comparing CCRT with CT+RT in locally advanced hypopharyngeal cancer. Patients and methods. Sixty-six consecutive patients treated with curative intent were analyzed retrospectively. Thirty-eight patients were treated with induction chemotherapy followed by definitive RT, and 28 patients with induction chemotherapy followed by concurrent chemoradiotherapy. All patients had more than three cycles of continuous infusion of cisplatin and 5-fluorouracil every 3 weeks. The median dose of irradiation was 70 Gy in the CT+RT group and 68.4 Gy in the CCRT group, respectively. Results. The overall 5-year survival rates were 24% for the CT+RT group and 42% for the CCRT group (p=0.031). The 3-year pharyngolaryngectomy-free survival rates were 32% for the CT+RT group and 63% for the CCRT group (p=0.032). The 3-year locoregional control rate for CCRT was significantly better than that for the CT+RT (52% vs 23%, p=0.004). Acute hematologic toxicity appeared in 39% of the CT+RT patients and 75% of the CCRT patients.

Long-term outcome and prognostic factors in patients with cervical carcinoma: a retrospective study

This study evaluates treatment outcomes and possible prognostic factors of inoperable cervical cancer patients treated with external beam radiotherapy (EBRT) and high–dose rate brachytherapy (HDR BRT). Between 1993 and 2000, 183 patients with cervical cancer were treated at our institute. Radiotherapy was the sole treatment modality until January 1997; after the announcement of National Cancer Institute in 1999, 40 mg/m2of cisplatin (49%) was routinely applied every week. Median age was 54 years (32–92 years). Most patients (88%) had advanced-stage disease (IIB–IIIB). With a median follow-up time of 45 months (6–121 months), the 5-year overall survival (OS), local recurrence–free survival, disease-free survival (DFS), and distant metastasis–free survival (DMFS) rates were 55%, 71%, 51%, and 77%, respectively. Univariate analysis revealed that age, tumor size, lymph node status, and concomitant cisplatin were prognostic factors for OS. The DFS rates were lower in young age group. Patients with tumor greater than 4 cm and age greater than 40 were at greater risk for local recurrence. Distant metastases were more frequent in patients with adenocarcinoma. Concurrent cisplatin use increases DMFS rates (91% vs 78%;P= 0.05). In multivariate analysis, extensive stage, parametrial infiltration, young age, adenocarcinoma histopathology, and lymph node metastasis were negative prognostic factors for OS while concomitant cisplatin increases OS. Likewise, patients with extensive stage, adenocarcinoma, and without concurrent cisplatin administration had more risk for distant metastasis. There was no treatment-related mortality. Grade 3–4 morbidity rates were seen only in eight patients (4%). The combination of EBRT and HDR BRT together with concomitant chemotherapy in the treatment of locally advanced carcinoma of cervix is safe and well tolerated with acceptable morbidity.

Long-term outcome and prognostic factors in patients with cervical carcinoma: a retrospective study

This study evaluates treatment outcomes and possible prognostic factors of inoperable cervical cancer patients treated with external beam radiotherapy (EBRT) and high-dose rate brachytherapy (HDR BRT). Between 1993 and 2000, 183 patients with cervical cancer were treated at our institute. Radiotherapy was the sole treatment modality until January 1997; after the announcement of National Cancer Institute in 1999, 40 mg/m(2) of cisplatin (49%) was routinely applied every week. Median age was 54 years (32-92 years). Most patients (88%) had advanced-stage disease (IIB-IIIB). With a median follow-up time of 45 months (6-121 months), the 5-year overall survival (OS), local recurrence-free survival, disease-free survival (DFS), and distant metastasis-free survival (DMFS) rates were 55%, 71%, 51%, and 77%, respectively. Univariate analysis revealed that age, tumor size, lymph node status, and concomitant cisplatin were prognostic factors for OS. The DFS rates were lower in young age group. Patients with tumor greater than 4 cm and age greater than 40 were at greater risk for local recurrence. Distant metastases were more frequent in patients with adenocarcinoma. Concurrent cisplatin use increases DMFS rates (91% vs 78%; P= 0.05). In multivariate analysis, extensive stage, parametrial infiltration, young age, adenocarcinoma histopathology, and lymph node metastasis were negative prognostic factors for OS while concomitant cisplatin increases OS. Likewise, patients with extensive stage, adenocarcinoma, and without concurrent cisplatin administration had more risk for distant metastasis. There was no treatment-related mortality. Grade 3-4 morbidity rates were seen only in eight patients (4%). The combination of EBRT and HDR BRT together with concomitant chemotherapy in the treatment of locally advanced carcinoma of cervix is safe and well tolerated with acceptable morbidity.

Neo/Adjuvant Therapy in Upper Tract Urothelial Carcinoma

Objectives Urothelial carcinoma of the renal pelvis and ureter is a relatively uncommon malignancy. The majority of patients present at a stage in which disease has not penetrated through the muscularis (Tis–T2). These patients are generally treated with radical nephroureterectomy or with renal-sparing procedures in select patients, and overall the prognosis is favorable in this group. However, in patients in whom disease has spread beyond the muscularis and involved adjacent tissues, organs, or lymph nodes, the prognosis is significantly worse, making it important to consider adjuvant or neoadjuvant therapy. Methods Literature search using PubMed was conducted to identify the related articles that formed the basis of this review. Results The role of adjuvant external beam radiotherapy in improving local control and survival is unclear both because of the limited number of patients and because of the contradictory results of different studies. Neoadjuvant chemotherapy and concurrent cisplatin administration during radiotherapy appears as an important factor in terms of survival at 5 yr. Similarly, available data in the literature indicate that neo/adjuvant systemic chemotherapy after nephroureterectomy may provide therapeutic benefit in patients with invasive transitional cell carcinoma of the upper urinary tract. Conclusions Adjuvant radiation therapy after radical upper urinary tract surgery has no impact upon clinical outcome, whereas systemic adjuvant or neoadjuvant chemotherapy does provide significantly better oncologic results.

Association of cisplatin and intra-arterial injection of 131I-lipiodol in treatment of hepatocellular carcinoma: Results of phase II trial

Intra-arterial injections of 131I-lipiodol (131I-Lip) provide an effective treatment for hepatocellular carcinoma. In hepatocellular carcinoma cell cultures, concurrent administration of cisplatin increases the cytotoxicity of 131I. The efficacy and tolerance of intra-arterial injections of 131I-Lip combined with systemic cisplatin was tested in a phase II trial. The inclusion criteria were proven unresectable nonmetastatic hepatocellular carcinoma, compensated liver disease, and adequate laboratory test findings. Treatment comprised the combination of intra-arterial injection of 131I-Lip (2.2 GBq) with intravenous infusion of low-dose cisplatin. The combined treatment could be repeated. A total of 41 patients were included; 37 had cirrhosis and 38 had measurable tumors. One to four treatments (median, two) were given. The cisplatin dose was 75 mg for the first course and 72 mg for the second. Grade 3-4 (n/n) adverse effects were observed in 14 patients, polymorphonuclear leukocytes (3/0), platelets (5/1), asthenia (1/0), pain (1/0), and vomiting (1/0). Four patients developed pulmonary toxicity; 2 cases were likely related to 131I-Lip administration and 1 was fatal. The response rate was 47% (18 of 38), and the 1- and 2-year survival rate was 73% +/- 7% and 48% +/- 9%, respectively. This combination had a tolerable toxicity profile and provided an objective response rate, warranting a phase III trial.

Organ preservation by weekly paclitaxel and carboplatin concurrent with radiation therapy in locally advanced laryngeal/hypopharyngeal carcinoma

5564 Background: The goal of preserving laryngeal function and structure has dominated the development of newer treatment approaches. Radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for organ preservation and locoregional control. This prospective phase II trial was conducted to evaluate the toxicity and organ preservation of weekly Paclitaxel (P), Carboplatin (C) and standard radiation therapy (RT) in previously untreated locally advanced laryngeal/hypopharynx (LA/HP) cancer. Material: Newly diagnosed patients (pt) with stage III-IV LA/HP carcinoma received weekly P (40/mg/m2 over 1 hour) and C (AUC:2) for 6 cycles starting on day 1 of RT which was given once daily for a total of 66.00Gy in 33 fractions. Re-evaluation with endoscopy, CT and PET scans was performed 6–8 weeks post RT. Salvage surgery was planned for residual, or recurrent, respectable disease. Result: 36 patients were included male: 23, median age 51, site: LA 20, HP: 16, Stage III/IV: 11/25. Tracheostomy tube was inserted for airway obstruction in 19 patients and 9 had tube feeding prophylactically. 75% of patients completed the planned therapy. Grade III-IV mucositis occurred in 48% of patients, while 2 patients developed grade IV skin necrosis around the tracheostomy tube. Hematologic toxicity was mild with febrile neutropenia in 4 patients. Weight loss was common and severe in 26% of patients despite admission for nutritional support of 9 patients. Local control for whole group was achieved in 22/36 (61%). With a median follow-up of 35 months, 16 patients (11 with LA and 5 with HP) are alive with no evidence of disease, two third of them with a functional larynx. Late complication in the form of laryngeal edema occurred in 1 patient. Conclusion: This combination proved feasible, with manageable toxicity, resulted in laryngeal preservation, and offered a high rate of disease control and survival in this population of locally advanced high risk LA/HP carcinoma. No significant financial relationships to disclose.

Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma.

To evaluate the antitumor activity and toxicity of concurrent biochemotherapy that uses cisplatin, vinblastine, and docarbazine (DTIC) (CVD) in combination with interferon alfa-2a (IFN-alpha) and interleukin-2 (IL-2) in patients with metastatic melanoma. Between October 1992 and October 1993, 53 patients with a documented diagnosis of metastatic melanoma with measurable lesions and an Eastern Oncology Cooperative Group (ECOG) performance status of 2 or less were enrolled onto this study. Patients were required to have no clinically significant cardiac dysfunction and to be free from symptomatic brain metastases. The treatment consisted of cisplatin 20 mg/m2 daily for 4 days; vinblastine 1.6 mg/m2 daily for 4 days; and DTIC 800 mg/m2 intravenously (i.v.) day 1 with IL-2 9 x 10(6) IU/m2 i.v. by continuous infusion daily for 4 days and IFN-alpha 5 x 10(6) U/m2 subcutaneously daily for 5 days, repeated at 21-day intervals. Response was assessed after two cycles and patients who responded were continued on treatment for a total of six cycles. Among 53 assessable patients, 11 patients (21%) achieved a complete response (CR) and 23 patients (43%) achieved a partial response (PR), for an overall objective response rate of 64%. The median time to disease progression for all patients was 5 months. The median survival of all patients entered onto the trial was 11.8 months. Among the 11 patients who achieved a CR, five patients (9%) have remained in continuous CR for 50+ to 61+ months. The toxicity of biochemotherapy consisted of severe myelosuppression, significant nausea and vomiting, and moderately severe hypotension that required inpatient hospital care for each 5-day cycle of treatment. There were no treatment-related deaths. Concurrent biochemotherapy for patients with advanced melanoma is capable of producing high CR and overall response rates and resulted in durable complete remissions in a small fraction of patients. Toxicity, although severe, was manageable in a routine inpatient hospital environment.

Accelerated bifractionated radiation with concurrent cisplatin administration in locally advanced head and neck cancer: a feasibility study.

To test the feasibility of accelerated interrupted twice-daily radiation and concurrent cisplatin administration in patients with locally advanced head and neck cancer. Nineteen patients with locally advanced head and neck cancer were treated with accelerated bifractionated radiation with concurrent administration of cisplatin. There were 18 men and 1 female with a median age of 60 years (range, 17-71) and median performance status of 90 (range, 80-100). Sixteen patients (85%) presented with stage IV disease. Primary site included the nasopharynx (n = 7), oropharynx (n = 5), hypopharynx (n = 1) and larynx (n = 6). Radiation consisted of two fractions of 1.6 Gy each daily, five times weekly to a total dose of 64 Gy. Cisplatin was administered at a dose of 100 mg/m2 on days 2 and 28 of the treatment period. Nine patients achieved a complete response (47%; 95% Cl, 25%-70%) and 5 a partial response (26%; 95% Cl, 7%-46%). Grade III-IV toxicity included leukopenia (16%), mucositis (26%), dry mouth (5%), weight loss (16%) and infection (5%). After a median follow-up of 27.11 months (range, 1-33 +), 9 patients have died. Median time to progression was 11 months (range, 1-32 +) and median survival 25 months (range, 1-32 +). Accelerated twice-daily radiation with concurrent cisplatin is effective in locally advanced head and neck cancer and can be safely given with manageable toxicity.

OPTIMIZING CHEMOTHERAPY AND RADIOTHERAPY IN LOCALLY ADVANCED NON–SMALL CELL LUNG CANCER

In recent years, three treatment methods have been shown to improve overall survival of patients with locally advanced non-small cell lung cancer. These are: sequential combined radiotherapy and cisplatin-based chemotherapy, concurrent administration of cisplatin and thoracic radiotherapy, and accelerated hyper fractionated radiotherapy. Optimization of results can be attained by integrating these three treatment approaches.

Clinical pharmacokinetics of vinorelbine.

Vinorelbine (5'-noranhydrovinblastine) is a recently developed semisynthetic anticancer drug which belongs to the Catharanthus alkaloid family. Its mechanism of action is only partially known but it is assumed that it acts, like vinblastine and vincristine, as an antimicrotubule agent arresting cell division in mitosis. Clinically, vinorelbine has mainly shown activity in the treatment of advanced non-small-cell lung cancer and the treatment of metastatic breast cancer. Early pharmacokinetic data were obtained with radioactive assays (radio-immunoassay or 3H-labelled vinorelbine), then with more selective high performance liquid chromatographic techniques. Vinorelbine is usually administered intravenously but there has also been some experimentation with an oral formulation. The bioavailability of a liquid filled gelatin capsule ranges between 12 and 59% with a mean value of 27% [standard deviation (SD) 12%]. Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours. In vitro, vinorelbine is mainly distributed into the blood cells, especially platelets (78%) and lymphocytes (4.8%) The unbound blood fraction is around 2%. In lung tissue vinorelbine concentrations are much higher than in serum, by up to 300-fold 3 hours after administration. Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. Urinary excretion of vinorelbine is low, accounting for less than 20% of the dose. Faecal elimination has been demonstrated in 2 patients who were administered 3H-labelled vinorelbine; the amount of radioactivity recovered in the faeces was 33.9 and 58.4% for the 2 patients, respectively. The pharmacokinetic profile of vinorelbine is often described as a 3-compartment model characterised by a long terminal half-life (t1/2) that varies between 20 and 40 hours and a large apparent volume of distribution (Vd) of around 70 L/kg. Systemic clearance ranges between 72.54 and 89.46 L/h (1209 and 1491 ml/min) when determined by high performance liquid chromatography and is higher than that reported by radioimmunoassay [46.2 L/h (770 ml/min)]. This could be due to the greater specificity of the chromatographic method. Vinorelbine has been administered by continuous intravenous infusion over 4 days. Steady-state was reached and the concentrations obtained were above the in vitro IC50 (concentration of drug causing 50% inhibition). The effect of liver disease on vinorelbine pharmacokinetics has been studied in patients with breast cancer. Patients with massive secondary liver disease had a lower systemic clearance than those who have no liver disease or a lesser invasion. In children, vinorelbine seems to display a shorter t1/2 (14.7 hours) than that found in adults. In addition, the systemic clearance is highly variable [from 12 to 93.96 L/h/m2 (200 to 1566 ml/min/m2)]. Vinorelbine is often co-administered with cisplatin in the treatment of advanced non-small-cell lung cancer. The disposition of the alkaloid is not altered by concurrent administration of cisplatin.