Cisplatin combination with paclitaxel

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. 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

Carboplatin in combination with paclitaxel has shown activity in recently reported phase II trials. Vaughn et al. [163] at the University of Pennsylvania reported a 50% response rate in previously untreated patients with advanced disease, while Droz et al. [164] observed responses in 14 of 38 patients (2 CRs). Randomized comparisons of this combination with M-VAC are expected. Kaufman et al. [165] reported promising results with the cisplatin/gemcitabine combination at ASCO in 1998 a 66% response rate (13 CRs) was observed in their Phase-II study of 47 patients. 

Bremnes RM, Sundstrom S, Aasebo U, Vilsvik J. Paclitaxel in combination with cisplatin, etoposide and thoracic radiotherapy for limited stage small cell lung cancer (SCLC) a phase II study (abstract 1826). ProAmSoc Clin Oncol 1998 17 475a. 

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-... 

Other potential radiation sensitizers for cervical cancer are being explored in phase I and II trials. Paclitaxel has been combined with cisplatin in several small phase I studies. Pignata et al. (29) found that 50 mg/m2 per week of paclitaxel could be combined with weekly cisplatin (30 mg/m2) and radiation therapy with acceptable toxicity, although 10 of 18 patients in their study had grade 3-4 hematologic toxicity. Chen etal. (30) also were able to give weekly paclitaxel at a dose of 50 mg/m2 (in this case combined with 50 mg/m2 of cisplatin every three weeks) with tolerable toxicity and minimal delay in planned radiation therapy. In both studies, the dose-limiting side effect appeared to be diarrhea. It should be noted that the total dose of cisplatin delivered in these trials was lower than that used in the most successful prospective trials of cisplatin or cisplatin and fluorouracil (Table 3). 

Paclitaxel is among the most active of all anticancer drugs, with significant efficacy against carcinomas of the breast, ovary, lung, head, and neck. It is combined with cisplatin in the therapy of ovarian and lung carcinomas and with doxorubicin in treating breast cancer. 

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. 

In 10 studies the corresponding clinical study protocol stipulated that cetuximab was to be given in combination with a chemotherapeutic agent (irinotecan, paclitaxel, gemcitabine, cisplatin, carboplatin, or doxorubicin) or in combination with radiation therapy. 

Larotaxel (XRP-9881, RPR 109881A) 59 (Sanofi-Aventis) is undergoing Phase III trials in patients with advanced pancreatic cancer who had been previously treated with gemcitabine, as well as in combination with cisplatin to treat locally advanced/metastatic urothelial tract or bladder cancer.124 A Phase III trial for the treatment of advanced breast cancer has been completed. Larotaxel 59129>130 js a semi-synthetic derivative of 10-deacetyl baccatin III with a docetaxel-like side chain that has a low affinity for the P-glycoprotein drug efflux pump, an efflux mechanism that diminishes the effectiveness of the marketed drugs paclitaxel 60 and docetaxel. Importantly, this low affinity should enable larotaxel 59 to be effective in tumours resistant to paclitaxel 60... 

Squalamine has been tested in mammary, ovary, and lung cancer xenograft mouse models [20,23-26]. Results sho ved that squalamine alone had a modest effect on tumor growth delay and in some cases it resulted in decreased number of lung metastases. However, in most studies, squalamine treatment was more efficacious when combined with previously established anticancer agents such as cyclophosphamide, cisplatin, carboplatin, paclitaxel, 5-fluorouracil, or genestein, or with radiation therapy. 

Previous treatment with other neurotoxic agents may compound the problem. In one study symptoms of neurotoxicity were observed in one patient who received concomitant cisplatin with paclitaxel (33). However, signs and symptoms of neurotoxicity have been insignificant in combination treatments of cisplatin and paclitaxel in other trials (1). Pre-existing neuropathy as a result of previous therapy is not a contraindication to paclitaxel (7). 

Neurotoxicity may be severe enough to require discontinuation treat myalgias/arthralgias with NSAIDs, narcotic analgesics In paclitaxel-cisplatin combination regimens, give paclitaxel first to decrease neutropenia... 

Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000 18 623-631. 

The combination of cyclophosphamide and cisplatin or carboplatin was once the first-line adjuvant therapy of choice in women with advanced-stage ovarian cancer. 5 However, paclitaxel alone, and in combination with platinum analogs, has shown significant... 

Schedules for optimal use alone or in combination with other drugs, including doxorubicin and cisplatin, still are evolving. Drug interactions have been noted the sequence of cisplatin preceding paclitaxel decreases paclitaxel clearance and produces greater toxicity than the opposite schedule. Paclitaxel decreases doxorubicin clearance and enhances cardiotoxicity, whereas docetaxel has no apparent effect on anthracycline pharmacokinetics. 

Cisplatin, in combination with bleomycin, etoposide, ifosfamide, or vinblastine, cures 90% of patients with testicular cancer. Used with paclitaxel, cisplatin induces complete response in most patients with carcinoma of the ovary. Cisplatin produces responses in cancers of the bladder, head and neck, cervix, and endometrium all forms of carcinoma of the lung anal and rectal carcinomas and neoplasms of childhood. The drug sensitizes cells to radiation therapy and enhances control of locally advanced lung, esophageal, and head and neck tumors when given with irradiation. 

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