Docetaxel and Radiation as Combined-Modality Therapy

ABSTRACT: Combined-modality approaches for the treatment of non-small-cell lung cancer (NSCLC), head and neck cancer, and esophageal cancer offer survival benefits by improving locoregional control and treating micrometastatic disease. The taxanes are active, tolerable drugs in these solid tumors and have radiation-sensitizing activity. Docetaxel (Taxotere) has been studied in combination with radiation with favorable results. In phase II trials, docetaxel combined with radiation therapy resulted in response rates of up to 80%, with the most commonly used schedule being docetaxel at 20 to 30 mg/m² per week with concomitant radiation administered at fractions of 1.8 to 2.0 Gy, 5 days a week over 5 to 6 weeks. Studies of docetaxel and platinum combinations have been conducted predominantly in patients with NSCLC. Early results show good activity and acceptable toxicity, with esophagitis or mucositis being dose-limiting. Doses of docetaxel at 20 mg/m² per week combined with cisplatin at 25 mg/m² or carboplatin (Paraplatin) at an area under the concentration-time curve (AUC) of 2 with concomitant radiation appear to be well tolerated and active. Future investigations, including phase III trials in patients with locally advanced NSCLC, are encouraged. Current trials are studying various design schedules, including induction chemotherapy with radiation followed by consolidation chemotherapy. [ONCOLOGY 16(Suppl 6):97-105, 2002]

The treatment of solid tumors including non-small-celllung cancer (NSCLC), head and neck cancer, and esophageal cancer continues to bechallenging and associated with a poor overall survival. Traditional treatmentshave included single modalities such as surgery, radiation, or chemotherapy.Combined modality approaches offer a theoretical benefit by improvinglocoregional control and treating micrometastatic disease. Among the variouschemotherapeutic agents administered concurrently with radiation therapy[1] arethe platinums, taxanes, and gemcitabine (Gemzar).[2-5] The taxanes, inparticular, are active, tolerable drugs for the treatment of solid tumors, andthey possess radiation-sensitizing activity. Docetaxel (Taxotere) has beenstudied in combination with radiation with favorable results. This report willfocus on the treatment of solid tumors with docetaxel and radiation ascombined-modality therapy.

Background

The taxanes are a class of antineoplastic agents, derived from plants, thathave demonstrated efficacy in various malignancies.[6-9] Taxanes are potentmitotic spindle poisons that bind to beta-tubulin, increase tubulinpolymerization, and promote microtubule assembly. The microtubules remainstabilized because the taxanes inhibit depolymerization.[10-15] The first taxoidwas discovered in the 1960s when it was determined that the bark of the Pacificyew tree, Taxus brevifolia, had activity against several murine tumors.Paclitaxel became the first commercially available taxane in 1992. Docetaxel,which was semisynthetically produced in 1986, is derived from10-deacetyl-baccatin III, a noncytotoxic precursor extracted from the needles ofthe European yew, Taxus baccata. Docetaxel has several properties that aredifferent from paclitaxel, including a higher uptake and accumulation in tumorcells and a greater affinity to microtubules.[16]

Preclinical Data

The radiation sensitizing effects of the taxanes are seen at drug levels wellbelow those required for cytotoxicity. Studies of docetaxel have shown anenhanced response to radiation with induced mitotic arrest and apoptosis inmurine tumor cells.[17,18] During the cell cycle, the G2/M phase has been foundto be the most radiosensitive. Docetaxel exposure arrests cells in the G2/Mphase, thus rendering them susceptible to radiation.[11,12,19-23] In addition,docetaxel induces apoptosis as well as direct cytotoxicity againstradioresistant S-phase cells.[17,23] In vitro data have demonstrated theputative role of the taxanes in phosphorylation of the bcl-2 antiapoptoticoncoprotein, suggesting that these agents may further enhance the efficacy ofradiation by facilitating the triggering of the apoptotic pathway after DNAdamage by radiotherapy.[24]

The effects of the combination of docetaxel and radiation have suggested asynergistic effect on tumor cell radiosensitivity.[7,11,13,14] This synergy hasbeen demonstrated in vitro as well as in vivo in murine models.[17] Docetaxelmay also have immunomodulating properties as well as antiangiogeniceffects.[25,26] Based on these preclinical results, phase I investigations ofdocetaxel with concurrent radiation therapy were initiated.

Phase I Trials

Multiple phase I trials have been conducted to assess the combination ofsingle-agent docetaxel chemotherapy and radiotherapy in patients with non-small-celllung cancer (NSCLC) and other solid tumors (Table1).

Non-Small-Cell Lung Cancer

The Choy et al Trial

Choy et al[27] conducted a phase I study of weeklydocetaxel with concurrent thoracic radiation therapy in patients withunresectable stage III NSCLC. Docetaxel was administered as a 1-hour infusionevery week for 6 weeks at an initial dose of 20 mg/m², escalated inincrements of 10 mg/m² as tolerated to each successive cohort of three patients.Thoracic radiation therapy was administered 5 days a week for 6 weeks to theprimary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumorand involved nodes (20 Gy). A total of 15 patients (11 males and 4 females)with a median age of 61 years were enrolled in the study. Patients had stageIIIA (nine) or IIIB (six) disease and had a performance status of 0 or 1.

The principal dose-limiting toxicity was esophagitis and themaximum-tolerated dose of docetaxel with concurrent radiation therapy was30 mg/m². Seven patients achieved a partial response for an overallresponse rate of 47%.

The Aamdal et al Trial

Aamdal et al[28] conducted a phase I study ofdocetaxel combined with radiation in 12 chemotherapy and radiotherapy-naivepatients with inoperable stage III NSCLC. Docetaxel at 20 to 40 mg/m²was administered as a 1-hour infusion on days 1, 8, 22, and 29. Radiationtherapy was administered in fractions of 2 Gy daily for 5 days over 5 weeks. Themaximum tolerated dose of docetaxel was 40 mg/m² and the dose-limiting toxicitywas reversible esophagitis-related dysphagia. The median survival was 15 months,with four patients still alive at 20 to 26 months’ follow-up. Therecommended phase II dose was 30 mg/m² of docetaxel.

The Koukourakis et al Trial

A similar trial was conducted by Koukourakiset al,[29] who investigated the radiosensitizing effects of docetaxel andconcomitant radiotherapy in 30 patients (all male) with advanced NSCLC, 18 ofwhom had stage IIIB disease and 12 who had stage IV disease. The median age was65 years. Patients were treated with a 20-minute infusion of docetaxel,20 to 40 mg/m²/wk. Radiation therapy was administered 5 d/wk for 5weeks to a total dose of 60 to 64 Gy using a concomitant boost technique.

Esophagitis, asthenia, and anorexia were the dose-limiting toxicities notedat the docetaxel dose of 40 mg/m². Complete responses were seen in 8 (27%)patients and partial responses in 15 (50%) for an overall response rate of 77%.The recommended phase II dose was 30 mg/m² of docetaxel.

Other Solid Tumors

The Mauer et al Trial

Mauer et al[30] studied different schedules of thecombination of docetaxel and concomitant thoracic radiation in 29 patients withNSCLC (20) or esophageal cancer (9). All patients had no prior history of taxaneexposure or radiotherapy. Docetaxel was administered either once every 3 weeks(1 dose per cycle); 2 of 3 weeks (2 doses per cycle); or weekly. Thetotal dose of docetaxel per 3-week cycle was escalated from 40 to 75 mg/m².Standard concomitant chest radiotherapy was delivered in 1.8- to 2.0-Gy dailyfractions to a total dose of 60 Gy over 6 weeks. The median age of the patientswas 64 years and most had a performance status of 0/1.

Dose-limiting esophagitis and neutropenia were encountered in the 1- or2-dose per cycle schedules at 60 mg/m² per cycle. The maximum tolerated dose forthese schedules was 40 mg/m² per cycle. No patients on the weekly scheduledeveloped neutropenia although dose-limiting esophagitis was observed. Themaximum tolerated dose for the weekly schedule was 60 mg/m² per cycle or 20 mg/m²weekly. The weekly schedule allowed administration of the the highesttotal dose of docetaxel with concomitant chest radiotherapy. Of 21 patients whowere assessable for response, two achieved a complete response and eight apartial response.

The Koukourakis et al Trial

Koukourakis investigated twice-weeklydocetaxel with conventionally fractionated radiotherapy in a phase I trialin 27 patients with lung, brain, and pelvic cancer.[31] The median age ofparticipants was 64 years and included 16 males and 11 females. Among enrolledpatients, nine had brain glioblastoma, nine had stage IIIB NSCLC, three hadstage IVA cervical cancer, three had endometrial adenocarcinoma, two hadbladder carcinoma, and one had an unknown pelvic primary.

Docetaxel was administered twice a week starting at 15 mg/m² and escalated inincrements of 4 mg/m² in three-patient cohorts. Radiotherapy consisted of 2Gy/d, 5 days a week for 6 weeks with a boost to a total of 60 Gy in patientswith chest tumors and 64 Gy in those with pelvic tumors. Patients with braintumors received hyperfractionated radiotherapy (1.4 Gy × 2 fractions per day)to a total dose of 74 Gy.

The maximum tolerated dose of docetaxel for chest and pelvic cancer patientswas 15 mg/m² twice a week with radiotherapy. The dose-limiting toxicities wereasthenia and mucosal toxicity. In patients with glioblastomas, no toxicity wasseen with a docetaxel dose of 23 mg/m² administered twice a week. Encouragingresponse rates were observed. In patients with NSCLC, three of nine patientsachieved a complete response and four of nine a partial response, for an overallresponse rate of 78%. Among patients with glioblastoma, three had a partialresponse and four of nine patients with pelvic malignancies had a completeresponse.

The Tishler et al Trial

Tishler et al[32] studied concurrent docetaxeland radiation therapy in head and neck cancer patients with a poor prognosis.Patients were eligible to enroll if they had received induction chemotherapywith cisplatin/fluorouracil (5-FU)/leucovorin or cisplatin/5-FU and failed toachieve a complete response or had a positive postinduction biopsy. Docetaxelwas given at doses of 20, 25, or 30 mg/m² weekly for 6 weeks concurrentlywith daily radiation, 2 Gy/d to a total dose of 66 to 74 Gy. Twenty-onepatients with stage III/IV head and neck cancer were treated, includingpatients with T3/T4 tumors (16 patients) and N2/N3 disease (11 patients). Thedose-limiting toxicities were mucositis, dermatitis, and 2-week treatmentinterruptions. The maximum tolerated dose of docetaxel was 25 mg/m² weekly.

The overall response rate was 86%, with 12 patients (57%) achieving acomplete response and 6 patients (29%), a partial response. At a medianfollow-up of 35 months, 17 patients were alive, 14 of whom had no evidence ofdisease. Late toxicities included percutaneous endoscopic gastrostomy in ninepatients, tracheostomy in four patients, and esophageal stenosis in onepatients.

These phase I trials,[27-32] helped establish the basis for phase II trials,which are discussed below (Table 2).[33-36] Encouraging activity was observedwith both in the 3-week and weekly schedules.

Phase II Trials

Docetaxel and Radiation Therapy

The Koukourakis et al Trial

A phase II trial of docetaxel and radiationtherapy in 35 patients with stage IIIA or IIIB NSCLC was conducted byKoukourakis et al (Table 2).[33] The dose of docetaxel, 30mg/m²/wk, wasestablished from their previous phase I trial.[29] In contrast to the phaseI study, conventionally fractionated radiotherapy was used in hopes of achievingbetter tolerance, fewer side effects, and similar efficacy. Patients wererequired to have a performance status of 0 to 2 and adequate bone marrow, andhepatic, renal, and pulmonary function. Patients who received prior treatmentwere included in the trial: chemonaive (20 patients), prior taxane (6 patients),prior platinum (10 patients).

Study patients received docetaxel, 30 mg/m², as a 1-hour infusion weeklyfor 6 weeks with concurrent radiation therapy (2 Gy/d for 5 days a week for atotal dose of 64 Gy over 6.5 weeks). The median age of participants was 64years, and 33 of the 35 patients were male. Squamous cell carcinoma was thepredominant histology (21 patients). The main side effects were asthenia andradiation-induced esophagitis, which required 2-week treatment delays in 6patients and minor delays of less than 1 week in 11 patients. Complete responseswere seen in 12 of the 35 patients (34%) and partial responses in 16 (46%), foran overall response rate of 80%. The overall and local progression-freesurvivals at 1 year were 60% and 48%, respectively.

The Aamdal et al Article

Aamdal et al reported the results of a phase IItrial of docetaxel combined with concurrent radiation therapy in 33 patientswith locally advanced NSCLC.[34] Based on their previous phase I study,docetaxel was administered at 30 mg/m² on days 1, 8, 22, and 29 of a 5-weekschedule.[28] Concurrent thoracic radiation of 2 Gy, 5 days a week for 5weeks was administered to patients who were chemo- and radiotherapy-naive withinoperable stage III NSCLC. The median age of patients was 57 years, with 18(55%) women and 15 (45%) men. Histologies included squamous cell (14 patients),adenocarcinoma (13 patients), and other types (6 patients). Esophagitis was themain toxicity, and was mild or moderate in 90% of patients. No grade 3/4neutropenia was observed.

Of 30 patients who were evaluable for response, 8 (27%) achieved a completeresponse and 7 (23%) a partial response, for an overall response rate of 50%.Stable disease was seen in one patient, and seven patients progressed. Themedian overall survival of all 33 patients was 13.6 months, and the median timeto progression was 12 months. Based on these encouraging data, a phase IIItrial is currently under way to compare the above chemoradiotherapy regimen toradiation alone.

The Sistermanns et al Trial

Researchers from Germany conducted a studyof the combination of weekly docetaxel and radiotherapy in 32 patients (10females, 22 males) with locally advanced, unresectable NSCLC.[35] The averageage of patients was 53 years. Docetaxel at 25 mg/m² was administered as a15-minute infusion on days 1, 8, 22, and 29 concurrently with thoracic radiationat 1.8 Gy/d over 6 weeks, for a total dose of 50.4 Gy. Histologies includedsquamous cell (14 patients), adenocarcinoma (9 patients), and large cell (9patients).

The overall response rate in this trial was 34%, with seven patients (22%)achieving a complete response and four (12.5%), a partial response. Theresponses were durable and lasted a median of 250 and 145 days for the completeresponses and partial responses, respectively. One patient had stable diseaseand 20 patients had progressive disease.

The most severe toxicities included grade 3 esophagitis and pneumonia;otherwise, treatment was well tolerated. Based on these results, a randomizedphase III study is currently comparing chemoradiotherapy with eithercisplatin/radiation or docetaxel/radiation in patients with locally advanced,inoperable NSCLC.

The Mauer et al Trial

Mauer et al performed a trial of inductionchemotherapy followed by chemoradiation in 54 patients with locally advancedadenocarcinoma of the esophagus and gastric cardia whose median age was 61years.[36] Eligibility criteria included stage II or III cancer of the esophagusor gastroesophageal junction, performance status of 0 to 2, adequate bonemarrow, hepatic and renal function, and no prior chemo- or radiotherapy.Patients initially received induction therapy with docetaxel at 75 mg/m² andcisplatin at 75 mg/m² on day 1 every 3 weeks for 3 cycles. Prophylacticgranulocyte colony-stimulating factor (G-CSF, Neupogen), 5 µg/kg/d, wasadministered beginning on day 3 until the white blood cell count rose above10,000/µL. The chemoradiotherapy treatment included weekly docetaxel at 20 mg/m², with chest radiotherapy delivered in fractions of 2 Gy/d, 5 days per weekfor 5 weeks, in resectable patients, to a total dose of 50 Gy. Patients who weredeemed unresectable received a total dose of 70 Gy over 7 weeks.

Most patients had a performance status of 0 (59%) and a histology ofadenocarcinoma (74%) or squamous cell (20%). Of 44 patients evaluable fortoxicity during induction chemotherapy, 17 experienced grade 3/4 neutropenia,including 6 with neutropenic fever. Of 36 patients evaluable for toxicity duringthe chemoradiotherapy phase, one developed neutropenic fever. Grade 3/4esophagitis (33%) and vomiting (8%) were the most common nonhematologictoxicities. Of 31 patients who received induction therapy followed bychemoradiotherapy, seven (23%) achieved a complete response and nine (29%), apartial response, for an overall response rate of 52%.

After the completion of chemoradiation, 23 patients were able to undergosurgical resection and 12 (52%) achieved a complete pathologic response, with 8(35%) having microscopic residual disease and 3 (13%) having gross residualdisease. Analysis to explain the dropout rate and/or why patients were not ableto complete the regimen (54 patients enrolled, 31 who completedchemoradiotherapy) are awaited, as are survival data.

Docetaxel/Cisplatin Therapy With Radiation

The combination of chemotherapeutic agents with radiation therapy has beenshown to be effective and improve survival compared to radiotherapy alone.[37]Phase III studies have demonstrated improved response and median survival ratesin patients with NSCLC who receive concurrent chemotherapy and radiotherapycompared to sequential treatment schedules.[38,39] The combination of docetaxeland cisplatin is well tolerated and effective in patients with advancedNSCLC.[40-44] The following studies helped to establish the optimal doses andschedules for docetaxel combined with platinums and radiation therapy.

The Segawa et al Trial

A phase I/II trial conducted by Segawa etal[45] from Japan evaluated docetaxel and cisplatin with concurrent thoracicradiation therapy in patients with locally advanced NSCLC and no prior therapy.Patients received a 1-hour infusion of docetaxel followed by a 1-hour infusionof cisplatin on days 1, 8, 29, and 36 of a 6-week schedule. Concurrent thoracicradiotherapy was administered in fractions of 2 Gy/d for 5 consecutive daysper week over 6 weeks, to a total dose of 60 Gy. The phase I portionescalated the doses of both docetaxel and cisplatin in three-patient cohorts.Doses of docetaxel/cisplatin were 20/30 mg/m², 25/30 mg/m²,30/30 mg/m², 30/35 mg/m², 30/40 mg/m², 35/40 mg/m²,40/40 mg/m², and 45/40 mg/m², respectively. Dose-limiting toxicitiesincluded esophagitis, leukopenia, neutropenia, and liver dysfunction for the 33evaluable patients. The maximum tolerated dose was docetaxel, 45 mg/m², withcisplatin, 40 mg/m²; thus, the recommended phase II dose was docetaxel, 40 mg/m², and cisplatin, 40mg/m².

In the phase II portion of the study, 42 patients were evaluated, including 6from the the phase I study. Patient characteristics included a median age of 67years, 86% males, 43% with a performance status of 0, and 83% with stage IIIBdisease, with squamous cell the most prevalent histology (62%). The most commonhematologic toxicities were grade 3/4 leukopenia (71%) and neutropenia (60%).Grade 3/4 esophagitis developed in 19% of patients.

One patient achieved a complete response and 32 had a partial response, foran overall response rate of 79%. One patient’s disease progressed while ontherapy. Early survival data indicate an actuarial 1-year survival rate of 80%in these patients. The regimen proved effective in combination with radiotherapyin patients with locally advanced NSCLC. Although there was considerabletoxicity, compliance analysis of the study showed the regimen was welltolerated.

The Moriyama et al Trial

A phase I trial conducted by Moriyama et alevaluated weekly docetaxel and cisplatin with concomitant thoracic radiation in21 patients (19 males, 2 females) with locally advanced NSCLC, who had no priorchemo- or radiotherapy.[46] The median age of patients was 65 years, and mosthad a performance status of 0 or 1. The predominant disease histology amongthese patients was squamous cell (76%). Chemotherapy was initially administeredon a split schedule (docetaxel at 20 mg/m², cisplatin at 25 mg/m² on days1, 8, 15, 29, 36, and 43) and then a continuous, once weekly schedule wasinitiated, with docetaxel at 20 mg/m² as a 1.5-hour infusion and a constant doseof cisplatin at 25 mg/m² as a 1-hour infusion. The dose of docetaxel wasescalated in increments of 5 mg/m² in successive cohorts of three patients.Thoracic radiation was administered concurrently at 2 Gy/d, 5 d/wk for6 weeks, for a total of 60 Gy.

Grade 3 neutropenia did not occur in the first cohort, but two patients inthe second cohort experienced grade 3 neutropenia. One episode of grade 3esophagitis was reported in the first cohort and two cases of grade 3esophagitis in the second cohort. Seven patients were treated on the continuousschedule. Grade 3 neutropenia developed in four patients and two patientsexperienced grade 3 esophagitis. Only four of seven patients completedchemoradiotherapy. Based on toxicity, the split schedule with docetaxel at 20 mg/m²and cisplatin at 25 mg/m² was best tolerated. All 21 patients wereevaluable for response. Complete responses occurred in 5 patients and partialresponses in 14 patients for an overall response rate of 90%. The two remainingpatients had stable disease. The 1-year survival and median progression-freesurvival rates were 48% and 52 weeks, respectively.

The Mudad et al Trial

Mudad et al conducted a phase I study of docetaxeland cisplatin with concomitant thoracic radiation in patients with locallyadvanced unresectable NSCLC.[47] All patients had stage IIIA or IIIB (nopleural effusion) disease and were deemed unresectable. Treatment compriseddocetaxel at 15 mg/m², escalated in increments of 5 mg/m² per cohort, andcisplatin at 25 mg/m² administered weekly for 6 weeks in combination withstandard thoracic radiation delivered at 1.8 Gy/d, 5 d/wk, to a total dose of 64Gy. Thus far, 8 of 11 patients have completed therapy. No grade 3/4 toxicitieshave been observed in the first cohort. In the second cohort, among sixpatients, one patient experienced grade 4 diarrhea, and one patient died ofprogressive disease. None of the remaining patients experienced any grade 3 or 4toxicities. This dose escalation study is ongoing.

Based on the current studies, the combination of docetaxel and cisplatinadministered concurrently with radiation is an effective regimen for locallyadvanced NSCLC. The recommended dose of docetaxel is 20 mg/m² and cisplatin, 25mg/m², administered once weekly concomitantly with radiation therapy at standarddoses.

Docetaxel/Carboplatin Therapy With Radiation

The Skarin et al Trial

Skarin et al[48] conducted a phase I trialof docetaxel and carboplatin as induction chemotherapy, followed by weeklydocetaxel/carboplatin with concurrent radiotherapy in 23 patients (14 female and9 male) with stage III NSCLC and a median age of 62 years (Table3). Stage IIIAdisease was present in 65% of patients and stage IIIB in 35% including 30% withsquamous cell and 30% with adenocarcinomas. Patients had received no prior chemo-or radiotherapy and had inoperable disease.

The induction regimen included docetaxel, 75 mg/m², with carboplatin at anAUC of 6, administered once every 3 weeks. After completing two cycles ofinduction chemotherapy, patients began chemoradiotherapy. Patient cohortsreceived weekly chemotherapy consisting of docetaxel in escalating doses from 10to 30 mg/m² with carboplatin at an AUC of 2. Concurrent radiotherapy wasadministered at 1.8 Gy/d, 5 d/wk, to a total dose of 54 Gy, over a 6-weekcourse. Responding patients went on to surgical resection.

Toxicities among the 21 patients completing induction chemotherapy includedgrade 3/4 neutropenia in 95% and grade 3/4 allergic reactions in 14%, with 15patients completing chemoradiotherapy. The maximum tolerated dose ofdocetaxel/carboplatin has yet been reached. Dose-limiting toxicities includedatrial fibrillation and transaminitis.

This trial has not been fully reported; to date, two partial responses (10%)were observed after induction chemotherapy. Responses to chemoradiotherapyincluded two complete responses and three partial responses, for an overallresponse rate of 33%. Of the seven patients with stage IIIA disease whounderwent surgery (five complete and two incomplete resections), two achieved apathologic complete response. Thus far, the median survival and medianprogression-free survival were 12 and 10 months, respectively.

The Choy et al Trial

A phase I dose-finding trial conducted by Choy etal[49] combined docetaxel at 20 mg/m² or 30 mg/m² per week with weeklycarboplatin at an AUC of 2 and radiotherapy in patients with stage IIIunresectable NSCLC. A total of eight patients were treated in the 20 mg/m² groupand three in the 30 mg/m² group. Radiotherapy was delivered in 2.0-Gy fractions,5 d/wk, to a total dose of 60 Gy over 6 weeks. The dose-limiting toxicity wasesophagitis, which was reported in one patient in the 20-mg/m² group and threepatients in the 30-mg/m² group. Grade 3 leukopenia developed in threepatients in the docetaxel 20 mg/m² group and grade 3 anemia in one patients inthe docetaxel 30 mg/m² group. Of nine evaluable patients, one achieved acomplete response (11%) and five, a partial response for an overall responserate of 67%. The maximum tolerated dose was docetaxel at 20 mg/m²/wk with weeklycarboplatin at an AUC of 2 along with a 60-Gy total dose of radiotherapy.

The Murakami et al Trial

Murakami et al[50] conducted a phase I trial ofweekly docetaxel and carboplatin with concomitant radiotherapy in patients withuntreated locally advanced NSCLC. Cohorts of six patients received docetaxel ata fixed dose of 20 mg/m²/wk with weekly carboplatin starting at an AUC of 1 withdose escalation. Radiotherapy was administered 5 d/wk to a total dose of 60 Gyover a 6-week period.

The characteristics of the 12 patients enrolled in the study included amedian age of 60 years, 10 males and 2 females, stage IIIA (5 patients) andstage IIIB (7 patients) disease, and a performance status of 1 (12 patients).Dose-limiting toxicities included radiation pneumonitis, which was grade 4 intwo patients, esophagitis, and liver dysfunction. A partial response wasachieved by 11 patients for an overall response rate of 92%. The maximumtolerated dose was found to be docetaxel 20 mg/m²/wk and carboplatin at anAUC of 1.5 per week with 60-Gy radiation therapy delivered over 6 weeks. Becauseof the pulmonary toxicity reported in this trial, no phase II study is planned.

The Nishimura et al Trial

A phase II study of induction docetaxel andcarboplatin with concomitant radiotherapy in patients with early-stage (IB, IIA,IIB) NSCLC was conducted by Nishimura et al.[51] The 30 enrolled patients (18male, 12 female) had a median age of 58 years, performance status of 0 or 1,varied clinical stage (15 IB, 2 IIA, 13 IIB) disease and histology (21adenocarcinoma, 8 squamous cell, 1 large cell).

Patients received two 28-day cycles of carboplatin (AUC 5) on day 1 anddocetaxel (60 mg/m²) on day 1, with concurrent radiotherapy delivered infractions of 2 Gy/d, 5 d/wk, to a total dose of 40 Gy over 4 weeks. Thepredominant toxicity was grade 3/4 neutropenia (87%), with two cases ofgrade 2 esophagitis observed. All 30 patients completed the inductionchemoradiotherapy, and the preoperative response rate was 70%. Among the 27patients who underwent a complete resection, 6 pathologic complete responseswere reported. All patients treated with surgery were disease-free after amedian follow-up of 14 months.

The Sakai et al Trial

Sakai et al[52] conducted a phase I/II trial ofdocetaxel and carboplatin with concurrent radiotherapy followed by consolidationdocetaxel/carboplatin in patients with unresectable stage III NSCLC. Successivecohorts of at least 3 patients received docetaxel/carboplatin at the followingdose levels (mg/m²/AUC): 20/2.5, 20/3.0, 30/2.5, 30/3.0, and 40/3.0,administered every 2 weeks (starting in week 1) over an 11-week period.Concurrent radiotherapy was administered in 2-Gy fractions 5 d/wk, to a totaldose of 60 Gy over 6 weeks. The phase I portion of the trial treated 23patients. The maximum tolerated dose of docetaxel was 40 mg/m² and carboplatinat an AUC of 3. Neutropenia was the dose-limiting toxicity.

The phase II recommended doses were 30 mg/m² of docetaxel and AUC 3 forcarboplatin, administered every 2 weeks. Of 16 patients entered into the phaseII portion of the study, 14 were evaluable for response. A partial response wasseen in 11 patients, for an overall response rate of 79%; two patients hadstable disease and one patient had progressive disease. The regimen was welltolerated and showed promising efficacy.

The combination of weekly docetaxel and carboplatin with radiation therapydemonstrates efficacy in patients with stage III NSCLC (Table 3).[48-52]When administered on a weekly basis, docetaxel at 20 mg/m² and carboplatinat AUC 2 are well tolerated. Some notable pulmonary toxicity was observed, andongoing trials will help to further delineate this effect.

Discussion

Docetaxel is an active agent in the treatment of NSCLC, as demonstrated bypreviously reported randomized phase III studies.[40,53-55] Because of itssignificant in vitro radiosensitizing properties, clinical investigations ofdocetaxel with radiotherapy have been conducted.[56] Docetaxel combined withradiation therapy resulted in encouraging response rates of up to 80% in phaseII trials. The most commonly used schedule has been docetaxel at 20 to 30 mg/m²weekly with concomitant radiation adminstered in fractions of 1.8 to 2.0 Gy, 5days a week over 5 to 6 weeks. Esophagitis has been the most commondose-limiting toxicity seen in both phase I and II trials.

Studies of docetaxel and platinum combinations have been conducted,predominantly in patients with NSCLC. Early results show good activity withacceptable toxicity, with the dose-limiting toxicities being esophagitis ormucositis. Although many studies are still ongoing, the combination ofdocetaxel, 20 mg/m²/wk, combined with cisplatin, 25 mg/m², or carboplatin at anAUC of 2 with concomitant radiation, appear to be well tolerated and active.

Docetaxel-based chemotherapy with concomitant radiation therapy is a welltolerated and effective regimen, particularly in patients with NSCLC. Futureinvestigations are encouraged including phase III trials in patients withlocally advanced NSCLC. Current trials are evaluating different designsincluding concurrent chemotherapy with radiation followed by consolidationdocetaxel. Additional trials of docetaxel-based chemoradiotherapy in theneoadjuvant and adjuvant settings in early NSCLC are warranted. Furthermore, itis essential that future studies of docetaxel include the use of novelbiological agents, both as treatment enhancers and as posttreatment maintenancetherapy, especially in NSCLC, in order to provide improved patient outcome.

References:

1. Choy H: Combining taxanes with radiation for solid tumors. Int J Cancer90:113-127, 2000.

2. Clamon G, Herndon J, Cooper R, et al: Radiosensitization with carboplatinfor patients with unresectable stage III non-small-cell lung cancer: A phaseIII trial of the Cancer and Leukemia Group B and the Eastern CooperativeOncology Group. J Clin Oncol 17(1):4-11, 1999.

3. Langer CJ: Concurrent chemoradiation using paclitaxel and carboplatin inlocally advanced non-small-cell lung cancer. Semin Radiat Oncol 9(2 suppl11):108-116, 1999.

4. Lee JS, Komaki R, Fossella FV, et al: A pilot trial of hyperfractionatedthoracic radiation therapy with concurrent cisplatin and oral etoposide forlocally advanced inoperable non-small-cell lung cancer: A 5-year follow-upreport. Int J Radiat Oncol Biol Phys 42(3):479-486, 1998

5. Vokes EE, Gregor A, Turrisi AT: Gemcitabine and radiation therapy for non-small-celllung cancer. Semin Oncol 25(4 suppl 9):66-69, 1998.

6. Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med 332:1004-1014,1995.

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

8. Piccart MJ, Gore M, Ten Bokkel Huinink W, et al: Docetaxel: An active newdrug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst87:676-681, 1995.

9. Belani CP, Aisner J, Hiponia D, et al: Paclitaxel and carboplatin with andwithout filgrastim support in patients with metastatic non-small-cell lungcancer. Semin Oncol 22(suppl 9):7-12, 1995.

10. Schiff PB, Fant S, Horwitz SB: Promotion of microtubule assembly in vitroby Taxol. Nature 277:665-667, 1979.

11. Gueritte-Voegelein F, Guenard D, Lavelle F, et al: Relationships betweenthe structure of Taxol analogues and their antimitotic activity. J Med Chem34:992-998, 1991.

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

13. Parness J, Horwitz SB: Taxol binds to polymerized tubulin in vitro. JCell Biol 91:479-87, 1981.

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

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

16. Von Hoff DD: The taxoids: Same roots, different drugs. Semin Oncol24:S13-3-S13-10, 1997.

17. Mason K, Hunter NR, Milas M, et al: Docetaxel enhances tumorradioresponse in vivo. Clin Cancer Res 3:2431-2438, 1997.

18. Choy H, Rodriguez F, Koester S, et al: Radiation sensitizing effects ofTaxotere (RP 56976). Proc Am Assoc Cancer Res 33:500, 1992.

19. Chaffey JT, Hellman S: Differing responses to radiation of murine bonemarrow stem cells in relation to the cell cycle. Cancer Res 31:1513-1516, 1971.

20. Terasima T, Tolmach LJ: Variations in several responses of HeLa cells toX-irradiation during the division cycle. Biophys J 3:11-33, 1963.

21. Sinclair WK, Morton RA: X-ray sensitivity during the cell generationcycle of cultured chinese hamster ovary cells. Radiat Res 29:450-474, 1966.

22. Winters HR, Mason KA, Reid BO, et al: Response of mouse intestine toneutrons and gamma rays in relation to dose fractionation and division cycle.Cancer 34:39-47, 1974.

23. Hennequin C, Giocanti N, Favaudon VC: Interaction of ionizing radiationwith paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ 20B cells.Cancer Res 56:1842-1850, 1996.

24. Halder S, Chintapalli J, Croce CM: Taxol induces bcl-2 phosphorylationand death of prostate cancer cells. Cancer Res 56:1253-1255, 1996.

25. Mason K, Ataab A, Hunter N, et al: Enhancement of tumor radio response bydocetaxel: Involvement of immune system. Int J Oncol 18:599-606, 2001.

26. Dicker AP, Williams T, Grant D: Inhibition of angiogenic processes inendothelial cells by docetaxel (Taxotere) and paclitaxel (Taxol) inducedradiosensitization: A potential antiangiogenic strategy. Presented at the 42ndAnnual Meeting of the American Society of Therapeutic Radiation Oncology,Boston, MA, 2000.

27. Choy H, DeVore R, Hande KR, et al: A phase I trial of outpatient weeklydocetaxel and concurrent radiation therapy for stage III unresectable non-smallcell lung cancer: A Vanderbilt Cancer Center Affiliate Network (VCCAN) trial.Clin Lung Cancer 1(suppl 1):27-31, 2000.

28. Aamdal S, Hallen MN, Tonelli D, et al: Docetaxel combined with radiationin locally advanced non-small-cell lung cancer—a phase I/II study (abstract1839). Proc Am Soc Clin Oncol 17:478a, 1998.

29. Koukourakis MI, Kourousis C, Kamilaki M, et al: Weekly docetaxel andconcomitant boost radiotherapy for non-small-cell lung cancer. A phase I/IIdose escalation trial. Eur J Cancer 34:838-844, 1998.

30. Mauer AM, Masters GA, Haraf DH, et al: Phase I study of docetaxel withconcomitant thoracic radiation therapy. J Clin Oncol 16:159-64, 1998.

31. Koukourakis M, Giatromanolaki A, Schiza S, et al: Concurrent twice-a-weekdocetaxel and radiotherapy: A dose escalation trial with immunological toxicityevaluation. Int J Radiat Oncol Biol Phys 34:107-114, 1999.

32. Tishler R, Covelas AD, Norris CM, et al: A phase I/II trial of concurrentdocetaxel (T) and once daily radiation following induction chemotherapy insquamous cell cancer of the head and neck (abstract 930). Proc Am Soc Clin Oncol20:233a, 2001.

33. Koukourakis MI, Bahlitzanakis N, Froudarakis M, et al: Concurrentconventionally fractionated radiotherapy and weekly docetaxel in the treatmentof stage IIIB non-small-cell ling carcinoma. Br J Cancer 80(11):1792-1796,1999.

34. Aamdal S, Lauvvang G, Owre K, et al: A phase I/II study of docetaxel (Taxotere)combined with concurrent radiation therapy in locally advanced non-small-celllung cancer (NSCLC) (abstract 327). Lung Cancer 29 (suppl 1):100, 2000.

35. Sistermanns J, Hoffmanns H: Phase II study of docetaxel with simultaneousradiochemotherapy in patients with locally advanced non-resectable non-small-celllung cancer—preliminary results (abstract 2014). Proc Am Soc Clin Oncol18:522, 1999.

36. Mauer AM, Haraf DC, Ferguson MK, et al: Docetaxel-based combined modalitytherapy for locally advanced carcinoma of the esophagus and gastric cardia(abstract 963). Proc Am Soc Clin Oncol 18:251a, 1999.

37. Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial ofinduction chemotherapy plus high-dose radiation vs radiation alone in stage IIInon-small-cell lung cancer. N Engl J Med 323(14):940-945, 1990.

38. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent vssequential thoracic radiotherapy in combination with mitomycin, vindesine, andcisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol17:2692-2699, 1999.

39. Curran W, Scott C, Langer C, et al: Phase III comparison of sequential vsconcurrent chemoradiation for pts with unresected stage III non-small-celllung cancer (NSCLC): Report of Radiation Therapy Oncology Group (RTOG) 9410(abstract 303). Lung Cancer 29(suppl1):93, 2000.

40. Rodriguez J, Pawel J, Pluzanska A, et al: A multicenter, randomized phaseIII study of docetaxel + cisplatin (DC) and docetaxel + carboplatin (DCB) vsvinorelbine + cisplatin (VC) in chemotherapy-naive patients with advanced andmetastatic non-small-cell lung cancer (abstract 1252). Proc Am Soc Clin Oncol20:314a, 2001.

41. LeChevalier T, Monnier A, Douillard JY, et al: Docetaxel (Taxotere) pluscisplatin: An active and well-tolerated combination in patients with advancednon-small-cell lung cancer. Eur J Cancer 34(13):2032-2036,
1998.

42. Georgoulias V, Androulakis N, Dimopoulos AM, et al: First-line treatmentof advanced non-small-cell lung cancer with docetaxel and cisplatin: Amulticenter phase II study. Ann Oncol 9:331-334, 1998.

43. Zalcberg J, Millward M, Bishop J, et al: Phase II study of docetaxel andcisplatin in advanced non-small-cell lung cancer. J Clin Oncol 16:1948-1953,1998.

44. Belani C: Phase II randomized trial of docetaxel in combination withcisplatin or carboplatin or vinorelbine plus cisplatin in advanced non-smallcell lung cancer: Interim analysis. Semin Oncol 28(3 suppl 9):10-14, 2001.

45. Segawa Y, Ueoka H, Kiura J, et al: A phase I/II study of docetaxel (TXT)and cisplatin (CDDP) with concurrent thoracic radiotherapy (TRT) for locallyadvanced non-small-cell lung cancer (LA-NSCLC) (abstract 1988). Proc Am SocClin Oncol 19:508a, 2000.

46. Moriyama A, Komiya K, Yamamoto N, et al: A phase I trial of weeklydocetaxel and cisplatin concomitant with thoracic radiation therapy for patientswith unresectable locally advanced non-small-cell lung cancer (abstract 110).Ann Oncol 11(suppl 4):, 2000.

47. Mudad R, Zakris EL: Concomitant docetaxel, cisplatin and radiation (XRT)in the treatment of locally advanced non-small-cell lung cancer (NSCLC): Aphase I study (abstract 2146A). Proc Am Soc Clin Oncol 19:544a, 2000.

48. Skarin AT, Lynch CM, Lucca J, et al: A phase I study of carboplatin (Car)and docetaxel (Doc) followed by weekly Car/Doc with concurrent radiotherapy(CT/RT) in patients (pts) with stage III non-small-cell lung cancer (NSCLC)(abstract 371). Lung Cancer 29
(suppl 1):112, 2000.

49. Choy H, DeVore R, Porter L, et al: Phase I trial of outpatient weeklydocetaxel (DTX) carboplatin (CBDCA) and concurrent thoracic radiation therapy (TRT)for stage III unresectable non-small-cell lung cancer: A Vanderbilt CancerCenter Affiliate Network (VCCAN) Trial (abstract 1833). Proc Am Soc Clin Oncol18:475a, 1999.

50. Murakami H, Jubota K, Ohe Y, et al: Phase I study of weekly docetaxel andcarboplatin with concurrent thoracic radiotherapy for stage III non-small-celllung cancer. Lung Cancer 29:1(suppl 1), 2000.

51. Nishimura T, Ikeda A, Katakami N, et al: Phase I study of inductioncarboplatin (CAR) and docetaxel (DOC) with concurrent thoracic radiation (CTRT)followed by surgical resection in stage IB, IIA and IIB non-small-cell lungcancer (NSCLC) (abstract 2767). Proc Am Soc Clin Oncol 20:254b, 2001.

52. Sakai H, Yoneda S, Noguchi Y, et al: A phase I/II study of biweeklydocetaxel (DOC) and carboplatin (CBDCA) with concurrent thoracic radiationtherapy (TRT) followed by consolidation chemotherapy with DOC/CBDCA for stageIII unresectable non-small cell lung cancer (NSCLC) (abstract 2704). Proc Am SocClin Oncol 20:238b, 2001.

53. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial ofdocetaxel vs best supportive care in patients with non-small-cell lung cancerpreviously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103,2000.

54. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial ofdocetaxel vs vinorelbine or ifosfamide in patients with advanced non-small-celllung cancer previously treated with platinum-containing chemotherapy regimens.The TAX 320 Non-Small-Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362,2000.

55. Schiller JH, Harrington D, Sandler A, et al: A randomized phase III trialof four chemotherapy regimens in advanced non-small-cell lung cancer (abstract2). Proc Am Soc Clin Oncol 19:1a, 2000.

56. Choy H, Rodriguez F, Wilcox B, et al: Radiation sensitizing effects ofTaxotere. Proc Am Assoc Cancer Res 33:500, 2000.