Paclitaxel and cisplatin

Neijt IP, Engelholm SA, Tuxen MK, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carbo-platin in advanced ovarian cancer. J Clin Oncol 2000 18 3084-3092. 

GOG-9803 Phase I/II Study of Radiotherapy Combined With Paclitaxel and Cisplatin in Patients With Stage IB2, IIA, IIB, IIIB, or IVA Invasive Carcinoma of the Cervix. 

GOG-9804 Phase I/II Study of Extended Field Radiation Therapy With Concurrent Paclitaxel and Cisplatin Chemotherapy in Patients With Previously Untreated Carcinoma of the Cervix Metastatic to the Para-aortic Lymph Nodes. Study Protocol, http //www.cancer.gov/search/clinical trials... 

The Eastern Cooperative Oncology Group has studied the combination of high-dose paclitaxel and cisplatin with G-CSF support in comparison to low-dose paclitaxel and cisplatin in a recent phase III trial (77). Patients with locally advanced, recurrent, or metastatic disease were randomly placed on arm A of paclitaxel (200 mg/m2 over a 24-h infusion), cisplatin (75 mg/m2), and G-CSF (starting d 3 until the ANC was >10,000/pL) or armB ofpaclitaxel (135 mg/m2 over a 24-h infusion) and cisplatin (75 mg/m2). The tre atment was repeated every 21 d until progression of disease or a total of 12 cycles. 

The RTOG has an ongoing phase II study analyzing the use of paclitaxel and cisplatin in combination with split-course concomitant radiotherapy in patients with recurrent squamous cell carcinoma requiring reirradiation. Cisplatin and paclitaxel are administered d 1-... 

Intraperitoneal chemotherapy has been under investigation for many years and accumulating positive indicators were recently reinforced by the phase III Gynecology Oncology Group study [GOG 172] (see Armstrong et al., 2006). This study randomized optimally debulked patients to either intravenous paclitaxel and cisplatin or to intravenous paclitaxel plus intraperitoneal paclitaxel and cisplatin. After a median follow-up of four years an overall survival advantage for the IP arm of 65.6 versus 49.7 months was seen. 

McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY et al. Cyclophosphamide and cis-platin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl JMed 1996 334 1-6. 

Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, several studies have shown that carboplatin and paclitaxel yields clinical results similar to what is achieved with the cisplatin plus paclitaxel combination however, because of reduced toxicity and greater ease of administration, carboplatin plus paclitaxel has now become the treatment of choice. In patients who present with recurrent disease, the topoisomerase I inhibitor topotecan, the alkylating agent altretamine, and liposomal doxorubicin are used as single agent monotherapy. 

Sorensen JB, Wedervang K, Dombernowsky P. Preliminary results of a phase II study of paclitaxel and cisplatin in patients with non-small cell lung cancer. Semin Oncol 1997 24(4 Suppl 12) S12-18, S12-20. 

V anhoefer U, Harstrick A, Wilke H, Schleucher N, WaUes H, Schroder J, Seeber S. Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro. Eur J Cancer 1995 31 A(l) 92-7. 

In aqueous alcoholic solutions, it very readily solubilizes essential oils. Aqueous solutions of hydrophobic drugs (e.g. miconazole, hexetidine, clotrimazole, benzocaine) can also be prepared with Cremophor EL. Cremophor EL has also been used as a solubilizing agent for drugs like cyclosporin A, paclitaxel, and cisplatin. Cremophor LLP is manufactured by purifying Cremophor EL and is therefore suitable for parenteral applications, e.g. Taxol preparations. In oral formulations, the taste of polyoxyl 35 castor oil (Cremophor EL) can be masked by a banana flavor. 

Covens A, Boucher S, Roche K, et al. Is paclitaxel and cisplatin a cost-effective first-line therapy for advanced ovarian carcinoma Cancer 1996 77 2086-2091. 

Raitanen M, Rantanen V, Kulmala J, et al (2002) Supra-ad-ditive effect with concurrent paclitaxel and cisplatin in vulvar squamous cell carcinoma in vitro. Int J Cancer 100 238-243... 

The incidence of neutropenia has also been investigated in combination schedules. Patients who receive paclitaxel in combination with cyclophosphamide have severe neutropenia more often than with monotherapy (72% of patients). Paclitaxel given as a 24-hour infusion before cyclophosphamide is more likely to cause severe neutropenia compared with patients who receive cyclophosphamide first [54 ]. Conversely, in studies of paclitaxel and cisplatin combination chemotherapy, myelosuppression is worse when paclitaxel is given after cisplatin rather than before. This appears to be due to reduced plasma clearance of paclitaxel when cisplatin is administered first... 

A similar small phase II trial from Germany has reported on seven patients receiving concurrent chemoradiation for transitional cell carcinoma of the bladder with cisplatin and paclitaxel (96). The authors conclude that this combination is at least feasible given an acceptable acute toxicity profile and reasonable efficacy. Another small series is reported by Nichols et al. (97) where eight patients received radiation with concurrent paclitaxel and carboplatin in an attempt at bladder preservation. Three of the patients remain free of distant metastases, and local recurrence has occurred in three. 

The lack of data reinforces the need to conduct randomized trials in the area of carcinoma of the bladder, and given the radiosensitizing action of the taxanes, they are worthy of consideration in these protocols. The RTOG phase I/II trial looking at concurrent cisplatin, paclitaxel, and hyperfractionated radiation with selective bladder preservation and adjuvant chemotherapy is ongoing and it may serve as the basis for future randomized trials in the area (98). 

Ettinger DS, Seiferheld WF, Abrams RA, et al. Cisplatin, etoposide, paclitaxel and concurrent hyperfractionated thoracic radiotherapy for patients with limited disease small-cell lung cancer Preliminary results of RTOG 96-09 (abstract 1917). Proc Am Soc Clin Oncol 2000 19 490a. 

Blanke CD, Chiappori A, Epstein B, et al. A Phase II Trial of Neoadjuvant Paclitaxel (T) and Cisplatin (P) with Radiotherapy, Followed by Surgery (S) and Postoperativve T with 5-Fluorouracil (F) and Leucovorin (L) in Patients (pts) with Locally Advanced Esophageal Cancer (LAEC). ProcAnnu Meet Am Soc Clin Oncol 1997 16 A1006. 

North American prospective trials of radiation sensitizers for cervical cancer have focused on the use of cisplatin, fluorouracil, and hydroxyurea. However, a number of other drugs also hold promise as effective radiation sensitizers for cervical cancer, including mitomycin C, epirubicin, paclitaxel, and carboplatin. 

Pignata S, Frezza P, Tramontana S, et al. Phase I study with weekly cisplatin-paclitaxel and concurrent radiotherapy in patients with carcinoma of the cervix uteri. Ann Oncol 2000 11 455 159. 

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