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Docetaxel in combined-modality treatment of inoperable locally or regionally advanced lung cancer
Lung Cancer46 SuppL 2 (2004) S13 S21
LUNG CANCER
ELSEVIER
www.etsev~eccom/tocate/tungcan
Docetaxe{ in combined-modatity treatment of inoperabte tocatty or regionatty advanced tung cancer Giorgio V. Scagliotti a, *, J.-Y. Douillard b °University o[ Turin, Department o[ Clinical & Biological Sciences, S. Luigi Hospital Thoracic Oncology Unit, Orbassano (Torino), Italy; bDepartment o[ Medical Oncology, Centre Ren# Gauducheau, St. Herblain, France
Summary Atthough most ctinicians use a combination of a ptatinumcontaining regimen and radiation therapy to treat non-smatt-cett tung cancer (NSCLC), there is no reference regimen for inoperabte stage-Ill NSCLC. Limited phase-Ill data suggest concurrent chemoradiotherapy is preferabte to sequentia[ therapy. Combined-modatity chemoradiotherapy with cisptatin ptus agents such as vindesine, mitomydn C, vinbtastine, etoposide, vinoretbine, or pactitaxe[ yietd a median survwa[ of onty 15 17 months, with distant metastases being the most common reason for faiture. The need for new therapeutic approaches to target distant metastases is a critica[ issue. In addition to its proven antitumor properties in NSCLC, docetaxe[ has radiosensitizing activity, making it weft-suited for use in combined-modatity regimens. Severat phase-I/ll studies have demonstrated that concurrent docetaxe[, cisptatin, and radiation therapy is a feasibte regimen, yietding objective response rates of 70 90%. A regimen of cisptatin ptus docetaxet induction fottowed by thoracic radiotherapy ptus docetaxe[ resutted in an objective response of 58% in a phase-II t r i a l A second phase-II tria[ evatuating a unique regimen of chemoradiotherapy using cisptatin and etoposide fottowed by consotidation docetaxe[ yietded a median survwa[ of 26 months. This compares favorabty to historica[ data demonstrating a median survwa[ of 15 months using cisptatin, etoposide, and radiation therapy without consotidation docetaxe[. Phase-Ill research is currentty underway to confirm the favorabte phase-II resutts with docetaxet. © 2004 Etsevier Science Ltd.
* Correspondenceto: Scagt~ott~G~orgbWttofio, Universityof Turin, Departmentof C[~n~ca[& Bbtog~ca[Sdences,S. Lu~g~Hosp~ta[, Thoradc OncotogyUnit, Regbne Gonzote, 10, 10043 Orbassano(Tofino), Itaty. TeL: +39-(011)-9026414; fax: +39-(011)-9038616. E-marl: g~org~o,scagtbtt~@un~to.~t 0169-5002/$ see front matter © 2004 Pubt~shedby Etsev~erIretand Ltd.
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G.V. Scagtiotti, J.-Y. Douittard
1. Introduction
administered without the risk of overlapping toxicities, chemotherapy-sensitive micrometastases may Approximately one-third of patients with non- be eliminated without delay, and cytoreduction small-celt lung cancer (NSCLC) have locally ad- from chemotherapy may allow the use of smaller vanced disease at initial presentation tl]. As radiation fields. This approach, however, does not patients with stage-Ill disease are a heterogeneous take advantage of the potential radiosensitizing population, clinical presentation, prognosis, and action of the chemotherapy, and cells resistant approach to treatments vary. Because of the poor to chemotherapy may metastasize before radiaprognosis for patients with totally advanced NSCLC, tion therapy is initiated. The administration of recent efforts to improve tong-term survwal have radiation therapy before chemotherapy allows for focused on combined-modatity approaches with the rapid local control, but also allows for growth of hope of eradicating total disease and reducing the micrometastases during the delay in administration occurrence of distant metastases. of chemotherapy. Concurrent administration of Although surgery currently offers the best chance chemotherapy and thoracic radiation therapy takes of cure in early-stage NSCLC, only a small advantage of the synergistic effect between the percentage of patients with locally advanced two treatment modalities, but also runs the risk disease are eligible for curative resection because of increased toxicity and, potentially, the inability of direct extension of the pMmary tumor into to deliver full doses of either or both modalities. adjacent structures, the presence of mediastina[ A hybrid approach consists of a short course of lymph-node metastases, or the presence of distant chemoradiation therapy followed by consolidation metastases [2]. Therefore, the majority of patients chemotherapy: in this way, the maximal antitumor must rely on non-surgical therapies. effect is achieved initially with the concomitant use Traditionally, patients with totally unresectabte of each modatity, at the time when the patient is disease were treated with radiotherapy atone, most fit, reducing at the same time the potential which palliates many symptoms of the disease but for severe toxicities. However, even with this does not improve survwa[ due to a high rate of conservative approach, the toxicity may preclude systemic failure. More recently in unresectabte some patients from completing subsequent consolstage-Ill disease, combination chemotherapy was idation therapy after the initial therapy [8]. added to thoracic radiation therapy in an atWhen concomitant and sequential chemoradiatempt to control both local disease and distant tion were compared head-to-head in two relametastases[3]. Although muttimodatity regimens tively large randomized phase-Ill trials, a modest have been investigated since the 1970s, this survival advantage was demonstrated [9 11], and approach began to yield improved outcomes only with the platinum-based chemotherapy regimens a third reported a trend [12] favoring concurrent chemotherapy and radiation therapy in surgicaUy in the 1980s. In general, platinum-containing muttimodatity regimens utilizing adequate chemo- unresectabte disease (Table 1). Although concurrent therapy doses show good tumor response rates and therapy was generaUy supenor, median survival was improved survwa[ compared with radiation therapy improved by only 3 months at best, and more atone [4 7]. Currently no single reference regimen than 75% of patients completing treatment died can be considered the standard of care in patients of recurrent disease. As in patients treated with with surgicaUy unresectabte, totally advanced dis- radiotherapy atone, the most common reason for ease. Agents under investigation include docetaxel failure was systemic recurrence [8], thus supporting the need for improved systemic therapies. (Taxotere®), paditaxel, iMnotecan, vinoretbine, and gemcitabine, most often in combination with a platinum compound. 3. Docetaxel for inoperable or regionally
advanced NSCLC 2. Combined modality: standard of care? A key management issue regarding the use of combined-modatity therapy is whether chemotherapy and radiation therapy should be used sequentially, concurrently, or both. There are theoretical advantages and disadvantages to each approach. When chemotherapy is followed by radiation therapy, futl doses of each modatity can be
Docetaxe[, one of the most active agents in the treatment of NSCLC, has demonstrated activity as a radiosensitizer in lung-cancer cell lines. The radiosensitizing effects are seen at doses below those required for cytotoxicity [13]. In a study performed in mice, docetaxe[ enhanced the response to radiotherapy, with the magnitude of the response dependent on the drug radiation schedule. In docetaxel-sensitive tumors, the best response was
Docetaxe[ in combined-moda[ity treatment of inoperable locally or regionally advanced lung cancer $15
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G.V. Scag[iotti, J.-Y. Doui[[ard
achieved by administration of a single large dose of docetaxe[ one day before beginning fractionated radiotherapy, white in docetaxet-resistant tumors, the best response was achieved with dairy concomitant administration of docetaxe[ and radiation therapy[14]. As randomized ctinica[ tMats and metaanatyses support combined-modatity approaches emptoying cisptatin-based chemotherapy with improved survwa[ compared with radiotherapy or surgery atone in stage-Ill NSCLC, this paper reviews a number of strategies incorporating docetaxeL 4. C o n c u r r e n t t h e r a p y w i t h s i n g l e - a g e n t docetaxel/radiation combination The feasibility of docetaxe[ in combination with radiotherapy in unresectab[e stage-Ill NSCLCwas assessed in several phase-I and -II trials [15 18]. Docetaxe[ was administered in doses of 20 40mg/m 2 on a weekly basis concurrently with radiotherapy at 50 64Gy over 5 6.5 weeks. Esophagitis and asthenia were the most commonly reported dose-limiting toxicities. Other frequent[y reported adverse events were grade-3/4 [ymphocytopenia and radiation pneumonitis. In addition, docetaxe[ plus radiation after cisp[atin-based induction chemotherapy has been evaluated in a phase-II trial [19]. Fifty patients with previously untreated stage-IliA N2 or -IIIB NSCLCwith an Eastern Cooperative Group (ECOG) performance status of 0 or 1 who responded to induction chemotherapy (dsp[atin 100mg/m 2 IV every 4 weeks for 2 cycles plus vinore[bine 25 mg/m 2 IV every week for 8 weeks) or had stable disease received therapy with docetaxe[ 25mg/m 2 IV weekly for 6 weeks plus concurrent radiation (66Gy in 33 fractions over 6.5 weeks). The overall response rate (ORR) to the induction therapy was 45% (intent-to-treat analysis; at[ partial responders). In the 40 patients who received consolidation therapy, the ORR was 45%; 15% had stable disease. Grade-3 esophagitis/pharyngitis occurred in 23%, and grade-3/4 pneumonitis occurred in 8%. These combinations of docetaxe[ and radiation therapy in early-phase trials yielded encouraging response rates and manageable toxicity, and served as the basis for continued evaluations utilizing different combinations and schedules.
5. D o c e t a x e l - p l a t i n u m c o m b i n a t i o n s with concurrent radiotherapy A series of phase-I/ll trials assessing concurrent docetaxe[, cisp[atin, and radiation therapy (total dose, 6065Gy) in locally advanced NSCLC demonstrate that the combination of
cisp[atin and docetaxe[ is feasible (Table 2). In these trials, objective response rates ranged from approximately 40% to 90%, and to[erabi[ity was acceptable, with esophagitis being doselimiting [20 23]. Docetaxe[ has also been studied in combination with carbop[atin [24 27]. A phase-I study combined weekly docetaxe[ with carbop[atin and concurrent thoracic radiotherapy for patients with inoperable stage-Ill disease [24]. Esophagitis was the dose-limiting toxicity, and the maximum tolerated dose of docetaxe[ was 20mg/m z weekly with carbop[atin (AUC 2). The objective response rate was 60% in 25 eva[uab[e patients. As a follow-up to this study, the investigators have initiated a trial to evaluate concurrent docetaxe[/ carbop[atin plus radiotherapy followed by consolidation with docetaxe[/carbop[atin in patients with stage-IIIA/lllB NSCLC. In a recently reported phase-II trial of concurrent radiochemotherapy with carbop[atin and docetaxe[, patients received carbop[atin (AUC 5) on days 1 and 29, docetaxe[ (15 mg/m z) weekly for 6 weeks, and radiotherapy concurrently to a total dose of 60Gy (2Gy/day) [27]. For the 47 patients enro[[ed, only 2 events of grade-4 hematologic toxicity were observed. Radiation-related esophagitis was mi[d (17 grade 0, 16 grade 1, 14 grade 2) and other than anorexia, there were no grade-3/4 nonhematologic toxicities reported. Median survival time was 16.6 months, with 66% (31 patients) achieving a partial response. The 3-year survival rate was 14.8%. As evidenced by these studies, the combination of docetaxe[ and carbop[atin is also a feasible and tolerable treatment approach for patients with unresectab[e locally advanced NSCLC. The combination docetaxe[ cisp[atin has also been studied in a randomized mu[ticenter phase-II that as induction chemotherapy prior to either concomitant chemoradiation (utilizing docetaxe[ in combination with radiation therapy) or radiation therapy atone[28 30]. One-hundred eight chemotherapy-naive patients with unresectab[e stage-IliA (with multiple N2 involvement) or stage-IIIB (without pleura[ or pericardia[ effusion, or gross vessel invasion) NSCLC and performance status 1 (Figure 1) received 2 courses of induction chemotherapy with cisp[atin (40mg/m z days 1 and 2, every 3 weeks) and docetaxe[ (85 mg/m z day 1, every 3 weeks). At restaging, patients with stable disease or objective response after induction therapy were randomized to thoracic radiotherapy (60Gy) with or without docetaxe[ (20 mg/m z weekly for 6 weeks). The study included only patients with stage-IIIB (75% of patients) or bulky stage-IliA disease (25% of patients). At completion of the induction phase, 44% (95% CI:
Docetaxe[ in combined-modaIity treatment of inoperable locally or re~ionaUy advanced [un~ cancer S17
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G.V. Sca~[iotti, J.-Y. Doui[[ard NSCLC stage IliA multiple N2 or IHIB
every 3 weeks followed by the concomitant administration of carbop[atin, pac[itaxe[, and radiotherapy. .............................................. Patients randomized to the chemoradiotherapy~ /~--~-----~v~K~ i~c°x atone arm (arm B)received the same regimen of concomitant chemoradiotherapy as arm A. Results demonstrated a 2.6-month increase in median surviva[ for the induction-chemotherapy arm, atthoush these findinss did not reach statistica[ sisnificance. At the present time, induction chemotherapy Docetaxel: 2O rng/m t w k x 6 w k RT: 5a~E~ 6 RT: 2 Gy~a,satwk~ 6 ~ k fottowed by a combined-modatity approach for the treatment of [oca[[y advanced NSCLC is not Fi~. 1. Study design of European randomized tMa[ in advocated outside a c[inica[ tria[. Sta~e-III NSCLC. duction chemotherapy, q 3 wks x 2 cycles ,I 85 mglrn2 d l + Cisplatin 40 mg/m ~ dl,d2 every
34.2 52.9) of patients had a partia[ response 6. Consolidation therapy (PR) and 86% had disease control (PR plus stable disease). Grade-3/4 toxicity included neutropeThe SWOG 9504 phase-II tria[ evatuated a difnia (46%), febri[e neutropenia (4%), diarrhea (1%), ferent approach to muttimodatity therapy with and dyspnea (1%). A tota[ of 89 patients were docetaxe[[32]. Patients with sta~e-IIIB NSCLC randomized to subsequent treatment. Objective received consotidation docetaxe[ (75ms/m 2 iniresponse rate was 58% for combined-moda[ity tia[[y, esca[atin~ to 100m~/m z) after concurrent treatment and 48% for radiation therapy atone. chemoradiotherapy with cisptatin (50ms/m 2 days The most common 8rade-3/4 toxicity was [ymphocytopenia, occurrin~ in 80% of patients receivin~ 1, 8, 29 and 36), etoposide (50m~/m z days 1 5 chemoradiation therapy and in 20% of those re- and 29 33), and thoracic radiotherapy (to a tota[ ceivin8 chemotherapy atone. Infection was reported dose of 61 Gy). The docetaxe[ was initiated 4 to in 5% of patients receivin8 combined-moda[ity 6 weeks after chemoradiation therapy. A tota[ treatment. There was no 8rade-3/4 neutropenia. As of 83 eti~ibte patients were enrotted, of whom of the most recent update, 70% of patients who 74 compteted chemoradiotherapy and 65 proceeded received combined-moda[ity therapy were alive to consolidation. Consolidation therapy with doceversus 65% of patients who received radiotherapy taxe[ was 8enera[[y tolerable. Grade-4 neutropenia atone. Overa[[ and 1-year surviva[ rates were occurred in 57% of patients durin8 consolidation 14.9 months (95% Cl: 10.0 22.2) and 55.8% (95% Cl: and was more frequent at hisher doses, but 39.9 70.2) with combined-moda[ity treatment ver- febrile neutropenia was observed in only 9% of sus 14 months (95% Cl: 11.1 15.7) and 58.7% patients. The overa[[ response rate was 67%; stab[e disease occurred in 23%. At a median fo[[ow-up of (95% Cl: 43.3 73) with radiotherapy atone [28,29]. In a recent[y reported phase-Ill tria[, 366 patients 32 months, median prosression-free surviva[ was with unresectab[e stase-III NSCLCwere randomized 16 months (95% Cl: 10 17mo), median surviva[ to receive induction chemotherapy followed by 26 months (95% Cl: 18 35 mo), and 1-, 2-, and 3-year concomitant chemoradiotherapy or to chemoradio- surviva[ rates were 76%, 54%, and 37%, respective[y. therapy atone[31]. Patients in arm A of the The site of fai[ure was [oca[ in 36% of patients, [oca[ trial received induction chemotherapy consistin~ of and distant in 11%, and distant in 53%. The most 2 cyc[es of carbop[atin and pac[itaxe[ administered common site of fai[ure was brain metastases (33%).
Docetaxe[ in combined-modatity treatment of inoperabte [ocatty or resionaUy advanced tun8 cancer S19 A historica[ comparison was performed to evatuate results of SWOG 9504 relative to those of an eartier reported phase-ll study (SWOG 9019) that was conducted in a simitar patient poputation (Tabte 3)[33]. In SWOG 9019, induction therapy consisted of 2 cyctes of cisptatin ptus etoposide concurrent with dairy thoracic radiotherapy (45 Gy). In the absence of prosressive disease, an additiona[ 16Gy of radiation therapy was administered aton8 with 2 additiona[ cyctes of cisptatin and etoposide. At a median fottow-up of 52 months, overat[ median survwa[ and 3- and 5-year survwa[ rates were 15 months (95% Cl: 10 22), 17%, and 15%, respectwety. The difference in resutts between SWOG 9019 and SWOG 9504 may be due, in part, to the use of fur[ doses of chemotherapy in combination with radiation therapy and to the sequentia[ use of a non-overtappin8 asent (docetaxe[) for consotidation therapy. The resutts of SWOG 9504 are now bein8 confirmed in severa[ phase-lll friars (Tabte 4, overteaf). A friar sponsored by the Hoosier Oncotosy Group (HOG) wit[ determine if consotidation with docetaxe[ is superior to observation after combined-modatity therapy with cisptatin, etoposide, and radiotherapy in patients with unresectab[e stase-IIIA or -IIIB disease. In a second Intersroup trial (S0023), patients with stase-IIIA or -IIIB disease wit[ receive induction chemotherapy with cisptatin, etoposide, and radiotherapy. Within 4 8 weeks after comptetion of the induction phase, patients with stabte disease wit[ receive consotidation docetaxe[. Within 4 7 weeks after comptetion of consotidation therapy, patients wit[ be randomized to oral 8efitinib or placebo for a maximum of 5 years or unti[ disease progression or unacceptable toxicity. S0023 incorporates bio[osica[ corretative studies designed to determine whether motecutarty defined subsets of patients can be identified who are more or tess [ikety to benefit from this therapy.
7. Summary Two potentia[ strategies for concurrent combinedmodatity therapy with docetaxe[ have been exptored in the phase-ll setting. The first uses induction (two courses of induction chemotherapy) fottowed by concurrent chemotherapy and radiation therapy[28 30]. The second uses a short course of concurrent chemotherapy and radiation therapy fottowed by adjuvant consotidation chemotherapy [32]. In SWOG 9504, combination chemoradiotherapy with cisptatin ptus etoposide was fottowed by consolidation with docetaxe[ [32]. There is 8ood
bioto~ica[ rationale for this approach. Cisptatin plus etoposide were used durin~ combination chemoradiotherapy because it has been shown that they can be de[wered in fu[[ doses a[on~ with radiation therapy. Consolidation therapy with docetaxe[ was based on evidence that it may be the most active new chemotherapy a~ent in NSCLC[34] and data demonstratin8 second-line activity in patients with advanced disease, inc[udin8 patients who experienced failure of prior cisp[atincontainin~ regimens [35]. Moreover, in prectinica[ modets, docetaxe[ was active asainst tumors bearin8 the p53 mutation and demonstrated mechanisms of action, inc[udin8 Bcl-2 phosphory[ation and p27 induction, that support its administration after DNA-damasin8 chemoradiotherapy [36,37]. The 8oat of therapy in inoperabte [ocatty advanced NSCLC is [oca[ contro[, eradication of distant metastases, and avoidance of excessive toxicity. Phase-I/ll studies demonstrate that the use of docetaxe[ plus radiation therapy is a feasible approach to meetin8 these 8oats, as is chemoradiation therapy with cisp[atin plus etoposide fottowed by docetaxe[. Phase-Ill studies are underway to confirm these phase-II findinss.
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LUNG CANCER
ELSEVIER
www.etsev~eccom/tocate/tungcan
Docetaxe{ in combined-modatity treatment of inoperabte tocatty or regionatty advanced tung cancer Giorgio V. Scagliotti a, *, J.-Y. Douillard b °University o[ Turin, Department o[ Clinical & Biological Sciences, S. Luigi Hospital Thoracic Oncology Unit, Orbassano (Torino), Italy; bDepartment o[ Medical Oncology, Centre Ren# Gauducheau, St. Herblain, France
Summary Atthough most ctinicians use a combination of a ptatinumcontaining regimen and radiation therapy to treat non-smatt-cett tung cancer (NSCLC), there is no reference regimen for inoperabte stage-Ill NSCLC. Limited phase-Ill data suggest concurrent chemoradiotherapy is preferabte to sequentia[ therapy. Combined-modatity chemoradiotherapy with cisptatin ptus agents such as vindesine, mitomydn C, vinbtastine, etoposide, vinoretbine, or pactitaxe[ yietd a median survwa[ of onty 15 17 months, with distant metastases being the most common reason for faiture. The need for new therapeutic approaches to target distant metastases is a critica[ issue. In addition to its proven antitumor properties in NSCLC, docetaxe[ has radiosensitizing activity, making it weft-suited for use in combined-modatity regimens. Severat phase-I/ll studies have demonstrated that concurrent docetaxe[, cisptatin, and radiation therapy is a feasibte regimen, yietding objective response rates of 70 90%. A regimen of cisptatin ptus docetaxet induction fottowed by thoracic radiotherapy ptus docetaxe[ resutted in an objective response of 58% in a phase-II t r i a l A second phase-II tria[ evatuating a unique regimen of chemoradiotherapy using cisptatin and etoposide fottowed by consotidation docetaxe[ yietded a median survwa[ of 26 months. This compares favorabty to historica[ data demonstrating a median survwa[ of 15 months using cisptatin, etoposide, and radiation therapy without consotidation docetaxe[. Phase-Ill research is currentty underway to confirm the favorabte phase-II resutts with docetaxet. © 2004 Etsevier Science Ltd.
* Correspondenceto: Scagt~ott~G~orgbWttofio, Universityof Turin, Departmentof C[~n~ca[& Bbtog~ca[Sdences,S. Lu~g~Hosp~ta[, Thoradc OncotogyUnit, Regbne Gonzote, 10, 10043 Orbassano(Tofino), Itaty. TeL: +39-(011)-9026414; fax: +39-(011)-9038616. E-marl: g~org~o,scagtbtt~@un~to.~t 0169-5002/$ see front matter © 2004 Pubt~shedby Etsev~erIretand Ltd.
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G.V. Scagtiotti, J.-Y. Douittard
1. Introduction
administered without the risk of overlapping toxicities, chemotherapy-sensitive micrometastases may Approximately one-third of patients with non- be eliminated without delay, and cytoreduction small-celt lung cancer (NSCLC) have locally ad- from chemotherapy may allow the use of smaller vanced disease at initial presentation tl]. As radiation fields. This approach, however, does not patients with stage-Ill disease are a heterogeneous take advantage of the potential radiosensitizing population, clinical presentation, prognosis, and action of the chemotherapy, and cells resistant approach to treatments vary. Because of the poor to chemotherapy may metastasize before radiaprognosis for patients with totally advanced NSCLC, tion therapy is initiated. The administration of recent efforts to improve tong-term survwal have radiation therapy before chemotherapy allows for focused on combined-modatity approaches with the rapid local control, but also allows for growth of hope of eradicating total disease and reducing the micrometastases during the delay in administration occurrence of distant metastases. of chemotherapy. Concurrent administration of Although surgery currently offers the best chance chemotherapy and thoracic radiation therapy takes of cure in early-stage NSCLC, only a small advantage of the synergistic effect between the percentage of patients with locally advanced two treatment modalities, but also runs the risk disease are eligible for curative resection because of increased toxicity and, potentially, the inability of direct extension of the pMmary tumor into to deliver full doses of either or both modalities. adjacent structures, the presence of mediastina[ A hybrid approach consists of a short course of lymph-node metastases, or the presence of distant chemoradiation therapy followed by consolidation metastases [2]. Therefore, the majority of patients chemotherapy: in this way, the maximal antitumor must rely on non-surgical therapies. effect is achieved initially with the concomitant use Traditionally, patients with totally unresectabte of each modatity, at the time when the patient is disease were treated with radiotherapy atone, most fit, reducing at the same time the potential which palliates many symptoms of the disease but for severe toxicities. However, even with this does not improve survwa[ due to a high rate of conservative approach, the toxicity may preclude systemic failure. More recently in unresectabte some patients from completing subsequent consolstage-Ill disease, combination chemotherapy was idation therapy after the initial therapy [8]. added to thoracic radiation therapy in an atWhen concomitant and sequential chemoradiatempt to control both local disease and distant tion were compared head-to-head in two relametastases[3]. Although muttimodatity regimens tively large randomized phase-Ill trials, a modest have been investigated since the 1970s, this survival advantage was demonstrated [9 11], and approach began to yield improved outcomes only with the platinum-based chemotherapy regimens a third reported a trend [12] favoring concurrent chemotherapy and radiation therapy in surgicaUy in the 1980s. In general, platinum-containing muttimodatity regimens utilizing adequate chemo- unresectabte disease (Table 1). Although concurrent therapy doses show good tumor response rates and therapy was generaUy supenor, median survival was improved survwa[ compared with radiation therapy improved by only 3 months at best, and more atone [4 7]. Currently no single reference regimen than 75% of patients completing treatment died can be considered the standard of care in patients of recurrent disease. As in patients treated with with surgicaUy unresectabte, totally advanced dis- radiotherapy atone, the most common reason for ease. Agents under investigation include docetaxel failure was systemic recurrence [8], thus supporting the need for improved systemic therapies. (Taxotere®), paditaxel, iMnotecan, vinoretbine, and gemcitabine, most often in combination with a platinum compound. 3. Docetaxel for inoperable or regionally
advanced NSCLC 2. Combined modality: standard of care? A key management issue regarding the use of combined-modatity therapy is whether chemotherapy and radiation therapy should be used sequentially, concurrently, or both. There are theoretical advantages and disadvantages to each approach. When chemotherapy is followed by radiation therapy, futl doses of each modatity can be
Docetaxe[, one of the most active agents in the treatment of NSCLC, has demonstrated activity as a radiosensitizer in lung-cancer cell lines. The radiosensitizing effects are seen at doses below those required for cytotoxicity [13]. In a study performed in mice, docetaxe[ enhanced the response to radiotherapy, with the magnitude of the response dependent on the drug radiation schedule. In docetaxel-sensitive tumors, the best response was
Docetaxe[ in combined-moda[ity treatment of inoperable locally or regionally advanced lung cancer $15
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G.V. Scag[iotti, J.-Y. Doui[[ard
achieved by administration of a single large dose of docetaxe[ one day before beginning fractionated radiotherapy, white in docetaxet-resistant tumors, the best response was achieved with dairy concomitant administration of docetaxe[ and radiation therapy[14]. As randomized ctinica[ tMats and metaanatyses support combined-modatity approaches emptoying cisptatin-based chemotherapy with improved survwa[ compared with radiotherapy or surgery atone in stage-Ill NSCLC, this paper reviews a number of strategies incorporating docetaxeL 4. C o n c u r r e n t t h e r a p y w i t h s i n g l e - a g e n t docetaxel/radiation combination The feasibility of docetaxe[ in combination with radiotherapy in unresectab[e stage-Ill NSCLCwas assessed in several phase-I and -II trials [15 18]. Docetaxe[ was administered in doses of 20 40mg/m 2 on a weekly basis concurrently with radiotherapy at 50 64Gy over 5 6.5 weeks. Esophagitis and asthenia were the most commonly reported dose-limiting toxicities. Other frequent[y reported adverse events were grade-3/4 [ymphocytopenia and radiation pneumonitis. In addition, docetaxe[ plus radiation after cisp[atin-based induction chemotherapy has been evaluated in a phase-II trial [19]. Fifty patients with previously untreated stage-IliA N2 or -IIIB NSCLCwith an Eastern Cooperative Group (ECOG) performance status of 0 or 1 who responded to induction chemotherapy (dsp[atin 100mg/m 2 IV every 4 weeks for 2 cycles plus vinore[bine 25 mg/m 2 IV every week for 8 weeks) or had stable disease received therapy with docetaxe[ 25mg/m 2 IV weekly for 6 weeks plus concurrent radiation (66Gy in 33 fractions over 6.5 weeks). The overall response rate (ORR) to the induction therapy was 45% (intent-to-treat analysis; at[ partial responders). In the 40 patients who received consolidation therapy, the ORR was 45%; 15% had stable disease. Grade-3 esophagitis/pharyngitis occurred in 23%, and grade-3/4 pneumonitis occurred in 8%. These combinations of docetaxe[ and radiation therapy in early-phase trials yielded encouraging response rates and manageable toxicity, and served as the basis for continued evaluations utilizing different combinations and schedules.
5. D o c e t a x e l - p l a t i n u m c o m b i n a t i o n s with concurrent radiotherapy A series of phase-I/ll trials assessing concurrent docetaxe[, cisp[atin, and radiation therapy (total dose, 6065Gy) in locally advanced NSCLC demonstrate that the combination of
cisp[atin and docetaxe[ is feasible (Table 2). In these trials, objective response rates ranged from approximately 40% to 90%, and to[erabi[ity was acceptable, with esophagitis being doselimiting [20 23]. Docetaxe[ has also been studied in combination with carbop[atin [24 27]. A phase-I study combined weekly docetaxe[ with carbop[atin and concurrent thoracic radiotherapy for patients with inoperable stage-Ill disease [24]. Esophagitis was the dose-limiting toxicity, and the maximum tolerated dose of docetaxe[ was 20mg/m z weekly with carbop[atin (AUC 2). The objective response rate was 60% in 25 eva[uab[e patients. As a follow-up to this study, the investigators have initiated a trial to evaluate concurrent docetaxe[/ carbop[atin plus radiotherapy followed by consolidation with docetaxe[/carbop[atin in patients with stage-IIIA/lllB NSCLC. In a recently reported phase-II trial of concurrent radiochemotherapy with carbop[atin and docetaxe[, patients received carbop[atin (AUC 5) on days 1 and 29, docetaxe[ (15 mg/m z) weekly for 6 weeks, and radiotherapy concurrently to a total dose of 60Gy (2Gy/day) [27]. For the 47 patients enro[[ed, only 2 events of grade-4 hematologic toxicity were observed. Radiation-related esophagitis was mi[d (17 grade 0, 16 grade 1, 14 grade 2) and other than anorexia, there were no grade-3/4 nonhematologic toxicities reported. Median survival time was 16.6 months, with 66% (31 patients) achieving a partial response. The 3-year survival rate was 14.8%. As evidenced by these studies, the combination of docetaxe[ and carbop[atin is also a feasible and tolerable treatment approach for patients with unresectab[e locally advanced NSCLC. The combination docetaxe[ cisp[atin has also been studied in a randomized mu[ticenter phase-II that as induction chemotherapy prior to either concomitant chemoradiation (utilizing docetaxe[ in combination with radiation therapy) or radiation therapy atone[28 30]. One-hundred eight chemotherapy-naive patients with unresectab[e stage-IliA (with multiple N2 involvement) or stage-IIIB (without pleura[ or pericardia[ effusion, or gross vessel invasion) NSCLC and performance status 1 (Figure 1) received 2 courses of induction chemotherapy with cisp[atin (40mg/m z days 1 and 2, every 3 weeks) and docetaxe[ (85 mg/m z day 1, every 3 weeks). At restaging, patients with stable disease or objective response after induction therapy were randomized to thoracic radiotherapy (60Gy) with or without docetaxe[ (20 mg/m z weekly for 6 weeks). The study included only patients with stage-IIIB (75% of patients) or bulky stage-IliA disease (25% of patients). At completion of the induction phase, 44% (95% CI:
Docetaxe[ in combined-modaIity treatment of inoperable locally or re~ionaUy advanced [un~ cancer S17
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G.V. Sca~[iotti, J.-Y. Doui[[ard NSCLC stage IliA multiple N2 or IHIB
every 3 weeks followed by the concomitant administration of carbop[atin, pac[itaxe[, and radiotherapy. .............................................. Patients randomized to the chemoradiotherapy~ /~--~-----~v~K~ i~c°x atone arm (arm B)received the same regimen of concomitant chemoradiotherapy as arm A. Results demonstrated a 2.6-month increase in median surviva[ for the induction-chemotherapy arm, atthoush these findinss did not reach statistica[ sisnificance. At the present time, induction chemotherapy Docetaxel: 2O rng/m t w k x 6 w k RT: 5a~E~ 6 RT: 2 Gy~a,satwk~ 6 ~ k fottowed by a combined-modatity approach for the treatment of [oca[[y advanced NSCLC is not Fi~. 1. Study design of European randomized tMa[ in advocated outside a c[inica[ tria[. Sta~e-III NSCLC. duction chemotherapy, q 3 wks x 2 cycles ,I 85 mglrn2 d l + Cisplatin 40 mg/m ~ dl,d2 every
34.2 52.9) of patients had a partia[ response 6. Consolidation therapy (PR) and 86% had disease control (PR plus stable disease). Grade-3/4 toxicity included neutropeThe SWOG 9504 phase-II tria[ evatuated a difnia (46%), febri[e neutropenia (4%), diarrhea (1%), ferent approach to muttimodatity therapy with and dyspnea (1%). A tota[ of 89 patients were docetaxe[[32]. Patients with sta~e-IIIB NSCLC randomized to subsequent treatment. Objective received consotidation docetaxe[ (75ms/m 2 iniresponse rate was 58% for combined-moda[ity tia[[y, esca[atin~ to 100m~/m z) after concurrent treatment and 48% for radiation therapy atone. chemoradiotherapy with cisptatin (50ms/m 2 days The most common 8rade-3/4 toxicity was [ymphocytopenia, occurrin~ in 80% of patients receivin~ 1, 8, 29 and 36), etoposide (50m~/m z days 1 5 chemoradiation therapy and in 20% of those re- and 29 33), and thoracic radiotherapy (to a tota[ ceivin8 chemotherapy atone. Infection was reported dose of 61 Gy). The docetaxe[ was initiated 4 to in 5% of patients receivin8 combined-moda[ity 6 weeks after chemoradiation therapy. A tota[ treatment. There was no 8rade-3/4 neutropenia. As of 83 eti~ibte patients were enrotted, of whom of the most recent update, 70% of patients who 74 compteted chemoradiotherapy and 65 proceeded received combined-moda[ity therapy were alive to consolidation. Consolidation therapy with doceversus 65% of patients who received radiotherapy taxe[ was 8enera[[y tolerable. Grade-4 neutropenia atone. Overa[[ and 1-year surviva[ rates were occurred in 57% of patients durin8 consolidation 14.9 months (95% Cl: 10.0 22.2) and 55.8% (95% Cl: and was more frequent at hisher doses, but 39.9 70.2) with combined-moda[ity treatment ver- febrile neutropenia was observed in only 9% of sus 14 months (95% Cl: 11.1 15.7) and 58.7% patients. The overa[[ response rate was 67%; stab[e disease occurred in 23%. At a median fo[[ow-up of (95% Cl: 43.3 73) with radiotherapy atone [28,29]. In a recent[y reported phase-Ill tria[, 366 patients 32 months, median prosression-free surviva[ was with unresectab[e stase-III NSCLCwere randomized 16 months (95% Cl: 10 17mo), median surviva[ to receive induction chemotherapy followed by 26 months (95% Cl: 18 35 mo), and 1-, 2-, and 3-year concomitant chemoradiotherapy or to chemoradio- surviva[ rates were 76%, 54%, and 37%, respective[y. therapy atone[31]. Patients in arm A of the The site of fai[ure was [oca[ in 36% of patients, [oca[ trial received induction chemotherapy consistin~ of and distant in 11%, and distant in 53%. The most 2 cyc[es of carbop[atin and pac[itaxe[ administered common site of fai[ure was brain metastases (33%).
Docetaxe[ in combined-modatity treatment of inoperabte [ocatty or resionaUy advanced tun8 cancer S19 A historica[ comparison was performed to evatuate results of SWOG 9504 relative to those of an eartier reported phase-ll study (SWOG 9019) that was conducted in a simitar patient poputation (Tabte 3)[33]. In SWOG 9019, induction therapy consisted of 2 cyctes of cisptatin ptus etoposide concurrent with dairy thoracic radiotherapy (45 Gy). In the absence of prosressive disease, an additiona[ 16Gy of radiation therapy was administered aton8 with 2 additiona[ cyctes of cisptatin and etoposide. At a median fottow-up of 52 months, overat[ median survwa[ and 3- and 5-year survwa[ rates were 15 months (95% Cl: 10 22), 17%, and 15%, respectwety. The difference in resutts between SWOG 9019 and SWOG 9504 may be due, in part, to the use of fur[ doses of chemotherapy in combination with radiation therapy and to the sequentia[ use of a non-overtappin8 asent (docetaxe[) for consotidation therapy. The resutts of SWOG 9504 are now bein8 confirmed in severa[ phase-lll friars (Tabte 4, overteaf). A friar sponsored by the Hoosier Oncotosy Group (HOG) wit[ determine if consotidation with docetaxe[ is superior to observation after combined-modatity therapy with cisptatin, etoposide, and radiotherapy in patients with unresectab[e stase-IIIA or -IIIB disease. In a second Intersroup trial (S0023), patients with stase-IIIA or -IIIB disease wit[ receive induction chemotherapy with cisptatin, etoposide, and radiotherapy. Within 4 8 weeks after comptetion of the induction phase, patients with stabte disease wit[ receive consotidation docetaxe[. Within 4 7 weeks after comptetion of consotidation therapy, patients wit[ be randomized to oral 8efitinib or placebo for a maximum of 5 years or unti[ disease progression or unacceptable toxicity. S0023 incorporates bio[osica[ corretative studies designed to determine whether motecutarty defined subsets of patients can be identified who are more or tess [ikety to benefit from this therapy.
7. Summary Two potentia[ strategies for concurrent combinedmodatity therapy with docetaxe[ have been exptored in the phase-ll setting. The first uses induction (two courses of induction chemotherapy) fottowed by concurrent chemotherapy and radiation therapy[28 30]. The second uses a short course of concurrent chemotherapy and radiation therapy fottowed by adjuvant consotidation chemotherapy [32]. In SWOG 9504, combination chemoradiotherapy with cisptatin ptus etoposide was fottowed by consolidation with docetaxe[ [32]. There is 8ood
bioto~ica[ rationale for this approach. Cisptatin plus etoposide were used durin~ combination chemoradiotherapy because it has been shown that they can be de[wered in fu[[ doses a[on~ with radiation therapy. Consolidation therapy with docetaxe[ was based on evidence that it may be the most active new chemotherapy a~ent in NSCLC[34] and data demonstratin8 second-line activity in patients with advanced disease, inc[udin8 patients who experienced failure of prior cisp[atincontainin~ regimens [35]. Moreover, in prectinica[ modets, docetaxe[ was active asainst tumors bearin8 the p53 mutation and demonstrated mechanisms of action, inc[udin8 Bcl-2 phosphory[ation and p27 induction, that support its administration after DNA-damasin8 chemoradiotherapy [36,37]. The 8oat of therapy in inoperabte [ocatty advanced NSCLC is [oca[ contro[, eradication of distant metastases, and avoidance of excessive toxicity. Phase-I/ll studies demonstrate that the use of docetaxe[ plus radiation therapy is a feasible approach to meetin8 these 8oats, as is chemoradiation therapy with cisp[atin plus etoposide fottowed by docetaxe[. Phase-Ill studies are underway to confirm these phase-II findinss.
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