The Safety of Paclitaxel/Platinum Combinations

Introduction

Taxanes represent a novel class of antineoplastic agents with broad antitumor activity. Paclitaxel(Drug information on paclitaxel) (Taxol) was the first taxane in clinical development and the numerous trials performed thus far have enabled researchers to precisely define its safety profile. Myelosuppression is dose- and schedule-dependent; musculoskeletal symptoms are dose-dependent and cumulative but not schedule-dependent. The safety profile of paclitaxel has been based on a careful analysis of these toxicities, allowing the best therapeutic regimen to be developed by combining paclitaxel with other drugs. This approach creates the most favorable therapeutic index.

Most patients with non–small-cell lung cancer present with advanced disease and, therefore, chemotherapy is indicated. Cisplatin(Drug information on cisplatin) (Platinol)-based chemotherapy regimens have been shown to produce a survival advantage over “best supportive care.” In a phase III randomized study performed by the Eastern Cooperative Oncology Group (ECOG), paclitaxel at 250 mg/m² over 24 hours with cisplatin at 75 mg/m², and paclitaxel at 135 mg/m² over 24 hours with cisplatin at 75 mg/m² were compared to the standard treatment with cisplatin at 75 mg/m²and etoposide(Drug information on etoposide) at 100 mg/m² for 3 days. The paclitaxel combinations proved more efficacious in terms of response and survival, with a similar toxicity profile in comparison to etoposide/cisplatin.

In another phase III study conducted by the European Organization for Research and Treatment of Cancer (EORTC), paclitaxel/cisplatin was compared to cisplatin/teniposide (Vumon). The paclitaxel combination was better tolerated with less severe myelosuppression, febrile neutropenia, infections, treatment delays, and dose reductions. The paclitaxel combination produced more hypersensitivity reactions, myalgia/arthralgia, and peripheral neurotoxicity.

As a single agent, carboplatin(Drug information on carboplatin) (Paraplatin), a cisplatin analog, has produced the best 1-year survival rate with the least toxicity in a five-arm ECOG study of patients with non–small-cell lung cancer. The Hellenic Cooperative Oncology Group (HECOG) completed a phase II study of paclitaxel at 175 mg/m², and carboplatin at an area under the concentration-time curve of 7 (AUC in mg/mL · min). In 55 patients, the response rate was 27.3% and the 1-year survival was 21.6%. The median survival was 8.95 months. Generally, mild toxicity was seen in this trial. World Health Organization (WHO) grade 3 neutropenia appeared in 7% of the patients, and no neutropenic infection occurred. Grade 3 myalgia/arthralgia was reported in 5%. One patient developed a hypersensitivity reaction shortly after the beginning of the administration of the second cycle.

Subsequently, our group initiated a phase III trial with two different doses of paclitaxel (225 mg/m² vs 175 mg/m²) and a fixed dose of carboplatin (AUC of 6). In this study, neutropenia and neurotoxicity were significantly worse at the higher paclitaxel dose. However, the treatments were well tolerated and no granulocyte–colony-stimulating factor was required.

The paclitaxel/cisplatin combination has been shown to have a similar toxicity profile to standard combinations when administered via 24-hour infusion and a better toxicity profile when given in a 3-hour infusion. Paclitaxel/carboplatin is an easier to administer and well-tolerated combination. A phase III randomized trial of the two platinum combinations is in progress.

Background

The taxanes are a novel class of antineoplastic agents with broad antitumor activity.[1] Paclitaxel was the first taxane in clinical development, and has since been administered to thousands of patients throughout the world. A variety of doses and schedules have been studied in an effort to optimize a favorable therapeutic index.[2] A careful analysis of paclitaxel-related side effects is important for a safer and more effective combination of this drug with other agents.

Myelosuppression and peripheral neuropathy are the major dose-limiting toxicities of paclitaxel. A peculiar characteristic of paclitaxel-induced neutropenia is the schedule-dependency, which confers a clear safety advantage to short (3-hour) infusions. This advantage facilitates the combination of paclitaxel with other antineoplastic agents. The lack of cumulative myelosuppression associated with paclitaxel is also important and beneficial for combination therapies.

Peripheral neuropathy is not schedule-dependent but cumulative (Table 1). For this reason, combining it with other neurotoxic agents such as cisplatin necessitates careful monitoring. Musculoskeletal symptoms such as myalgia and arthralgia are dose-dependent and transient, but not cumulative.

As experience with paclitaxel increased, it became evident that hypersensitivity reactions could be prevented by proper premedication, and that cardiac abnormalities associated with the drug consisted mainly of asymptomatic bradycardia or hypertension.[3] Additional care must be taken for patients with preexisting cardiac conditions.

Emesis is very mild during paclitaxel treatment. Liver function is rarely impaired, and renal function is usually unaffected.

Paclitaxel/Cisplatin Combinations

Cisplatin combination chemotherapies are the cornerstone of treatment for non–small-cell lung cancer. A meta-analysis has shown a survival advantage that did not exist before the availability of cisplatin.

Many phase I and II studies have been undertaken with paclitaxel and cisplatin in non–small-cell lung cancer. The most important dose-limiting toxicity has been neurotoxicity. In one of these studies, Le Chevalier treated 32 patients at five dose levels. Neurotoxicity appeared to be dose-limiting, with 200 mg/m² of paclitaxel and 100 mg/m² of cisplatin defined as the maximum tolerated dose. Neurotoxicity was observed earlier with higher doses.[4]

Two major phase III trials have compared paclitaxel/cisplatin with standard chemotherapies for non–small-cell lung cancer. One was conducted in Europe through EORTC, using cisplatin/teniposide as the standard arm.[5] The second trial was conducted in the United States through ECOG using cisplatin/etoposide as the standard arm.[6] In both studies, the paclitaxel/cisplatin combination was used as the experimental arm. Paclitaxel was infused over 3 hours in Europe, and over 24 hours in the United States. In addition, ECOG used a third arm with high-dose paclitaxel/cisplatin and growth factor.

Myelosuppression appeared to be the most important toxicity seen in these studies. In the EORTC trial, myelosuppression and its complications, neutropenic fever and infection, were significantly worse in the cisplatin/teniposide arm. In the ECOG trial, however, myelosuppression was more prominent in the paclitaxel/cisplatin arms. Neutropenic infections were not more frequent among patients receiving paclitaxel. It is evident that the use of the 24-hour infusion increases myelosuppression. In both studies, peripheral neuropathy and myalgia appeared more pronounced in the paclitaxel/cisplatin arms.

Based on these studies, paclitaxel (175 to 200 mg/m² over a 3-hour infusion) combined with cisplatin (75 to 100 mg/m²) is a safe and active combination for non–small-cell lung cancer.

Paclitaxel/Carboplatin Combinations

In a five-arm randomized trial conducted by ECOG, carboplatin was shown to offer the best 1-year survival rate with the least toxicity in patients with non–small-cell lung cancer. Several phase I and II studies have investigated the combined use of paclitaxel and carboplatin. Langer et al used paclitaxel in a 24-hour infusion along with carboplatin at an AUC of 7.5.[7] The combination was well tolerated except for myelosuppression. In this study, 71% of patients developed grade 3 or 4 granulocytopenia.

Most of the investigators, mainly in Europe, have used paclitaxel as a 3-hour infusion. Among them, the HECOG initiated a phase II trial for patients with inoperable non–small-cell lung cancer. Paclitaxel was given at a dose of 175 mg/m² as a 3-hour infusion, and carboplatin at an AUC of 7. The treatment was repeated every 3 weeks without the use of growth factors.[8]

Among the 60 patients in the HECOG trial, 55 were evaluable. The response rate was 27.1%, overall median survival was 8.95 months, and 1-year survival was 21%. The median relative dose intensity for paclitaxel was 0.995. The combination was extremely well tolerated. Hematologic toxicity was mild with grade 3 granulocytopenia occurring in 7% of patients and grade 3 and 4 thrombocytopenia occurring in 4%. Nonhematologic toxicity was also mild. Grade 2 neurotoxicity occurred in 3% of patients and one patient developed a severe hypersensitivity reaction despite the administration of premedication.

The Hellenic Cooperative Oncology Group initiated a second trial in an effort to examine a possible dose-response relationship for paclitaxel. In both arms of this randomized phase III study, carboplatin was given at an AUC of 6. Paclitaxel was also given, at a dose of 175 mg/m² in the first arm (Group A) and 225 mg/m² in the second arm (Group B). The duration of infusion was 3 hours, and the treatment was repeated every 3 weeks without the use of growth factors.[9]

Accrual was completed recently and the toxicity was analyzed. Again, hematologic toxicity was mild (Table 2) Grades 3 and 4 leukopenia were observed in 12% of patients in the high-dose paclitaxel arm. Overall leukopenia appeared significantly worse in the high-dose paclitaxel recipients. Neither neutropenic febrile episodes nor toxic deaths were observed, and nonhematologic toxicity was also mild (Table 3). The most troublesome toxicity was peripheral neuropathy, which appeared to be significantly worse in the high-dose arm. Nausea/vomiting and myalgia/arthralgia were mild in both groups and were well tolerated.

Based on these and other combination studies, it seems that paclitaxel, 200 mg/m² as a 3-hour infusion, and carboplatin at an AUC of 6, both given every 3 weeks, is a safe and active combination for non–small-cell lung cancer. The results of an ongoing phase III study comparing paclitaxel/cisplatin and paclitaxel/carboplatin are anticipated with interest.