Taxanes in Combined- Modality Therapy for Solid Tumors

October 1, 1999

The taxanes, paclitaxel and docetaxel, are novel antimitotic agents that are under extensive investigation in clinical trials in patients with various solid tumors. The taxanes have demonstrated significant activity against

ABSTRACT: The taxanes, paclitaxel and docetaxel, are novel antimitotic agents that are under extensive investigation in clinical trials in patients with various solid tumors. The taxanes have demonstrated significant activity against many solid tumors as single agents and in combination with other chemotherapeutic agents. In addition, paclitaxel and docetaxel arrest cells at the G2/M phase of the cell cycle, which is the most radiosensitive phase. Numerous clinical trials have assessed paclitaxel-based chemoradiation therapy in a variety of tumor types, including non–small-cell lung cancer, small-cell lung cancer, head and neck cancers, esophageal cancer, brain tumors, pancreatic and gastric tumors, and locally advanced breast cancer. Fewer clinical trials have assessed docetaxel plus radiation therapy in these tumor types. This review highlights recent clinical trials of the taxanes in combination with radiation therapy for solid tumors. [ONCOLOGY 13(Suppl 5):23-38, 1999]

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 (Taxol) and 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 [Platinol], 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 (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) 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 (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 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 (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.

Docetaxel

Preclinical data indicate that docetaxel has radiosensitizing properties,[6-9,27] and clinical trials of docetaxel plus radiation therapy have been initiated in patients with non–small-cell lung cancer and esophageal cancer.[82,83] In a recent phase I study[82] designed to determine the maximum tolerated dose and optimal schedule of docetaxel with concurrent radiotherapy, 29 patients (20 with non–small-cell lung cancer and nine with esophageal cancer) initially received docetaxel 40 mg/m² on day 1 of 21-day cycles, docetaxel 20 mg/m² on days 1 and 8 of 21-day cycles, or docetaxel 20 mg/m² each week of 21-day cycles; doses were escalated to 60 mg/m² per 21-day cycle and 75 mg/m² per 21-day cycle, with a weekly administration schedule used in some patients. Concurrent radiotherapy was administered at daily doses of 1.8 to 2.0 Gy to a total dose of 45 to 70 Gy. Within the radiation field, there was an overall response rate of 40% among 20 evaluable patients with non–small-cell lung cancer and 22% among nine evaluable patients with esophageal cancer. Esophagitis and neutropenia were dose-limiting toxicities. The maximum tolerated doses of docetaxel with concurrent radiation therapy were 40 mg/m² per cycle when given as one or two doses per cycle and 60 mg/m² when given as three doses per cycle (ie, 20 mg/m2 weekly). Although concurrent docetaxel and radiation therapy appeared to be feasible, the patient group was heterogeneous, and further studies are warranted.

Another phase I trial[83] evaluated docetaxel 20 to 40 mg/m² per week plus concurrent radiation therapy (40-Gy primary dose with 20-Gy boost) in 11 patients with unresectable stage III non–small-cell lung cancer. Response and survival data are not yet available; grade 4 toxicities (including hyperglycemia, esophagitis, and skin toxicity) were observed in all dose groups.

An ongoing SWOG phase II trial is assessing docetaxel as consolidation chemotherapy for patients with stage IIIB non–small-cell lung cancer.[74] In this study, patients receive cisplatin/etoposide with 60 Gy of concurrent radiation therapy, followed by three cycles of docetaxel. Further investigation is necessary to determine the role of docetaxel in combined-modality therapy for unresectable stage III non–small-cell lung cancer.

Small-Cell Lung Cancer

Combinations of etoposide and platinum agents are used commonly as standard chemotherapy regimens for the treatment of extensive-stage small-cell lung cancer. For patients with limited-stage disease, radiation therapy has been added to these regimens, resulting in good efficacy and potential for cure. Small but significant improvements in survival were measured in two meta-analyses of patients who received chemotherapy in addition to radiation therapy.[84,85] No chemoradiotherapy regimen emerged from these studies as clearly superior,[86] and newer chemotherapeutic agents with activity in small-cell lung cancer continue to be evaluated.

Paclitaxel

Studies coordinated by ECOG and the North Central Cancer Treatment Group demonstrated the activity of single-agent paclitaxel in small-cell lung cancer.[87,88] Subsequently, paclitaxel in combination with etoposide and/or platinum agents has been evaluated in numerous studies in small-cell lung cancer patients, with encouraging response rates.[89]

Studies have evaluated paclitaxel-containing chemotherapy and radiation therapy in patients with limited-stage small-cell lung cancer (Table 2).[90-92] In a phase II trial by Hainsworth et al paclitaxel/carboplatin plus etoposide at two dose levels were evaluated with concurrent radiation therapy in 56 patients with limited-stage small-cell lung cancer.[90] With the low-dose regimen, six of 15 evaluable patients achieved a complete response (40%) and eight patients (53%) achieved a partial response, for an overall response rate of 93%; with the high-dose regimen, 29 of 41 evaluable patients achieved a complete response (71%) and 11 patients (27%) achieved a partial response, for an overall response rate of 98%. Median survivals for the low-dose and high-dose regimens were 17 months and > 16 months, respectively. Both regimens were generally well tolerated, with a higher incidence of myelosuppression observed with the high-dose regimen. Other grade 3/4 toxicities included esophagitis, anemia, and leukopenic fever.

An ongoing phase II trial is evaluating the addition of paclitaxel to cisplatin/etoposide plus radiation therapy in patients with limited-stage small-cell lung cancer (Table 2).[91] In 20 evaluable patients thus far, 16 achieved a complete response (80%), and three achieved a partial response (15%), for an overall response rate of 95%. The regimen was generally well tolerated; the most common grade 3/4 toxicities included leukopenia and thrombocytopenia. Grade 3 esophagitis was observed in two patients.

Other trials evaluating chemoradiation therapy in limited-stage small-cell lung cancer are ongoing by RTOG and ECOG. The results of these trials should contribute to a better understanding of the importance of dose and schedule of paclitaxel in chemoradiation therapy for small-cell lung cancer.

Docetaxel

To date, no data on docetaxel in combined-modality therapy for small-cell lung cancer have been published. Only one new chemotherapeutic agent (topotecan [Hycamtin]) and one new biologic treatment (marimastat) are currently being evaluated in randomized clinical trials in small-cell lung cancer.[86] The current status of research in this area reflects the need for evaluation of new treatments.

Head and Neck Cancer

Although radical neck dissection previously was preferred in the treatment of neck metastases,[93] a combination of surgery and radiation therapy improves local and regional control of stages III and IV head and neck cancers.[94,95] However, 5-year survival rates remain below 40% and do not differ significantly from those in patients who undergo surgery alone.[95,96] The addition of chemotherapy to the treatment of locally advanced head and neck cancers may improve prospects for long-term survival. Chemotherapeutic agents used in the treatment of squamous cell carcinoma of the head and neck in the past included methotrexate, bleomycin, cisplatin, 5-FU, and carboplatin, with single-agent response rates of 15% to 31%.[97,98] Newer chemotherapeutic agents (eg, paclitaxel, docetaxel) result in single-agent response rates of approximately 38%.[97,98] Randomized trials also demonstrated that chemoradiation therapy results in increased time to progression and increased overall survival rates.[99,100]

Paclitaxel

Numerous phase I and II trials have evaluated paclitaxel (as a single agent and in combination with other chemotherapeutic agents) plus radiation therapy in patients with locally advanced head and neck cancer (Table 3). Phase I trials evaluated various paclitaxel doses and administration schedules with radiation therapy.[101-104] Grade 3/4 toxicities included mucositis, skin toxicity, and myelosuppression; toxicities generally were manageable. Response rates were encouraging, with complete response rates ranging from 50% to 75% and overall response rates of 90% to 100%. Two phase II trials evaluated paclitaxel/platinum chemoradiation regimens in patients with locoregionally advanced head and neck cancers.[105,107] One phase II trial[105] assessed weekly paclitaxel/carboplatin with concurrent radiation therapy, and one phase II trial[107] assessed induction chemotherapy with paclitaxel/carboplatin and concurrent radiation therapy followed by follow-up chemotherapy with 5-FU, interferon alfa, and cisplatin. Results of these trials were encouraging, with complete response rates of 57% to 78%. Principal toxicities included mucositis, skin toxicity, and myelosuppression.

A regimen of 5-FU/hydroxyurea plus radiation therapy (FHX) was developed at the University of Chicago for the treatment of patients with locally advanced head and neck cancer, which has resulted in encouraging response and survival rates, with good tolerability.[108] Additional studies demonstrated that this widely used regimen was effective even in previously irradiated patients.[109] Recent trials evaluated the feasibility of adding other agents, such as cisplatin or paclitaxel, to the FHX regimen in poor-prognosis patients who had failed to respond to earlier surgery or radiation therapy.[108,110] The addition of cisplatin to the FHX regimen was generally tolerable with granulocyte colony-stimulating factor (G-CSF) support, and the regimen resulted in a high locoregional control rate and a long failure-free interval.[110]

More recently, paclitaxel was added to the FHX regimen to enhance locoregional control and treat systemic micrometastatic disease. In a phase I trial, 55 patients with poor-prognosis head and neck cancer received 14-day cycles of 5-FU (600-800 mg/m²/day for 5 days), hydroxyurea (500 mg or 1,000 mg twice daily for 11 days), and escalating paclitaxel doses (5 to 25 mg/m² per day for 5 days) plus concurrent radiation therapy (2 Gy on days 2 through 6 or 1.5 Gy twice daily) and G-CSF support.[108] The addition of paclitaxel to the FHX regimen is feasible, and patients generally experienced less toxicity with this regimen than with the cisplatin-FHX regimen. Consequently, a phase II study of the paclitaxel-FHX regimen was initiated in previously untreated patients with locoregionally advanced head and neck cancer.[111] At a median follow-up of 10 months, 29 of 57 patients had achieved a complete response and 14 of 57 patients had achieved a partial response, for an overall response rate of 75%. Therefore, this intensive concurrent chemoradiotherapy regimen resulted in encouraging locoregional control in patients with advanced disease.

Encouraging results in trials including paclitaxel-containing regimens stimulated further investigation of novel administration schedules and investigation of other new chemotherapeutic agents. A phase II study recently was initiated to evaluate a simplified paclitaxel/FHX regimen with paclitaxel administered over 1 hour on day 1 of chemoradiotherapy between the two daily radiation fractions.[112]

Docetaxel

Docetaxel has substantial activity in squamous cell carcinoma of the head and neck.[113,114] Two phase II studies including a total of 74 patients evaluated the activity, safety, and tolerability of docetaxel 100 mg/m² infused over 1 hour every 3 weeks in patients with locoregional or metastatic squamous cell carcinoma of the head and neck.[113,114] Docetaxel was generally tolerable and could be safely administered on an outpatient basis.[114] Overall response rates for single-agent docetaxel in these trials ranged from 32% to 42%.[113,114] In a recent phase II study, a combined regimen of docetaxel with cisplatin was investigated in locally advanced, recurrent, and/or metastatic squamous cell carcinoma of the head and neck.[115] Analysis of this study has not been completed yet.

A phase I/II trial explored the use of induction chemotherapy followed by radiation therapy in 23 previously untreated patients with advanced squamous cell carcinoma of the head and neck.[116] Induction chemotherapy consisted of docetaxel (25 mg/m², 45 mg/m², or 60 mg/m² with and without growth factor support) plus cisplatin (25 mg/m²), 5-FU (700 mg/m²), and leucovorin (500 mg/m²) (PFL) every 28 days for up to three cycles; 72 to 74 Gy of radiation therapy was administered to the primary site following induction chemotherapy. The maximum tolerated dose of docetaxel was 60 mg/m² when combined with the PFL regimen. The dose-limiting toxicity was neutropenia; other major toxicities included nausea, mucositis, diarrhea, peripheral neuropathy, and nephropathy. In 22 evaluable patients, clinical complete responses at the primary site were observed in 19 patients (86%), and clinical partial responses were observed in three patients (14%), for an overall response rate of 100%. The encouraging results of this study merit further evaluation of this combination. An ongoing phase I study is evaluating induction chemotherapy followed by weekly 1-hour docetaxel infusions and concurrent radiotherapy for 6 weeks in previously untreated patients with advanced squamous cell carcinoma of the head and neck.[117]

Esophageal Cancer

Radiation therapy plays an important role in the management of esophageal cancer, mainly as a component of multimodality therapy. Chemoradiation currently is considered the nonsurgical standard of care for local-regional esophageal cancer and may prolong survival and increase cure rates when administered prior to surgical resection. Chemoradiation therapy has been the focus of many studies in esophageal cancer because several chemotherapeutic agents active against this tumor are known radiosensitizers (eg, paclitaxel, 5-FU, and cisplatin).[118]

Paclitaxel

Paclitaxel has substantial single-agent activity in advanced or metastatic esophageal cancer, with acceptable toxicity. Paclitaxel is therefore under investigation in neoadjuvant chemoradiation regimens in combination with cisplatin[119] or cisplatin or carboplatin plus 5-FU (Table 4).[120,121,123,124] Paclitaxel was evaluated at various doses and administration schedules. Preliminary results of these trials are encouraging, with overall response rates in phase II trials ranging from 42% to 81%.[119,121,123] Principal grade 3/4 toxicities included esophagitis and myelosuppression. Additional phase I and II trials are in progress to explore the use of paclitaxel in combination with cisplatin or carboplatin as neoadjuvant therapy in patients with potentially resectable esophageal cancer[125] and in patients with unresectable locally advanced or metastatic esophageal cancer.[126,127] Results of these trials should further define the role of paclitaxel-containing chemoradiation therapy in esophageal cancer.

Docetaxel

Data on docetaxel in combined-modality therapy for esophageal cancer are limited. Two recent phase I trials evaluated docetaxel 40 to 75 mg/m² per 21-day cycle with concurrent radiation therapy at 2 Gy/day in patients with advanced unresectable malignancies, including esophageal cancer.[82,128] The MTDs in one trial[82] were 40 mg/m² per cycle when administered once every 3 weeks or for 2 weeks of every 3 weeks and 60 mg/m² per cycle when administered weekly for 3 weeks (ie, 20 mg/m² per week). Similarly, the MTDs of docetaxel in the other phase I trial was 20 mg/m² per week in combination with radiation therapy.[128] Esophagitis and neutropenia were the DLTs.[82,128] Partial responses were observed in both studies, encouraging further investigation of docetaxel in combined-modality therapy for esophageal cancer.

Brain Tumors

Progress in the treatment of brain tumors since the early 1980s has been limited, and standard radiation treatments frequently fail to achieve local control of the disease.[129] Despite the need for newer therapeutic approaches, little information is available concerning treatment of primary brain tumors with paclitaxel, which is effective against a wide range of solid tumors.[129] Brain tumor sensitivity to single-agent paclitaxel appears to be dependent on histology. Newly diagnosed or recurrent glioblastomas multiforme are relatively resistant to single-agent paclitaxel, while gliomas and brain metastases with oligodendroglial components appear to be sensitive to the effects of paclitaxel. The in vitro radiosensitizing properties of paclitaxel and activity against glioma cell lines stimulated the design of several recent trials of multimodality therapy for primary brain tumors (Table 5).

In addition to these trials, a phase III study coordinated by RTOG is evaluating the use of paclitaxel with conventional cranial irradiation for newly diagnosed malignant astrocytomas or with stereotactic radiosurgery for recurrent tumors.[133] Concurrent chemotherapy and radiation therapy also may be effective in the treatment of metastatic brain tumors. Further study of the pharmacokinetics of paclitaxel in patients with brain tumors is important, and the optimal dose and schedule of administration are critical questions in the treatment of this tumor type, as for others.[133] In a phase I/II investigation of combined-modality therapy including conventional cranial irradiation, a weekly schedule of paclitaxel was used.[129,131] When pharmacologic properties and safety are considered, a weekly paclitaxel administration schedule is preferable, but additional studies are required for confirmation of its utility.

Docetaxel has not been used extensively in the treatment of brain tumors, either in chemotherapy or chemoradiotherapy regimens. In a phase II trial of docetaxel 75 mg/m² (when prior adjuvant therapy was administered) or 100 mg/m² (when no prior chemotherapy was administered) in 18 patients with recurrent malignant gliomas (five with glioblastoma multiforme and the remainder with other malignant gliomas), no complete or partial responses were observed.[134] A lack of central nervous system penetration was observed in a single case study of a patient with leptomeningeal carcinomatosis.[135] While these data are limited, docetaxel does not appear to have significant activity against brain tumors.

Pancreatic and Gastric Cancers

More effective means of local disease control are needed in the treatment of pancreatic, gastric, and gastroesophageal adenocarcinomas. Most patients with pancreatic cancer have extensive, unresectable disease at the time of diagnosis. Historically, attempts to use combined-modality therapy (eg, 5-FU, mitomycin, and radiation therapy) in the treatment of pancreatic cancer did not yield encouraging results,[136] and newer, less toxic agents with good activity are needed to treat this disease. The incidence of gastric and gastro-esophageal junction adenocarcinomas is rising. In patients with gastric cancer, local recurrence of disease after surgical resection is an important cause of treatment failure. Newer approaches, including more effective neoadjuvant regimens, are needed for the treatment of these upper gastrointestinal malignancies.

A trial similar to that conducted for non–small-cell lung cancer[58] was completed recently for the treatment of gastric-pancreatic cancer.[137] Paclitaxel 30 to 60 mg/m²IV over 3 hours was administered weekly for 6 weeks with concurrent radiation therapy

(50 Gy delivered in 28 fractions of 1.8 Gy each) in patients with locally advanced pancreatic (n = 18) or gastric (n = 16) cancer. Substantial activity was observed in this study against both pancreatic and gastric cancers. Among the 13 patients with pancreatic cancer evaluable for response, there were no complete responses and four partial responses, for an overall response rate of 31%. Among 10 evaluable patients with gastric cancer, there were no complete responses and seven partial responses, for an overall response rate of 70%. The dose-limiting toxicities in this study were abdominal pain within the irradiated field, nausea, and anorexia, which occurred at a paclitaxel dose of 60 mg/m².

Two phase II studies were initiated to evaluate paclitaxel 50 mg/m² per week with concurrent radiation therapy (at a total dose of 50 Gy) in patients with locally advanced pancreatic and gastric cancers.[138] After enrollment of 25 patients in the pancreatic cancer trial, six of 18 evaluable patients achieved a partial response, for a preliminary response rate of 33%. Grade 3/4 toxicities included hypersensitivity reactions, neutropenia, and nonneutropenic biliary sepsis. Among the first 16 patients with gastric cancer, one complete response and eight partial responses were observed, for an overall preliminary response rate of 56%. In this trial, grade 3/4 toxicities observed included nausea, anorexia, esophagitis, and gastritis. In 24 patients with adenocarcinomas of the gastroesophageal junction, there were four complete responses and 14 partial responses, for an overall response rate of 75%. Grade 3/4 toxicities included neutropenia, nausea, and dehydration. These trials demonstrated that chemoradiation including paclitaxel is well tolerated and has substantial activity against locally advanced upper gastrointestinal malignancies.

Ongoing trials are evaluating paclitaxel with concurrent radiotherapy for pancreatic and gastric cancers.[139-141] Results of these trials should further define the role of paclitaxel-based chemoradiation therapy for these tumor types.

The role of docetaxel in combined-modality therapy for gastric cancers has not been established. Preliminary results of phase II clinical trials have confirmed the single-agent activity of docetaxel against gastric cancers.[4] Further investigation is necessary.

Breast Cancer

Standard therapy for locally advanced breast cancer consists of systemic neoadjuvant chemotherapy followed by surgery and then radiation therapy.[142] The toxicity of some chemotherapy regimens (eg, anthracycline-based regimens) limit their utility in combined-modality therapy. Chemoradiation therapy has demonstrated efficacy in the treatment of other tumor types, and newer radiosensitizing agents (eg, paclitaxel) that are effective against breast cancer are now available.[143,144] The effects of preoperative chemoradiation were assessed in a pilot trial evaluating 5-FU (200 mg/m² as a continuous infusion) plus radiation therapy (50 Gy at 2-Gy/fraction) in 35 patients with locally advanced breast cancer.[145] Treatment resulted in an overall response rate of 72% (complete and partial responses) and was well tolerated; furthermore, all patients could then undergo modified radical mastectomy.

Paclitaxel is highly active as a single agent against breast cancer,[143,146,147] and its radiosensitizing properties were demonstrated both in vitro and in vivo.[5,12,17,20,21] Preliminary results of a trial assessing paclitaxel plus radiation therapy in patients with locally advanced breast cancer were reported recently.[142] Patients initially received paclitaxel 60 mg/m² per week plus radiation therapy 50 Gy (in 2-Gy fractions) over 5 weeks. Due to toxicity experienced by the first two patients, the chemotherapy regimen was modified to paclitaxel 30 mg/m² twice weekly. Patients were then resected and received anthracycline-containing follow-up chemotherapy. Of the 13 patients enrolled thus far, eight patients are evaluable for response and toxicity. The twice-weekly schedule was more easily tolerated, and four patients (50%) achieved a pathological response (including complete and partial responses). Correlation of biomarkers with response will be attempted in a subset of patients in this trial. Loss of p53 function confers sensitivity to paclitaxel in several cell types,[148] and identification of relevant tumor characteristics may lead to better patient selection for taxane-based treatment.

Although docetaxel is highly active against breast cancer,[4] no results of clinical trials evaluating docetaxel in combined-modality therapy for breast cancer have been reported to date.

Summary

In recent studies, the activity of taxanes (as single agents and in combination with other chemotherapeutic agents) plus radiation therapy has been evaluated in a variety of tumor types. For locally advanced non–small-cell lung cancer, results available from phase I and II trials indicate that combined-modality therapy including paclitaxel is generally well tolerated and achieves control of local and metastatic disease. Novel paclitaxel administration schedules, including weekly and twice-weekly infusions, are being evaluated in combination with standard and hyperfractionated radiation therapy. Trials adding platinum compounds to paclitaxel-based regimens are also yielding encouraging results. Ongoing trials are evaluating docetaxel plus radiation therapy in patients with locally advanced unresectable non–small-cell lung cancer. Taxane-based chemotherapy plus radiation therapy is being explored for small-cell lung cancer, poor-prognosis squamous cell carcinoma of the head and neck, esophageal cancer, brain tumors, pancreatic and gastric cancers, and locally advanced breast cancer. Ongoing trials also are beginning to evaluate concurrent paclitaxel and radiotherapy for pelvic malignancies.[149-152]

Molecular genetic alterations in tumor cells are the focus of a growing number of studies. Tumors with p53 gene mutations may respond in unique ways to radiation and chemotherapy, possibly requiring cytotoxic agents with novel mechanisms of action. An evaluation of the response of tumors with p16INK4a gene product mutations to paclitaxel and radiation therapy also is of interest. A better understanding of the role played by biomarkers should lead to more effective treatment and patient selection. Much of the current research should help define critical doses and administration schedules and should lead to better treatment and patient selection methods for many of these common solid tumors.

References:

1. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: First analysis of randomized trial in 353 patients. J Natl Cancer Inst 83:417-423, 1991.

2. Tannock IF: Treatment of cancer with radiation and drugs. J Clin Oncol 14:3156-3174, 1996.

3. Choy H, Rodriguez FF, Koester S, et al: Investigation of Taxol as a potential radiation sensitizer. Cancer 71:3774-3778, 1993.

4. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655, 1995.

5. Geard CR, Jones JM: Radiation and Taxol effects on synchronized human cervical carcinoma cells. Int J Radiat Oncol Biol Phys 29:565-569, 1994.

6. Griffon-Étienne G, Merlin J-L, Marchal C: In vitro evaluation of Taxol combined with radiations in human squamous cell carcinoma spheroids. Cancer Lett 109:23-32, 1996.

7. Guéritte-Voegelein F, Guénard D, Lavelle F, et al: Relationships between the structure of Taxol analogues and their antimitotic activity. J Med Chem 34:992-998, 1991.

8. Gupta N, Hu LJ, Deen DF: Cytotoxicity and cell-cycle effects of paclitaxel when used as a single agent and in combination with ionizing radiation. Int J Radiat Oncol Biol Phys 37:885-895, 1997.

9. Hennequin C, Giocanti N, Favaudon V: Interaction of ionizing radiation with paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells. Cancer Res 56:1842-1850, 1996.

10. Jaakkola M, Rantanen V, Grénman S, et al: In vitro concurrent paclitaxel and radiation of four vulvar squamous cell carcinoma cell lines. Cancer 77:1940-1946, 1996.

11. Leonard CE, Chan DC, Chou T-C, et al: Paclitaxel enhances in vitro radiosensitivity of squamous carcinoma cell lines of the head and neck. Cancer Res 56:5198-5204, 1996.

12. Liebmann J, Cook JA, Fisher J, et al: In vitro studies of Taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 86:441-446, 1994.

13. Liebmann J, Cook JA, Fisher J, et al: Changes in radiation survival curve parameters in human tumor and rodent cells exposed to paclitaxel (Taxol). Int J Radiat Oncol Biol Phys 29:559-564, 1994.

14. Lokeshwar BL, Ferrell SM, Block NL: Enhancement of radiation response of prostatic carcinoma by Taxol: Therapeutic potential for late-stage malignancy. Anticancer Res 15:93-98, 1995.

15. Mason KA, Hunter NR, Milas M, et al: Docetaxel enhances tumor radioresponse in vivo. Clin Cancer Res 3:2431-2438, 1997.

16. Milross CG, Mason KA, Hunter NR, et al: Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel. J Natl Cancer Inst 88:1308-1314, 1996.

17. Minarik L, Hall EJ: Taxol in combination with acute and low dose rate irradiation. Radiother Oncol 32:124-128, 1994.

18. Steren A, Sevin B-U, Perras J, et al: Taxol sensitizes human ovarian cancer cells to radiation. Gynecol Oncol 48:252-258, 1993.

19. Stromberg JS, Lee YJ, Armour EP, et al: Lack of radiosensitization after paclitaxel treatment of three human carcinoma cell lines. Cancer 75:2262-2268, 1995.

20. Tishler RB, Schiff PB, Geard CR, et al: Taxol: A novel radiation sensitizer. Int J Radiat Oncol Biol Phys 22:613-617, 1992a.

21. Tishler RB, Geard CR, Hall EJ, et al: Taxol sensitizes human astrocytoma cells to radiation. Cancer Res 52:3495-3497, 1992.

22. Zanelli GD, Quaia M, Robieux I, et al: Paclitaxel as a radiosensitiser: A proposed schedule of administration based on in vitro data and pharmacokinetic calculations. Eur J Cancer 33:486-492, 1997.

23. Manfredi JJ, Parness J, Horwitz SB: Taxol binds to cellular microtubules. J Cell Biol 94:688-696, 1982.

24. Parness J, Horwitz SB: Taxol binds to polymerized tubulin in vitro. J Cell Biol 91:479-487, 1981.

25. Schiff PB, Horwitz SB: Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 77:1561-1565, 1980.

26. Bhalla K, Ibrado AM, Tourkina E, et al: Taxol induces internucleosomal DNA fragmentation associated with programmed cell death in human myeloid leukemia cells. Leukemia 7:563-568, 1993.

27. Choy H, Rodriguez F, Koester S, et al: Radiation sensitizing effects of Taxotere (RP 56976). Proceedings of the 83rd Annual Meeting of the American Association for Cancer Research, Vol. 33:500, May 1992.

28. Liebmann J, Herscher L, Fisher J, et al: Antagonism of paclitaxel cytotoxicity by x-rays: Implications for the sequence of combined modality therapy. Int J Oncol 8:991-996, 1996.

29. van Rijn J, van den Berg J, Meijer OW: Proliferation and clonal survival of human lung cancer cells treated with fractionated irradiation in combination with paclitaxel. Int J Radiat Oncol Biol Phys 33:635-639, 1995.

30. Ingram ML, Redpath JL: Subadditive interaction of radiation and Taxol in vitro. Int J Radiat Oncol Biol Phys 37:1139-1144, 1997.

31. Rodriguez M, Sevin B-U, Perras J, et al: Paclitaxel: A radiation sensitizer of human cervical cancer cells. Gynecol Oncol 57:165-169, 1995.

32. Choy H, DeVore RF III, Kande KR, et al: Preliminary analysis of a phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small cell lung cancer. Semin Oncol 24(4 suppl 2):S12/21-S12/26, 1997.

33. Perez CA, Stanley K, Grundy G, et al: Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung: Report by the Radiation Therapy Oncology Group. Cancer 50:1091-1099, 1982.

34. Ellis PA, Smith IE, Hardy JR, et al: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71:366-370, 1995.

35. Grilli R, Oxman AD, Julian JA: Chemotherapy for advanced non-small-cell lung cancer: How much benefit is enough? J Clin Oncol 11:1866-1872, 1993.

36. Souquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non small cell lung cancer: A meta-analysis. Lancet 342:19-21, 1993.

37. Ramanathan RK, Belani CP: Chemotherapy for advanced non-small cell lung cancer: Past, present, and future. Semin Oncol 24:440-454, 1997.

38. Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 323:940-945, 1990.

39. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-1215, 1996.

40. Pritchard RS, Anthony CP: Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer. Ann Intern Med 125:723-729, 1996.

41. Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87:198-205, 1995.

42. Schaake-Koning C, van den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524-530, 1992.

43. Choy H, Safran G, Akerley W, et al: Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Clin Cancer Res 4:1931-1936, 1998.

44. Anasari R, Takars R, Fisher W, et al: A phase III study of thoracic radiation with or without concomitant cisplatin in locoregional unresectable non-small cell lung cancer (NSCLC): A Hoosier Oncology Group (HOG) protocol (abstract 823). Proc Am Soc Clin Oncol 10:241, 1991.

45. Chan PYM, Byfield JE, Kagan AR, et al: Unresectable squamous cell carcinoma of the lung and its management by combined bleomycin and radiotherapy. Cancer 37:2671-2676, 1976.

46. Landgren RC, Hussey DH, Barkley HT, et al: Split-course irradiation compared to split-course irradiation plus hydroxyurea in inoperable bronchogenic carcinoma—A randomized study of 53 patients. Cancer 34:1598-1601, 1974.

47. Soresi E, Clerici M, Grilli R, et al: A randomized clinical trial comparing radiation therapy versus radiation therapy plus cis-dichlorodiammine platinum (II) in the treatment of locally advanced non-small cell lung cancer. Semin Oncol 15(suppl 7):20-25, 1988.

48. Belani CP, Aisner J, Hiponia D, et al: Paclitaxel and carboplatin with and without filgrastim support in patients with metastatic non-small cell lung cancer. Semin Oncol 22(suppl 9):7-12, 1995.

49. Cerny T, Kaplan S, Pavlidis N, et al: Docetaxel (Taxotere) is active in non-small-cell lung cancer: A phase II trial of the EORTC Early Clinical Trials Group (ECTG). Br J Cancer 70:384-387, 1994.

50. Fossella FV, Lee JS, Murphy WK, et al: Phase II study of docetaxel for recurrent or metastatic non-small-cell lung cancer. J Clin Oncol 12:1238-1244, 1994.

51. Francis PA, Rigas JR, Kris MG, et al: Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer. J Clin Oncol 12:1232-1237, 1994.

52. Johnson DH, Paul DM, Hande KR, et al: Paclitaxel plus carboplatin in advanced non-small cell lung cancer: A phase II trial. J Clin Oncol 14:2054-2060, 1996.

53. Kunitoh H, Watanabe K, Onoshi T, et al: Phase II trial of docetaxel in previously untreated advanced NSCLC: A Japanese Cooperative study. J Clin Oncol 14:1649-1655, 1996.

54. Langer CJ, Movsas B, Hudes R, et al: Induction paclitaxel and carboplatin followed by concurrent chemoradiotherapy in patients with unresectable, locally advanced non-small cell lung carcinoma: Report of Fox Chase Cancer Center Study 94-001. Semin Oncol 24(suppl 12):S12/89-S12/95, 1997.

55. Miller VA, Rigas JR, Francis PA, et al: Phase II trial of a 75-mg/m2 dose of docetaxel with prednisone premedication for patients with advanced non-small cell lung cancer. Cancer 75:968-972, 1995.

56. Rigas JR: Docetaxel in stage III and stage IV non-small cell lung cancer. Eur J Cancer 31A:S18-S20, 1995.

57. Vafai D, Israel Z, Zaretsky S, et al: Phase I/II trial of combination carboplatin and Taxol in non-small cell lung cancer (NSCLC) (abstract 1067). Proc Am Soc Clin Oncol 14:352, 1995.

58. Choy H, Akerley W, Safran H, et al: Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer. J Clin Oncol 12:2682-2686, 1994.

59. Lau DHM, Ryu JK, Gandara DR, et al: Twice-weekly paclitaxel and radiation for stage III non-small cell lung cancer. Semin Oncol 24(suppl 12):S12/106–S12/109, 1997.

60. Choy H: Concurrent paclitaxel, carboplatin, and radiation therapy for non–small-cell lung cancer. The Fox Chase Cancer Center and Free University Hospital Paclitaxel Investigators’ Workshop and Consensus Conference. St. Thomas, US Virgin Islands, March 26-28, 1998. Oral Presentation.

61. Choy H, DeVore RD, Hande KR, et al: Phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small cell lung cancer: A Vanderbilt Cancer Center Affiliate Network (VCCAN) trial (abstract 1794). Proc Am Soc Clin Oncol 17:467a, 1998. Poster presented at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, May 16-19, 1998, Los Angeles, CA.

62. Belani CP: Paclitaxel and carboplatin in resectable and locally advanced NSCLC. The Fox Chase Cancer Center and Free University Hospital Paclitaxel Investigators’ Workshop and Consensus Conference. St. Thomas, US Virgin Islands, March 26-28, 1998. Oral Presentation.

63. Belani CP, Ramanathan RK: Combined-modality treatment of locally advanced non-small cell lung cancer: Incorporation of novel chemotherapeutic agents. Chest 113:53S-60S, 1998.

64. Belani CP, Aisner J, Bahri S, et al: Chemoradiotherapy in non-small cell lung cancer: Paclitaxel/carboplatin/radiotherapy in regionally advanced disease. Semin Oncol 23(suppl 16):113-116, 1996.

65. Lau D: Concurrent twice-weekly paclitaxel, carboplatin, and radiation for stage III non-small cell lung cancer. The Fox Chase Cancer Center and Free University Hospital Paclitaxel Investigators’ Workshop and Consensus Conference. St. Thomas, US Virgin Islands, March 26-28, 1998. Oral Presentation.

66. Socinski MA, Clark JA, Halle J, et al: Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced unresectable non-small cell lung cancer: Preliminary report of a phase I trial. Semin Oncol 24(suppl 12):S12/117-S12/122, 1997.

67. Socinski M: Paclitaxel/carboplatin and conformal RT in non-small cell lung cancer. The Fox Chase Cancer Center and Free University Hospital Paclitaxel Investigators’ Workshop and Consensus Conference. St. Thomas, US Virgin Islands, March 26-28, 1998. Oral Presentation.

68. Greco FA, Stroup SL, Gray JR, et al: Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer. J Clin Oncol 14:1642-1648, 1996.

69. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989.

70. Choy H, Akerley W, Safran H, et al: Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer. J Clin Oncol 16:3316-3322, 1998.

71. Choy H, Safran H: Preliminary analysis of a phase II study of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer. Semin Oncol 22(suppl 9):55-57, 1995.

72. Kirkbride P, Gelmon K, Eisenhauer E, et al: A phase I/II study of paclitaxel (Taxol) and concurrent radiotherapy in advanced non small cell lung cancer. Int J Radiat Oncol Biol Phys 39:1107-1111, 1997.

73. Rathmann J, Rigas JR, Leopold KA, et al: Daily paclitaxel and thoracic radiation therapy for the treatment of stage II and III non-small cell lung cancer (NSCLC) (abstract 1722). Proc Am Soc Clin Oncol 16:478a, 1997.

74. Bunn PA Jr, Vokes EE, Langer CJ, et al: An update on North American randomized studies in non-small cell lung cancer. Semin Oncol 25 (suppl 9):2-10, 1998.

75. NCI-96-C-0054: Phase II study of neoadjuvant continuous-infusion TAX plus bolus CDDP followed by thoracic radiotherapy for stage III non-small cell lung cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

76. UCMC-967222, NCI-V97-1331, ALZA-UCMC-967222. Phase II study of amifostine with paclitaxel, carboplatin and concurrent radiation therapy for unresectable stage II, IIIA, and all stage IIIB non-small cell lung cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

77. RTOG-9801: Phase III randomized study of amifostine mucosal protection in patients with favorable performance inoperable stage II, IIIA, or IIIB non-small cell lung cancer receiving sequential induction and concurrent hyperfractionated radiotherapy with paclitaxel and carboplatin. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

78. TJUH-969139: Phase II study of induction paclitaxel plus carboplatin followed by thoracic radiation therapy with concurrent paclitaxel and amifostine for unresectable locally advanced or partially resected non-small cell lung cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

79. CLB-9534: Phase II study of TAX/CBDCA followed by concomitant chemoradiotherapy for inoperable stage IIIA/B non-small cell lung cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

80. CLB-39801. Phase III randomized study of concurrent carboplatin, paclitaxel, and radiation therapy with or without prior induction carboplatin and paclitaxel in patients with unresectable stage III non-small cell lung cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

81. Vokes EE, Leopold KA, Herndon JE II, et al: A CALGB randomized phase II study of gemcitabine or paclitaxel or vinorelbine with cisplatin as induction chemotherapy and concomitant chemoradiotherapy in stage IIIB non-small cell lung cancer: Feasibility data (CALGB study #9431) (abstract 1636). Proc Am Soc Clin Oncol 16:455a, 1997.

82. Mauer AM, Masters GA, Haraf DJ, et al: Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 16:159-164, 1998.

83. Teng M, Choy H, DeVore RD, et al: Phase I trial of outpatient weekly docetaxel and concurrent radiation therapy for stage III unresectable non-small-cell lung cancer: A Vanderbilt Cancer Center Affiliate Network (VCCAN) trial (abstract 1938). Proc Am Soc Clin Oncol 17:503a, 1998.

84. Pignon JP, Arriagada R, Ihde D, et al: A meta-analysis of thoracic radiotherapy for small cell lung cancer. N Engl J Med 327:1618-1624, 1992.

85. Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small cell carcinoma of the lung? J Clin Oncol 10:890-895, 1992.

86. Bonomi P: Review of selected randomized trials in small cell lung cancer. Semin Oncol 25(4 suppl 9):70-78, 1998.

87. Ettinger DS, Finkelstein DM, Sarma RP, et al: Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 13:1430-1435, 1995.

88. Jett JR, Kirschling RJ, Jung S-H, et al: A phase II study of paclitaxel and granulocyte colony-stimulating factor in previously untreated patients with extensive-stage small cell lung cancer: A study of the North Central Cancer Treatment Group. Semin Oncol 22(suppl 6):75-77, 1995.

89. Bunn PA Jr: Defining the role of paclitaxel in lung cancer: Summary of recent studies and implications for future directions. Semin Oncol 24(suppl 12):S12-153–S12-162, 1997.

90. Hainsworth JD, Gray JR, Stroup SL, et al: Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: Comparison of sequential phase II trials using different dose-intensities. J Clin Oncol 15:3464-3470, 1997.

91. Bremnes RM, Sundstrøm S, Aasebø U, et al: Paclitaxel in combination with cisplatin, etoposide and thoracic radiotherapy for limited small cell lung cancer (SCLC): A phase II study (abstract 206). Proc Am Soc Clin Oncol 17:475a, 1998.

92. Bremnes RM, Sundstrøm S, Aasebø U, et al: Treatment of limited small cell lung cancer (SCLC) with paclitaxel, cisplatin, etoposide and radiation therapy (abstract). Lung Cancer 18(suppl 1):54, 1997.

93. Jesse RH, Fletcher GH: Treatment of the neck in patients with squamous cell carcinoma of the head and neck. Cancer 39:868-872, 1977.

94. Fletcher GH, Jesse RH: The place of irradiation in the management of the primary lesion in head and neck cancers. Cancer 39:862-867, 1977.

95. Jesse RH, Lindberg RD: The efficacy of combining radiation therapy with a surgical procedure in patients with cervical metastasis from squamous cancer of the oropharynx and hypopharynx. Cancer 35:1163-1166, 1975.

96. Kramer S, Gelber RD, Snow JB, et al: Combined radiation therapy and surgery in the management of advanced head and neck cancer: Final report of study 73-03 of the Radiation Therapy Oncology Group. Head Neck Surg 10:19-30, 1987.

97. Lippman SM: Paclitaxel-based therapy of head and neck cancer: Current and future directions: The Fox Chase Cancer Center and Free University Hospital Paclitaxel Investigators’ Workshop and Consensus Conference. St. Thomas, US Virgin Islands, March 26-28, 1998. Oral Presentation.

98. Schantz SP, Harrison LB, Hong WK: Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology, 5th ed, pp 574-630. Philadelphia, JB Lippincott Co, 1997.

99. Vokes EE, Weichselbaum RR: Concomitant chemoradiotherapy: Rationale and clinical experience in patients with solid tumors. J Clin Oncol 8:911-934, 1990.

100. Vokes EE: Interactions of chemotherapy and radiation. Semin Oncol 20:70-79, 1993.

101. Amrein PC, Wang CC, Daly M, et al: Concurrent Taxol and bid radiotherapy in patients with advanced stage squamous cell carcinoma of the head and neck (abstract 1548). Proc Am Soc Clin Oncol 17:402a, 1998.

102. Kroog GS, Van Waes C, Thomas G, et al: A pilot study of 120-hour paclitaxel with radiation therapy for locally advanced head and neck cancer (abstract 1528). Proc Am Soc Clin Oncol 17: 396a, 1998.

103. Machtay M, Rosenthal DI, Aviles V, et al: A phase I trial of 96-hour Taxol infusion plus accelerated radiotherapy for unresectable head and neck cancer (abstract 1524). Proc Am Soc Clin Oncol 17:395a, 1998.

104. Steinberg L, Hassen M, Hoppel C, et al: A phase I study of radiotherapy and simultaneous paclitaxel in patients with locally advanced squamous cell carcinoma of the head and neck (abstract 913). Proc Am Soc Clin Oncol 15:321, 1996.

105. Chougule P, Wanebo H, Akhtar M, et al: Concurrent paclitaxel, carboplatin and radiotherapy in advanced head and neck cancers: A phase II study (abstract 1468). Proc Am Soc Clin Oncol 17:381a, 1998.

106. Chougule P, Wehbe T, Leone L, et al: Concurrent Taxol, carboplatin and radiotherapy in advanced head and neck cancers: A phase II study (abstract 898). Proc Am Soc Clin Oncol 15:317, 1996.

107. Gonzalez MF, Clowney BW, Cafferty B, et al: Phase II trial of concomitant carboplatinum and paclitaxel with radiation therapy followed by cisplatin, fluorouracil and interferon alpha-2a in unresectable head and neck carcinoma (abstract 1525). Proc Am Soc Clin Oncol 17:395a, 1998.

108. Brockstein B, Haraf DJ, Stenson K, et al: Phase I study of concomitant chemoradiotherapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-stimulating factor support for patients with poor-prognosis cancer of the head and neck. J Clin Oncol 16:735-744, 1998.

109. Haraf DJ, Weichselbaum RR, Vokes EE: Re-irradiation with concomitant chemotherapy of unresectable recurrent head and neck cancer: A potentially curable disease. Ann Oncol 7:913-918, 1996.

110. Vokes EE, Haraf DJ, Mick R, et al: Intensified concomitant chemoradiotherapy with and without filgrastim for poor-prognosis head and neck cancer. J Clin Oncol 12:2351-2359, 1994.

111. Vokes EE: A phase II study of paclitaxel, fluorouracil, hydroxyurea and twice-daily radiotherapy with filgrastim support for locoregionally advanced head and neck cancer. The Fox Chase Cancer Center and Free University Hospital Paclitaxel Investigators’ Workshop and Consensus Conference. St. Thomas, US Virgin Islands, March 26-28, 1998. Oral Presentation.

112. Vokes EE, Haraf DJ, Brockstein BE, et al: Paclitaxel, fluorouracil, hydroxyurea, and concomitant radiation therapy for poor-prognosis head and neck cancer. Semin Radiat Oncol 9(2 suppl 1):70-76, 1999.

113. Catimel G, Verweij J, Mattijssen V, et al: Docetaxel (Taxotere): An active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 5:533-537, 1994.

114. Dreyfuss AI, Clark JR, Norris CM, et al. Docetaxel: An active drug for squamous cell carcinoma of the head and neck. J Clin Oncol 14:1672-1678, 1996.

115. Forastiere A, Glisson B, Murphy B, et al: A phase II study of docetaxel and cisplatin in patients with locally advanced, recurrent, and/or metastatic squamous cell carcinoma of the head and neck, not curable by standard therapy (abstract 1540). Proc Am Soc Clin Oncol 17:399a, 1998.

116. Colevas AD, Busse PM, Norris CM, et al: Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: A phase I/II trial. J Clin Oncol 16:1331-1339, 1998.

117. DFCI-95041: Phase I study of docetaxel plus concurrent radiotherapy after induction chemotherapy for squamous cell cancer of the head and neck. Study protocol. Available at: http://cancernet.nci.nih.gov/cgi-bin. Accessed February 22, 1999.

118. Roth JA, Putnam JB Jr, Rich TA, et al: Cancer of the esophagus, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology, 5th ed, pp 1731-1737. Philadelphia, JB Lippincott Co, 1997.

119. Safran H, Gaissert H, Akerman P, et al: Neoadjuvant paclitaxel, cisplatin and radiation for esophageal cancer (abstract 994). Proc Am Soc Clin Oncol 17:259a, 1998.

120. Bernard S, Poole M, Socinski M, et al: Paclitaxel combined with 5-fluorouracil and cisplatin concomitant with radiotherapy in locally advanced or metastatic esophageal cancer—Preliminary report of a phase I/II trial (abstract 1102). Proc Am Soc Clin Oncol 17:286a, 1998.

121. Lynch TJ, Choi N, Wright C, et al: A phase I/II trial of preoperative Taxol, cisplatin, 5-FU and concurrent boost radiation in esophageal cancer (abstract 928). Proc Am Soc Clin Oncol 16:261a, 1997.

122. Meluch AA, Hainsworth JD, Gray JR, et al: Preoperative therapy with paclitaxel, carboplatin, 5-FU and radiation in the treatment of local esophageal cancer (abstract 995). Proc Am Soc Clin Oncol 17:259a, 1998.

123. Blanke C, Chiappori A, Epstein B, et al: A phase II trial of neoadjuvant paclitaxel and cisplatin with radiotherapy, followed by surgery and postoperative Taxol with 5-fluorouracil and leucovorin in patients with locally advanced esophageal cancer (abstract 1006). Proc Am Soc Clin Oncol 16:283a, 1997.

124. Weiner LM, Colarusso P, Goldberg M, et al: Combined-modality therapy for esophageal cancer: Phase I trial of escalating doses of paclitaxel in combination with cisplatin, 5-fluorouracil, and high-dose radiation before esophagectomy. Semin Oncol 24(suppl 19):S19/93 - S19/95, 1997.

125. MSKCC-97088: Phase II study of preoperative cisplatin and paclitaxel followed by radiation therapy with concurrent cisplatin and paclitaxel and then surgery for localized esophageal carcinoma. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

126. MSKCC-95073A4: Phase I study of TAX/CDDP concurrent with radiotherapy and of TAX/CDDP preceding and concurrent with radiotherapy for localized esophageal cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

127. UNC-LCCC-9622: Phase I/II study of paclitaxel/fluorouracil/cisplatin concurrent with radiotherapy for locally advanced or metastatic esophageal cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

128. Vokes EE, Mauer AM, Hoffman PC, et al: Combined modality therapy in non–small cell lung and esophageal cancer: A phase I dose-escalation study of docetaxel with concurrent radiotherapy. Semin Oncol 25(3 suppl 8):28-32, 1998.

129. Glantz MJ, Choy H, Kearns CM, et al: Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas. J Clin Oncol 14:600-609, 1996.

130. Lederman G, Odaimi M, Fine M, et al: Recurrent glioblastoma multiforme: Potential benefits using fractionated stereotactic radiosurgery and concurrent Taxol (abstract 1441). Proc Am Soc Clin Oncol 16:404a, 1997.

131. Glantz MJ, Choy H, Akerley W, et al: Weekly paclitaxel with and without concurrent radiation therapy: Toxicity, pharmacokinetics, and response. Semin Oncol 23(suppl 16):128-135, 1996.

132. Rosenthal DI, Close LG, Lucci JA III, et al: Phase I studies of continuous-infusion paclitaxel given with standard aggressive radiation therapy for locally advanced solid tumors. Semin Oncol 22(suppl 9):13-17, 1995.

133. Glantz MJ, Chamberlain MC, Chang SM, et al: The role of paclitaxel in the treatment of primary and metastatic brain tumors. Semin Radiat Oncol 9(2 suppl 1):27-33, 1999.

134. Forsyth P, Cairncross G, Stewart D, et al: Phase II trial of docetaxel in patients with recurrent malignant glioma: A study of the National Cancer Institute of Canada Clinical Trials Group. Invest New Drugs 14:203-206, 1996.

135. Herrington JD, DiNunno L, Reinhart JJ, et al: Lack of CNS penetration of docetaxel in a patient with leptomeningeal carcinomatosis. Ann Pharmacother 32:611-612, 1998.

136. Hoffman JP, Lipsitz S, Pisansky T, et al: Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: An Eastern Cooperative Oncology Group study. J Clin Oncol 16:317-323, 1998.

137. Safran H, King TP, Choy H, et al: Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: A phase I study. J Clin Oncol 15:901-907, 1997.

138. Safran H, Akerman P, Cioffi W, et al: Paclitaxel and concurrent radiation for locally advanced adenocarcinomas of the pancreas, stomach and GE junction. Semin Radiat Oncol 9(2 suppl 1):53-57, 1999.

139. BRUOG-PG-38/P: Phase II study of paclitaxel and radiotherapy followed by surgical resection for pancreatic adenocarcinoma. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

140. RTOG-9812: Phase II study of external irradiation and weekly paclitaxel in patients with nonmetastatic unresectable pancreatic cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

141. BRUOG-PG-38/G: Phase II study of paclitaxel and radiotherapy followed by surgical resection for gastric adenocarcinoma. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

142. Formenti SC, Symmans WF, Volm M, et al: Concurrent paclitaxel and radiation therapy for breast cancer. Semin Radiat Oncol 9(2 suppl 1):34-42, 1999.

143. Bishop JF, Dewar J, Tattersall MH, et al: A randomized phase III study of Taxol (paclitaxel) vs CMFP in untreated patients with metastatic breast cancer (abstract 107). Proc Am Soc Clin Oncol 15:110, 1996.

144. Buzdar AU, Morris A, Hortobagyi GN, et al: Prospective randomized trial of Taxol (Tax) alone versus fluorouracil, doxorubicin, cyclophosphamide (FAC) as an induction therapy in patients with operable breast cancer (abstract 498). Proc Am Soc Clin Oncol 16:141a, 1997.

145. Formenti SC, Dunnington G, Uzieli B, et al: Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-fluorouracil and radiation therapy. Int J Radiat Oncol Biol Phys 39:1059-1068, 1997.

146. Holmes FA, Valero V, Walters RS, et al: The M.D. Anderson Cancer Center experience with Taxol in metastatic breast cancer. Natl Cancer Inst Monogr 15:161-169, 1993.

147. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized trial of two doses of paclitaxel in metastatic breast cancer. J Clin Oncol 14:1858-1867, 1996.

148. Wahl AF, Donaldson KL, Fairchild C, et al: Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nat Med 2:72-79, 1996.

149. GOG-9804: Phase I/II study of extended field radiation therapy with concurrent paclitaxel and cisplatin chemotherapy in patients with cancer of the cervix metastatic to the para-aortic lymph nodes. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

150. GOG-9803: Phase I/II study of whole pelvic radiation therapy in combination with paclitaxel and cisplatin chemotherapy in patients with cervical cancer limited to the pelvis. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

151. UCCRC-8270: Phase I study of concomitant chemoradiotherapy with vinorelbine and paclitaxel in patients with advanced pelvic malignancies. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.

152. RTOG-9708: Phase II study of adjuvant postoperative irradiation combined with cisplatin and paclitaxel chemotherapy following total abdominal hysterectomy and bilateral salpingo-oophorectomy in patients with high risk endometrial cancer. Study protocol. Available at http://cancernet.nci.nih.gov/cgi-bin. Accessed February 16, 1999.