Taxanes in Combined- Modality Therapy for Solid Tumors

Introduction

Solid tumors present a significant treatment challenge due to poor overall cure rate. However, increasing use of chemotherapy and radiation may lead to improved local control as well as overall survival of patients with many locally advanced tumors treated traditionally with radiation alone, surgery alone, or chemotherapy alone. Radiation therapy alone may fail due to the inability to deliver higher than standard doses without unacceptable toxicities and the presence of a subpopulation of tumor cells that are relatively insensitive to radiation therapy.[1] Surgery alone may fail due to the presence of disease outside of the surgical bed. In addition, chemotherapy alone has limited activity against many common solid tumors.[2]

The taxanes have several properties that are favorable for combined-modality therapy. Both paclitaxel(Drug information on paclitaxel) (Taxol) and docetaxel(Drug information on docetaxel) (Taxotere) are generally well tolerated, with significant activity in the treatment of many tumor types and a high potential for radiosensitization.[3-22] Extensive clinical experience has been gained with paclitaxel in combined-modality therapy. Recent and ongoing clinical trials are beginning to explore the radiosensitization properties of docetaxel. Both taxanes, paclitaxel and docetaxel, can be administered on an outpatient basis, and extensive clinical experience has enabled the circumvention of anaphylactic reactions. Furthermore, combinations of taxane and radiation therapy may result in less toxicity than other concurrent chemotherapy/radiotherapy regimens (eg, cisplatin(Drug information on cisplatin) [Platinol], etoposide(Drug information on etoposide), and irradiation). Major advances in the use of the taxanes in combined-modality therapy for different tumor types are discussed here.

Taxanes as Radiosensitizers

Taxanes are mitotic inhibitors that stabilize microtubules by promoting their assembly and retarding their depolymerization.[23,24] After exposure to the taxanes, cells are arrested in the G₂/M phase of the cell cycle, which is the most radiosensitive phase.[7,25] In addition to enhanced response to radiation, other effects have been observed that depend on factors that are only partially understood at present. For example, stimulation of apoptosis with paclitaxel has been observed in cell cultures[26] and in vivo.[16] Recently, the effects of paclitaxel were evaluated with 16 different murine tumors.[16] With a single dose of paclitaxel at 40 mg/kg, mitotic arrest was induced to some degree in all tumor types, and apoptosis was observed in 50% of the tumors. The kinetics of mitotic arrest and apoptosis were studied in these tumors to determine the possible mechanism of taxane effects. Apoptosis, rather than mitotic arrest, appeared to predict antitumor efficacy (as determined by the delay in tumor growth).[16] Tumor reoxygenation and repopulation occurring with taxanes also may be important in radiation enhancement.[15]

The increased cell radiosensitivity with exposure to the taxanes is evident at very low levels of the agents, below the levels required for cytotoxic effects. Numerous studies have demonstrated the radiosensitizing properties of paclitaxel in various cell lines.[3,5,12,17,20,21] Docetaxel also has been shown to enhance response to radiation and induce mitotic arrest and apoptosis in murine tumor cells.[15,27] The effects of taxane exposure have been studied with numerous human cell lines derived from lung tumors,[12,13,22,28,29] head and neck tumors,[6,9,11,30] brain tumors,[8,20,21] breast tumors,[12,13,19,28] colon tumors,[19] pancreatic tumors,[12] ovarian tumors,[12,13,18] cervical tumors, [5,9,17,31] vulvar tumors,[10] prostate tumors,[14,19] and from melanoma[22] and leukemia[3] cells. A supra-additive effect was observed most frequently, but additive or subadditive effects also were demonstrated under some experimental conditions. The extent of enhancement of the taxane-radiation interaction is dependent on the specific cell line, growth status, and intensity and duration of drug exposure.

Most in vivo studies analyzing taxane-induced radiopotentiation focused on paclitaxel and characterized both paclitaxel-sensitive and paclitaxel-resistant tumor types.[16] Radiation-induced inhibition of tumor growth is possible even in tumors that are resistant to single-agent paclitaxel, and the effects of the taxanes on the radioresponse of normal tissues are clearly less significant. The results of preclinical studies also suggest that the timing of exposure to paclitaxel relative to radiation may be critical and that the optimal timing may vary depending on the sensitivity of tumor type to the taxane. Preclinical evidence also indicates possible applications of docetaxel in combined modality therapy. Collectively, these observations form a compelling basis for the continued design of clinical trials including the taxanes in chemoradiation treatment.

Combined-modality therapy including paclitaxel or docetaxel results in substantial responses in several tumor types. Extensive experience has been gained with non–small-cell lung cancer, head and neck tumors, and esophageal tumors. Additional information will be required to determine the optimal dose and schedule of taxanes for different tumor types, the exact mechanism of action of taxane-induced radiosensitization, and the most effective use of radiation therapy in combined-modality therapy.

Non–Small-Cell Lung Cancer

No single modality of therapy has emerged as clearly most beneficial for stage III non–small-cell lung cancer.[32] Long-term survival is rare (5% to 15% of patients), regardless of whether patients undergo surgical resection or standard radiation therapy.[33] Although chemotherapy results in improved quality of life and modest survival benefits in patients with advanced, recurrent, and metastatic non–small-cell lung cancer, it is rarely effective for cure.[34-36] Several new agents with substantial activity in advanced and metastatic non–small-cell lung cancer are now available.[37] Combined chemotherapy and radiation therapy have been evaluated extensively in patients with locally advanced, unresectable non–small-cell lung cancer.[38-42]

The use of chemotherapy with radiation therapy potentially may improve control of local disease and distant micrometastases in patients with stage III non–small-cell lung cancer.[43] Early trials of chemoradiation therapy included radiation-sensitizing agents, such as hydroxyurea, bleomycin(Drug information on bleomycin) (Blenoxane), 5-fluorouracil (5-FU), and cisplatin,[42,44-47] and did not improve patient survival appreciably. A pivotal Cancer and Leukemia Group B (CALGB) trial, CALGB 8433, determined that sequential chemotherapy (cisplatin and vinblastine(Drug information on vinblastine)) followed by radiation therapy conferred a significant survival advantage over radiation alone in patients with inoperable stage III non–small-cell lung cancer.[38,39] Both taxanes have substantial activity as observed in phase II studies of previously untreated patients with metastatic non–small-cell lung cancer.[48-57] Their radiosensitizing properties stimulate continued interest in combined chemoradiation therapy using these agents.[3]

Paclitaxel

Paclitaxel, as a single agent and combined with other chemotherapeutic agents, has been investigated in several phase I and II studies in combination with radiation therapy in patients with unresectable, stage III non–small-cell lung cancer (Table 1). In a series of studies at Brown University and at Vanderbilt University,[43,58,61,70] paclitaxel and concurrent radiation therapy were assessed. The maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of paclitaxel with concurrent thoracic radiation were determined in a phase I study in which paclitaxel was administered weekly as a 3-hour infusion, starting at 10 mg/m² per week.[54] Over a period of 6 weeks, 27 patients were treated with paclitaxel at seven different dose levels, ranging from 10 to 70 mg/m² per week, with concomitant chest irradiation (60 Gy total). The MTD of paclitaxel was 60 mg/m² per week, and reversible esophagitis was the principal DLT.

In another phase I trial, Lau et al evaluated paclitaxel administered twice weekly plus concurrent radiation therapy in 26 patients with locally advanced, unresectable non–small-cell lung cancer (Table 1).[59] In 25 evaluable patients, three (12%) achieved a complete response, and 17 (68%) achieved a partial response, for an overall response rate of 80%. The most common toxicity was esophagitis, which occurred in approximately 50% of patients who received paclitaxel doses > 30 mg/m² twice weekly.

In a phase II trial (LUN-27), the response rate, toxicity, and 2-year survival rate were assessed in 33 patients who received weekly paclitaxel and concurrent radiation therapy (Table 1).[43] Previously untreated patients with histologically documented unresectable stage IIIA or stage IIIB non–small-cell lung cancer received paclitaxel 60 mg/m² administered weekly as a 3-hour infusion with concurrent radiation therapy (60 Gy total) for 6 weeks. Of 27 evaluable patients, three patients (10%) achieved a complete response and 22 patients (76%) achieved a partial response, for an overall response rate of 86% (95% confidence interval, 68% to 96%). The median follow-up duration was ³ 20 months. The 1-, 2-, and 3-year survival rates for all patients were determined to be 61%, 33%, and 18%, respectively, and the median overall survival was 20 months. Esophagitis was the most significant toxicity noted, but this adverse effect was manageable and reversible.

Paclitaxel in combination with platinum agents also has been investigated in the context of combined-modality therapy. A recent phase II trial (LUN-56) of paclitaxel/radiation therapy added two adjuvant cycles of chemotherapy to a regimen of induction chemoradiotherapy and was designed to enhance both systemic and local disease control.[70] This trial added carboplatin(Drug information on carboplatin) (Paraplatin), an agent with radiation-sensitizing potential and systemic activity when used in combination with paclitaxel. Forty previously untreated patients (25 male, 15 female) with stages IIIA and IIIB non–small-cell lung cancer entered the trial. On an outpatient basis for 7 weeks, patients received paclitaxel 50 mg/m² per week as a 1-hour infusion and carboplatin at an area under the plasma concentration-time curve of 2 (AUC in mg/mL • min) weekly as a 30-minute infusion, with radiation to the tumor and regional lymph nodes (44 Gy) followed by a boost to the tumor (22 Gy). Following chemoradiation therapy, patients received an additional two cycles of paclitaxel (200 mg/m² as a 3-hour infusion) and carboplatin (AUC of 6) every 3 weeks.

In 39 eligible patients, 12- and 24-month survival rates were 55.7% and 40.6%, respectively, with a median overall survival of 20.5 months. The 12- and 24-month progression-free survival rates in 39 eligible patients were 48.3% and 38.6%, respectively, with a median progression-free survival of 8.8 months. The overall response rate (partial plus complete response) of 37 evaluable patients was 75.7%. The major nonhematologic toxicity was esophagitis. Seventeen patients (46%) developed grade 3 or 4 esophagitis at the end of the concurrent phase. However, only two patients developed late esophageal toxicity, with stricture at 3 and 6 months posttreatment. This study demonstrated that combined-modality therapy with paclitaxel, carboplatin, and radiation is a promising treatment for locally advanced non–small-cell lung cancer, by virtue of a high response rate, acceptable toxicity, and survival rates that compare favorably with those in other multimodality studies.[70]

In a Vanderbilt Cancer Center Affiliate Network (VCCAN) phase II study (LUN-63), chemotherapy with concurrent hyperfractionated radiation therapy was investigated.[61] Forty-three patients with unresectable stage IIIA/IIIB non–small-cell lung cancer received weekly treatment with paclitaxel/carboplatin plus hyperfractionated radiation therapy, followed by two cycles of consolidation paclitaxel/carboplatin administered 3 weeks apart. Of the 42 patients evaluable for response, three patients (7%) experienced a complete response and 30 patients (71%) experienced a partial response for an overall response rate of 79%. The 1-year overall survival rate was 63% for all patients. As in previous studies, esophagitis was the principal toxicity; grade 3 or 4 esophagitis occurred in 11 patients (26%). Although a randomized trial is necessary to fully evaluate this regimen, these results with concurrent weekly paclitaxel/carboplatin and hyperfractionated radiation therapy are promising.

Another phase II trial[65] evaluated twice-weekly paclitaxel/weekly carboplatin plus concurrent radiation therapy followed by consolidation paclitaxel/carboplatin in patients with locally advanced, unresectable non–small-cell lung cancer. In 17 evaluable patients, complete responses were achieved in two patients (12%) and partial responses in eight patients (47%), for an overall response rate of 59%. Grade 3/4 toxicities included esophagitis, myelosuppression, and nausea/vomiting; these occurred primarily during the concurrent chemoradiation therapy phase of treatment.

Other trials of chemoradiotherapy with paclitaxel/platinum compounds involved various paclitaxel doses and administration schedules (Table 1).[62,66-68,71-73] Induction chemotherapy was used in some studies, in which concurrent chemoradiation therapy with paclitaxel and platinum combinations was initiated following induction.[54,67,68] Results of these trials also are encouraging, with overall response rates of 59% to 82%, and 1-year survival rates of 60% to 74%.[54,67,68]

Results of recent trials of paclitaxel/carboplatin and radiation therapy demonstrated manageable toxicity and highlight the importance of chemoradiation therapy for locally advanced non–small-cell lung cancer.[63] Several current and proposed trials are being conducted by the large cooperative oncology groups in the United States.[74] Ongoing phase II and III trials are evaluating the utility of continuous infusion of paclitaxel,[75] amifostine(Drug information on amifostine) mucosal protection,[76,77] as well as induction chemotherapy with paclitaxel plus concurrent chemoradiotherapy.[78-80] In the CALGB 9431 trial,[81] induction chemotherapy with subsequent concomitant chemoradiotherapy is being investigated. Patients with stage IIIB non–small-cell lung cancer are receiving four cycles of cisplatin 80 mg/m², with two cycles being administered concurrently with gemcitabine(Drug information on gemcitabine) (Gemzar) 1,250 mg/m² (arm 1), paclitaxel 225 mg/m² (arm 2), or vinorelbine (Navelbine) 25 mg/m² (arm 3), and a total of 60 Gy of radiation. In an early analysis of the results of this trial, the treatments in all three study arms generally were tolerable.

In the CALGB 9531 trial, patients with stage IIIB non–small-cell lung cancer receive two cycles of induction chemotherapy with paclitaxel 200 mg/m² and carboplatin (AUC of 6), followed by paclitaxel 50 mg/m² per week and carboplatin (AUC of 2) weekly with concurrent radiation therapy. The results of this trial will determine the protocol for a randomized phase III CALGB trial in which patients will receive either concurrent chemoradiotherapy with paclitaxel/carboplatin or two cycles of induction chemotherapy with paclitaxel/carboplatin followed by concurrent chemoradiotherapy with paclitaxel/carboplatin.[74]

Paclitaxel/carboplatin was evaluated in a recent phase III Eastern Cooperative Oncology Group (ECOG) 1594 study of patients with stage IV (and selected stage IIIB) non–small-cell lung cancer. The ECOG is planning to use

a similar regimen of paclitaxel/carboplatin in patients with stage III non–small-cell lung cancer in a trial evaluating two cycles of induction paclitaxel/carboplatin followed by randomization to conventional daily radiotherapy (64 Gy/7 weeks) or hyperfractionated accelerated radiation therapy (57.8 Gy/36 fractions/15 treatment days).[74]

The Southwestern Oncology Group (SWOG) is conducting a trial of induction paclitaxel/carboplatin followed by weekly paclitaxel/carboplatin plus concurrent radiation therapy and consolidation paclitaxel/carboplatin in patients with unresectable stage III non–small-cell lung cancer.[74] The Radiation Therapy and Oncology Group (RTOG) is conducting a phase II trial (RTOG 9801) of induction paclitaxel/carboplatin followed by paclitaxel/carboplatin plus concurrent radiation therapy, with or without amifostine for mucosal protection.[77] Results of these ongoing trials should further define the role of paclitaxel-based chemoradiation therapy in patients with unresectable stage III non–small-cell lung cancer.