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Docetaxel-Based Combined-Modality Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer

^a University of Turin, Department of Clinical and Biological Sciences, S. Luigi Hospital, Thoracic Oncology Unit, Torino, Italy; ^b Medical University of South Carolina, Charleston, South Carolina, USA

Correspondence: Andrew T. Turrisi, III, M.D., Medical University of South Carolina, 169 Ashley Avenue, P.O. Box 250318, Charleston, South Carolina 29425, USA. Telephone: 843-792-3271; Fax: 843-792-5498; e-mail: turrisi{at}radonc.musc.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
After completing this course, the reader will be able to:

1. Offer a critical analysis of docetaxel radiotherapy clinical studies and provide background basic science support.
   
2. Discuss dose/administration/timing information, as available, for docetaxel and radiotherapy, and provide a foundation for clinical use and a platform for further research.
   
3. Explain the potential benefit and outline the toxicities of the combination as used in international studies.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
The cytotoxic agent docetaxel not only has proven activity in non-small cell lung cancer—when used alone or in combination—but is also a potent radiosensitizer, and improved treatments are needed in all stages of this disease. In patients with locoregionally advanced (stage III) disease, docetaxel has shown efficacy with manageable toxicities when used alone or in combination with a platinum compound in a sequential manner before localized radical radiotherapy/surgery. Presently, therapeutic gains appear to be maximized by the use of concurrent chemotherapy and irradiation. This review focuses on research with combinations of docetaxel with either cisplatin or carboplatin and radiotherapy. Overall response and survival rates to date provide data worth pursuing. From phase I data, weekly docetaxel at 20 mg/m² plus cisplatin at 25 mg/m² or carboplatin to an area under the concentration time curve of 2 mg/ml•min with concurrent radiotherapy to 60 Gy over 6 weeks appear to be suitable for phase II trials. Predominant toxicities are esophagitis and neutropenia, but a low frequency of pulmonary toxicity is reported. Induction, concurrent, and consolidation docetaxel-based chemoradiotherapy in potentially resectable disease are all being investigated. Future research could include the investigation of computed tomography/ positron emission tomography-derived target volume radiotherapy, dose-escalated therapy, and alternative fractionation schedules in combination with docetaxel-based cytotoxic chemotherapy.

Key Words. Chemotherapy • Docetaxel • Non-small cell lung carcinoma • Radiotherapy • Review

	INTRODUCTION

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
Almost one million new cases of lung cancer occur worldwide each year [1]. The current prognosis for most patients with lung cancer remains poor, with an overall survival at 5 years of only 13% [2].

The four major histologic types of lung cancer (squamous cell, adenocarcinoma, large cell or undifferentiated, and small cell) are all associated with smoking [3]. Non-small cell lung cancer (NSCLC) comprises the first three types and accounts for approximately 75%-85% of all cases [4, 5]. Accurate staging of NSCLC optimizes recommended management of the groupings [6, 7].

Patients with stage IIIA disease with clinically evident N2 nodal spread have an overall 5-year survival rate of only 10%-15%, although this falls to 2%-5% in those with bulky mediastinal N2 involvement [8]. Selected patients with stage IIIA disease may still be considered as candidates for radical surgery (although the surgical management of stage IIIA NSCLC remains highly controversial), but most patients with stage IIIB disease are generally considered inoperable [2]. Consequently, for the vast majority of these patients, radiotherapy and chemotherapy, or combinations of modalities, represent frontline treatments.

Radiotherapy used alone is associated with a long-term survival rate of only 5%-10% for patients with stage IIIA NSCLC. Significant palliation may result, but the majority of patients do not achieve a complete response [8]. The poor long-term prognosis for most patients with stage III disease has prompted intensive efforts to find new therapeutic modalities that will provide survival improvements. During the 1980s and 1990s, platinum-based chemotherapy demonstrated improved survival for patients with locally advanced disease treated with radiotherapy as well as those with metastatic (stage IV) NSCLC. Cisplatin-based therapy has been used preoperatively (neoadjuvant chemotherapy) in resectable stage IIIA disease [9–13]. Findings from these small randomized trials suggest a survival benefit is conferred by such a combined approach, but this still requires confirmation in larger trials.

Over the past 10 years, the use of combined modality regimens that integrate systemic chemotherapy into treatments based on radiotherapy or surgery has been increasingly explored. The goals of these approaches are to gain control of localized disease and to eradicate distant micrometastatic disease. A meta-analysis of data from 11 randomized clinical trials has shown that the addition of cisplatin-based chemotherapy to radiotherapy is associated with a 10% reduction, relative to radiotherapy alone, in the risk of death (p = 0.006) [14]. Sequential platinum-based chemotherapy followed by radiotherapy improved survival in unresectable stage III NSCLC when compared with radiotherapy alone; the most notable results in this respect were reported by the Cancer and Leukemia Group B (CALGB) [15] and the Radiation Therapy Oncology Group (RTOG) [16]. Randomized trials at the time when the meta-analysis was performed infrequently used concurrent therapy. More recently, concurrent administration of chemotherapy and radiotherapy has been reported to be superior to sequential therapy by the RTOG [17] and by Japanese investigators [18, 19].

A range of new agents with potential in multimodality therapy has become available for the treatment of NSCLC over the past decade [20]. These drugs include antimetabolites, such as gemcitabine and pemetrexed, the antitubulin vinorelbine, the taxanes, and topoisomerase I inhibitors such as irinotecan. The present review specifically examines the use of one novel agent, the taxane docetaxel (Taxotere^®; Aventis Pharmaceuticals; Bridgewater, NJ; http://www.aventispharma-us.com), in the setting of chemoradiotherapy in patients with locally advanced NSCLC.

	RADIOTHERAPY SCHEDULES

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
Radiotherapy variables include total dose, volume of irradiation, fractionation (daily or multiple daily dose), and timing with other modalities. Until recently, 60 Gy of radiation delivered with conventional daily fractionation was considered as standard treatment for patients undergoing primary radiotherapy with curative intent [2, 21]. In patients with favorable stage III NSCLC, this yields median survival times of 9–11 months, with a 5-year overall survival rate of less than 6% [22]. Although standard radiotherapy doses have been increased to 66–70 Gy in recent years, there is no controlled evidence that these doses are superior to the 60–65 Gy standards of past years. Current research with three-dimensional radiotherapy techniques explores dose escalation beyond 100 Gy with smaller target volumes. Previous dogma ordered that uninvolved lymph node stations be part of all target volumes, but some current research directs radiation only to clearly involved tumor and nodal stations [23]. These research efforts attempt to control visible disease with higher doses and minimize normal tissue toxicities by excluding them from high-dose target volumes. Alterations in fractionation have been used in an attempt to increase the intensity of radiotherapy (higher dose/unit of time) and, thereby, response rates and survival.

Hyperfractionation—or the delivery of radiation fractions (usually 0.9–1.3 Gy) twice daily over a similar period to standard regimens—achieves an increase in total radiation dose of 20%-30% over standard fractionation, with the intention of reducing late tissue toxicity. Although these schedules commonly subtly increase the total dose, the repair occurring after each fraction makes the absolute value of this dosing difficult to compare with total doses in once-daily schemes. Therefore, much of the apparent increase in dose may only compensate for the repair occurring between fractions.

Accelerated hyperfractionation—or the delivery of fractions (usually 1.5–2.0 Gy) more than once daily over a shorter period than with standard fractionation—delivers a lower total dose than conventional regimens but provides a dose-dense radiation schedule over less time. Thus, even if the total dose value appears lower, the delivery of the dose in a shorter time frame may increase its biologic effect. This approach is used with the intention of reducing repopulation by lung tumor cells with short potential doubling times [22]. Improved survival with hyperfractionated schedules in NSCLC specifically has yet to be demonstrated in prospective, randomized trials. In fact, when compared with standard schedules with the addition of chemotherapy, two randomized trials showed less favorable outcomes with the hyperfractionated regimen [16, 17]. In contrast, there is evidence that survival is improved with accelerated fractionation schemes [24, 25]. Continuous hyperfractionated accelerated radiotherapy (CHART) has also shown potential advantages over conventional fractionation. Data from a randomized, multicenter trial in over 500 patients with NSCLC localized to the chest showed an improvement in the overall 2-year survival rate of 9% (p = 0.004) with CHART (1.5 Gy three times daily to a total of 54 Gy in 12 days) relative to standard radiotherapy (30 fractions of 2–60 Gy in 6 weeks) [25].

Hypofractionated irradiation, whereby fewer fractions of radiation are delivered with considerably higher doses per fraction (e.g., 4 Gy instead of 2 Gy), has been explored in few modern studies. This approach is commonly used for palliation worldwide and forms the basis for achieving local control in nations challenged by restricted access to linear accelerators. Hypofractionation presents potential for improvements in patient convenience and cost savings, but has been approached with caution because of concerns over disproportionate increases in late normal tissue toxicity [26]. A nonrandomized study from the early 1990s in 301 patients with unresectable stage III NSCLC showed survival comparable with that seen with conventional radiotherapy in patients with stage IIIA disease who received a 40-Gy split course of radiation [27]. Patients with stage IIIB disease who received 24 Gy of radiation in three weekly fractions showed survival rates comparable with those achieved with higher total doses given in more fractions. Overall, the hypofractionated schemes were well tolerated, with no serious complications being reported.

	RATIONALE FOR CHEMOTHERAPY AND RADIOTHERAPY IN COMBINATION

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
The biologic rationale underlying the use of chemotherapy and radiotherapy in combination was reviewed recently by Hennequin and Favaudon [28], and the reader is referred to that paper for a full discussion of this issue.

Molecular Interactions
Chemotherapeutic drugs can add to or modify the damage caused to tumor DNA by radiotherapy. Examples of this include the effect of cisplatin on adduct formation in the presence of radiation-induced single-strand breaks and etoposide-induced double-strand breaks in addition to radiation-induced G₂ blockade. Radiosensitization linked to inhibition or alteration of radiation-induced DNA damage may also be achieved with some agents, notably the fluoropyrimidines, thymidine analogs, gemcitabine, and hydroxyurea.

Cellular Interactions
Sensitizing arises most notably through cytokinetic cooperation of drugs or radiation linked to the specific phases of the cell cycle. The S phase is the most radioresistant, and the G₂/M phase is the most radiosensitive. Thus, increased radiosensitivity can be achieved by exposing proliferating cells to radiation at about the same time as drugs that kill cells in the S phase of replication. Responses to radiotherapy may also be enhanced by synchronization (or accumulation) of cells in the radiosensitive G₂/M phase: this has been proposed as the mechanism underlying the in vitro radiosensitization of cells by some fluoropyrimidines. Promotion of apoptosis independent of sensitization may also be achieved by combined therapy, although this has not been established.

Interactions at the Tissue Level
Reductions in tumor volume after treatment with a single modality may result in an improved blood supply to the tumor, which leads to reoxygenation and increased radiosensitivity and chemosensitivity. For example, fractionated irradiation may facilitate access of drugs, such as carboplatin or 5-fluorouracil, to tumors via increased blood flow. Radiosensitivity might also be increased by the inhibition of tumor regrowth by epidermal growth factor receptor inhibition or by the inhibition of angiogenesis (which is essential for tumor growth).

	RATIONALE FOR COMBINED MODALITY THERAPY WITH DOCETAXEL

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
The taxanes are potent mitotic spindle poisons, which bind to ß-tubulin, increase tubulin polymerization, and promote microtubule assembly. They have been shown to be effective radiosensitizers in in vitro studies in various human cell lines [29, 30], with enhancement factors ranging from 1.1 to more than 3.0—together with additive or subadditive effects—being reported. In vivo data show strong enhancement of tumor radioresponse, with major mechanisms being reoxygenation of radioresistant hypoxic cells and G₂/M arrest [30]. Overall, preclinical studies show that the taxanes can enhance the radiation sensitivity of tumor cells, potentiate tumor responses, and increase the therapeutic ratio of radiotherapy [30].

In mice bearing the murine mammary carcinoma MCA-4, docetaxel specifically induces both mitotic arrest and apoptosis in vivo, with maximal enhancement of radioresponse when given within 2 days prior to irradiation [31]. In a further investigation in mice carrying docetaxel-sensitive MCA-4 tumors [32], single-bolus docetaxel administered 24 hours before the start of fractionated irradiation produced optimal results. The reoxygenation of hypoxic tumor cells during the interval between drug treatments, which likely caused tumor cell kill, and radiation delivery may explain the efficacy of this method. In contrast, in mice carrying docetaxel-resistant SCC-VII squamous cell carcinoma cells, therapeutic gains were achieved with intermittent multiple doses of docetaxel during fractionated radiotherapy. This enhancement of therapeutic activity was attributed to sensitization, as cells were arrested by docetaxel in the radiosensitive G₂/M phase of the cell cycle. Other in vivo murine data suggest that docetaxel also stimulates tumor infiltration by immune cells, which then participate in the antitumor action of the drug used alone or in combination with radiotherapy [33].

An in vitro study suggests enhancement of the effect of radiation by docetaxel plus carboplatin in H460 human lung carcinoma cells, with the combination being more effective than either drug given separately [34]. In that investigation, the mechanism of radiopotentiation of docetaxel did not appear to involve G₂/M arrest—unlike that of paclitaxel. This difference between the two taxanes serves as a reminder that these agents are distinguished from each other in several important pharmacologic aspects and cannot, therefore, be regarded as clinically equivalent alternatives. Docetaxel has a greater affinity for tubulin than paclitaxel, and this may contribute to the prolonged intracellular retention of the former agent. Microtubules formed after docetaxel exposure differ structurally from those observed with paclitaxel, and the two drugs are believed to act at different phases of the cell cycle [35]. Docetaxel is almost totally lethal to radioresistant S-phase cells, a property not shared by paclitaxel [29, 34, 36]. Most importantly, a lack of crossresistance to the taxanes has also been shown, with docetaxel demonstrating activity (overall response rate of 18%) in patients with paclitaxel-resistant breast cancer [37].

The potential of docetaxel as a radiotherapy partner for locally advanced NSCLC is further strengthened by the already demonstrated activity of the drug in randomized phase III clinical studies. The efficacy of single-agent docetaxel as first-line therapy (100 mg/m² every 3 weeks) has been shown in 207 patients with metastatic or unresectable disease, in which a 2-year survival rate of 12% in the docetaxel arm was compared with no survival beyond 20 months in patients who received best supportive care only [38]. The role of single-agent docetaxel in second-line therapy has been investigated in two major studies in a total of 476 patients in which docetaxel, at doses of 75 or 100 mg/m², was compared with best supportive care alone [39] or with a control regimen of vinorelbine or ifosfamide [40] after failure of platinum-based chemotherapy. Time to progression (10.6 versus 6.7 weeks, p < 0.001) and median survival time (7.0 versus 4.6 months, p = 0.047) were significantly greater with docetaxel than with best supportive care in the first study [39], and time to progression and progression-free survival at 26 weeks were significantly longer with docetaxel than with vinorelbine or ifosfamide in the second trial [40].

	INDUCTION CHEMOTHERAPY FOLLOWED BY RADIOTHERAPY (SEQUENTIAL THERAPY)

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
The dominant pattern of failure in curatively resected or radically irradiated patients is distant metastatic failure. Thus, the rationale for chemotherapy given to potentially curative patients with NSCLC is prevention of distant relapse. Indeed, it is reported that at least 80% of patients treated with local modalities alone will have micrometastases and will, therefore, relapse [41, 42].

The benefit of induction chemotherapy before radiotherapy in stage III NSCLC was established by the CALGB 8433 [15] and subsequently verified by the RTOG 8808 [16] randomized phase III studies. Induction chemotherapy in both trials consisted of cisplatin, 100 mg/m² on days 1 and 29, plus vinblastine, 5 mg/m² weekly for 5 weeks. Standard irradiation consisted of 60 Gy given in 30 fractions beginning on day 1 in the standard radiotherapy arms and on day 50 in the chemoradiotherapy arms of both studies. The RTOG 8808 trial, which also enrolled a small number (approximately 5%) of patients with stage II disease, included a third treatment arm in which patients received hyperfractionated irradiation at 1.2 Gy twice daily to a total of 69.6 Gy. After more than 7 years’ follow-up in 155 initially evaluable patients in the CALGB 8433 trial, median survival times in the chemoradiotherapy arm and the radiotherapy-only arm were 13.7 and 9.6 months, respectively (p = 0.012) [15] (Fig. 1). Median survival times after 5 years in the RTOG 8808 trial (458 initially evaluable patients) were 11.4 months with standard irradiation, 13.2 months with chemoradiotherapy, and 12 months with hyperfractionated irradiation. Log-rank testing indicated a statistically significant survival advantage in the chemoradiotherapy arm (p = 0.04) [16].

View larger version (12K): [in this window] [in a new window]   Figure 1. CALGB 8433: percentages of patients surviving from 1 to 7 years after radiotherapy (total dose of 60 Gy given as 30 fractions) given either alone or after induction chemotherapy with cisplatin, 100 mg/m2 on days 1 and 29, plus vinblastine, 5 mg/m2 once weekly for 5 weeks [15].

Docetaxel plus a Platinum Agent Followed by Radiotherapy/ Surgery
Combinations of docetaxel plus cisplatin or carboplatin have been extensively investigated in patients with advanced NSCLC, and an extensive review has been published [47]. The potential of docetaxel plus platinum chemotherapy in advanced NSCLC was suggested by the preliminary results from a large randomized phase III trial in 1,218 patients [48, 49]. Patients treated with docetaxel plus cisplatin were shown to have a longer median survival time and significantly better quality of life than patients treated with vinorelbine plus cisplatin (median survival 11.3 versus 10.1 months, p = 0.044).

A few studies support the use of cisplatin or carboplatin plus docetaxel in combination before surgery for patients with locally advanced disease. Betticher and colleagues [43] studied the efficacy of three 3-week cycles of neoadjuvant chemotherapy with docetaxel, 85 mg/m² on day 1, plus cisplatin, 40 mg/m² on days 1 and 2, in 34 patients with stage IIIA (N2) NSCLC. Patients with complete or partial responses to chemotherapy underwent radical surgery, with postoperative radiotherapy added for incomplete resection or if the uppermost mediastinal lymph node was involved at the time of resection. The rate of overall response to chemotherapy was 66%, and there were no postoperative pulmonary complications.

In a feasibility study of 28 patients (13 stage IV, 15 stage IIIB NSCLC), those patients with locally advanced disease received four cycles of induction docetaxel, 100 mg/m², plus carboplatin to an area under the plasma concentration versus time curve (AUC) of 7.5 mg/ml•min before surgery and irradiation [44]. As good results have been achieved in late-stage patients, many physicians theorize that there will be a measurable benefit in early-stage patients. A phase II trial was carried out in 19 patients with earlier disease (stages IB, IIA, and IIB) who received two induction cycles of docetaxel, 60 mg/m², plus carboplatin, to an AUC of 5 mg/ml•min, with concurrent irradiation at 2 Gy/day to a total of 40 Gy before surgery [46]. All patients completed induction chemoradiotherapy, with major responses observed in 14 patients (74%). The major adverse effect of treatment was neutropenia. After surgical resection in 15 patients, no treatment-related deaths had been reported, and all patients were disease free after a median follow-up of 18 weeks. The phase II Bimodality Lung Oncology Team trial assessed perioperative paclitaxel plus carboplatin chemotherapy in patients with early-stage NSCLC [50]. Two chemotherapy cycles were administered prior to surgery, with three postoperative cycles planned for patients undergoing complete resections. Of 94 patients, only one experienced a complete response, and 52 patients had partial responses to the preoperative chemotherapy. The group has an ongoing, prospective, randomized trial comparing three cycles of induction chemotherapy and surgery with surgery alone in early-stage NSCLC. The aim is to improve tumor response prior to surgery, thus avoiding the difficulty of administering chemotherapy postoperatively. Virtually identical randomized trials testing the same combination or other regimens in the same patient population are currently ongoing in Europe.

In a larger phase II study (120 evaluable patients with stage IIB-IV NSCLC), docetaxel, 100 mg/m², was administered with carboplatin to an AUC of 6 mg/ml•min every 28 days, with the intention of administering up to eight cycles [45]. Responders (4% complete and 40% partial responses) received radiotherapy (50 Gy over 4 weeks) between cycles 6 and 8, and those with early progression underwent irradiation between cycles 2 and 3. In total, 15% of patients had progressive disease. The median overall survival time was 12 months (18 and 20 months, respectively, for patients with stage IIIA and IIIB disease). Major toxicities were grade 3/4 neutropenia (15%) and peripheral neuropathy (13.3%).

Docetaxel as a Radiosensitizer Before Hypofractionated Irradiation
A phase I study has been conducted in 26 patients with locally advanced NSCLC who received docetaxel at doses ranging from 10 to 45 mg/m² 24 hours before starting hypofractionated irradiation with 5 Gy once weekly for 10 weeks to a total dose of 50 Gy [51]. No significant hematologic toxicity was noted, and grade 2 radiation pneumonitis was reported in one patient (4%) only. Of 23 evaluable patients, one exhibited a complete response and 13 showed partial responses, with stable disease in all other patients. The authors concluded that, with the schedule investigated, hypofractionated irradiation could be preceded by docetaxel, 35 mg/m². The efficacy of this unconventional approach should be further explored in a larger patient population.

	CONCURRENT CHEMORADIOTHERAPY

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
The superiority of concurrent administration of chemotherapy and radiotherapy over sequential therapy has been supported by two influential studies: RTOG 9410 [17] and a study from Japan [18, 19]. The RTOG 9410 study assessed 597 patients with stage II-III NSCLC [17]. Cisplatin, 100 mg/m² on days 1 and 29, with vinblastine, 5 mg/m² weekly for 5 weeks, and with radiotherapy, started on day 50 and administered to a total dose of 60 Gy, was compared with the same chemotherapy regimen plus radiotherapy started on day 1. A third group received concomitant chemoradiotherapy involving cisplatin/oral etoposide and hyperfractionated radiotherapy (total dose, 69.6 Gy). This divergent third group, justified by some good results from an RTOG pilot study [52], distracts from the simple hypothesis: is a concurrent strategy worth the extra toxicities it causes over a sequential method with the identical drugs? Median survival times for the three respective treatment groups were 14.6, 17.0, and 15.6 months. These data were reported at several meetings [17, 53, 54] and show a strong trend favoring concurrent chemotherapy with standard radiation therapy over sequential or hyperfractionated treatment groups.

The West Japan Lung Cancer Group studied 314 evaluable patients with unresectable stage III NSCLC and showed a 3.2-month median survival advantage (p = 0.04) when irradiation was administered in what is currently considered an outdated schedule, with 28 Gy in 14 fractions at five fractions per week administered twice in a split-course regimen (total dose 56 Gy) concurrently with cisplatin, vindesine, and mitomycin rather than sequentially after the completion of chemotherapy at five fractions weekly to a total of 56 Gy [19]. Despite the disadvantages of split-course techniques, which allow not only the repair of normal tissues but also proliferation of tumor clones during the break, the 5-year survival rate significantly favored the concurrent approach. Notwithstanding these two important studies, of which only one has been published, no benefits have yet been seen with the concurrent usage of these new drug combinations.

Single-Agent Docetaxel Plus Radiotherapy
The therapeutic feasibility of concurrent treatment with docetaxel-based chemotherapy and radiotherapy has been reported from a series of small phase I studies in patients with unresectable advanced NSCLC. Three of these NSCLC studies [55–57] involved 57 patients who received weekly docetaxel, 20–40 mg/m² per dose, to a total of four to six doses over 5–6 weeks. The concurrent radiation therapy was given as five fractions per week to total doses ranging from 50 to 64 Gy. A fourth study [58] involved 20 patients with advanced NSCLC (and nine patients with esophageal cancer). Patients received two cycles of docetaxel at doses of 40, 60, and 75 mg/m² per cycle every 3 weeks. The first two dose levels were given as the total dose on day 1 or as half doses on days 1 and 8. In addition, some 60-mg/m² doses and all 75-mg/m² doses were split into three parts (given on days 1, 8, and 15). Radiotherapy was delivered concurrently over 6 weeks in fractions of 1.8–2.0 Gy/day.

Dose-liming toxicities were esophagitis and neutropenia, with esophagitis consistently the dose-limiting toxicity across these trials. Pulmonary toxicity was noted in one study [58]. Doses of docetaxel recommended for phase II studies consisted of four to six doses of 30 mg/m² over 5–6 weeks when used concurrently with irradiation. Although these were phase I studies, efficacy data from the first three studies included a median survival time of 15 months [55] and overall response rates of 47% [59] and 77% [56]. In one trial [56], complete tumor responses were reported in 8 of 30 patients (27%) and, in another study [58], there were two complete and six partial in-field responses in 20 patients (40%) with NSCLC. In the latter study, the recommended dose of docetaxel was 20 mg/m² weekly for 6 weeks, together with a total radiation dose of 60 Gy (2 Gy/day, 5 days/week for 6 weeks).

For stage IIIA or IIIB NSCLC, phase II studies have shown overall tumor response rates of 35%-80% [60–62]. These studies employed conventional daily fractions of 1.8 [62] or 2.0 Gy/day [60, 61] over 5 [60], 6 [62], or 6.5 [61] weeks. The decision to use conventional fractionation isolates the variable of the addition of docetaxel, which might attenuate the rapid tumor repopulation by a cell synchronization effect [61]. Altered fractionation schemes also alter tumor cell repopulation kinetics; however, these effects might confound one another and add to normal tissue toxicity. Docetaxel was administered by i.v. infusion at a dose of 30 mg/m² per cycle in two studies [60, 61] and at 25 mg/m² per cycle in the other [62]. Among these trials, four to six weekly doses of docetaxel were administered over 5–6 weeks (Table 1).

Median survival times were 12–13.6 months [60, 61]. In addition, median time to progression was 12 months in one study [60]; overall and local progression-free survival rates at 1 year were 48% and 60%, respectively, in another [61]. As with previous phase I experience, esophagitis was consistently the main adverse event across these trials. Another cause of concern was the unpredictable occurrence of pulmonary toxicity, which occurred in two of the three studies [61, 62]. In their 1999 American Society of Clinical Oncology abstract, Sistermanns and Hoffmanns [62] reported that pneumonia up to grade 3 and grade 2 radiation pneumonitis occurred. The authors noted that the toxicities were manageable, and no fatalities were reported. In the trial by Koukourakis et al. [61], 25% of patients developed localized pulmonary fibrosis and one patient (3.7%) died from radiation pneumonitis 4 months after radiotherapy. Although patients with impaired pulmonary reserve caused by their tumors or by coexisting severe chronic obstructive pulmonary disease (which is very often observed in these patients) were eligible for this trial, no predictive factors for the development of pulmonary toxicity were clearly identified. In particular, the role of volume of irradiation in these trials was not defined [60–62]. Many radiation oncologists continue to treat clinically uninvolved mediastinal and hilar nodes, a traditional technique that necessarily includes much of the esophagus. Restricting the volume of irradiation offers the possibility of reducing normal tissue exposure and allowing a higher total dose of radiotherapy without increasing normal tissue toxicity [63, 64]. The use of targeted volumes and the selection of patients with adequate pulmonary function tests would be a logical approach to managing potential pulmonary toxicities.

Docetaxel and Cisplatin or Carboplatin plus Radiotherapy
Cisplatin is the benchmark agent for concurrent use with radiotherapy. Thus, the combination of new agents with cisplatin and defining the benefits and toxicities are crucial for further clinical development. Practitioners, particularly in the U.S., generally consider that carboplatin has equal efficacy to and less toxicity than cisplatin. Methods for employing doublet therapy include weekly administration during radiotherapy and the more typical once-every-3-weeks schedule. The activity and acceptable toxicity of these regimens have been demonstrated in a range of phase I and II studies, most of which investigated concurrent therapy given over 6 weeks, although a small number of trials also evaluated the effect of induction chemotherapy administered before chemoradiotherapy.

Phase I and II combination studies of docetaxel/cisplatin combined with radiotherapy are summarized in Table 2. All these trials recruited patients with unresectable stage III NSCLC [65–70] and reported encouraging overall tumor response rates in the range of 44%-91%, with 6%-24% complete responses being recorded [67, 68]. Overall, weekly doses of docetaxel, 20 mg/m², and cisplatin, 25 mg/m², in conjunction with 60 Gy of radiation over 6 weeks appear safe, tolerable, and effective for phase II studies. Across all studies, the main adverse events were esophagitis and neutropenia. Pulmonary toxicity was reported in two of the six trials [69, 70]. Grade 3 pneumonitis occurred in 4% of patients receiving docetaxel plus radiotherapy and 3% of patients receiving radiotherapy alone after induction chemotherapy in the study by Scagliotti et al. [70]; one death due to pneumonitis, occurring 3 months after therapy completion, was reported by Nyman and Mercke [69] among 20 treated patients. Segawa et al. [66] reported a median survival time of 23 months in patients with stage IIIA (N2) or stage IIIB disease, with survival rates of 74% after 1 year and 41% after 2 years. Yamamoto et al. [68], after recruiting 21 patients firstly via two split-schedule regimens and then via a continuous schedule (Table 2), reported a 1-year survival rate of 48% and a median progression-free survival time of 12 months. These survival data compare favorably with those of many new agents, but only a randomized trial will be able to establish the relative benefits and liabilities.

Docetaxel plus carboplatin with concurrent radiotherapy has also been investigated in phase I and II studies in patients with stage III disease [57, 73–75]; one trial [76] assessed patients with early, resectable NSCLC (Table 3). Choy et al. [57] tested five dose levels of docetaxel in 26 patients with unresectable stage III NSCLC, with the first three cohorts receiving docetaxel alone at doses of 20, 30, or 40 mg/m² weekly for 6 weeks. Dose-limiting toxicity (esophagitis) was noted at 40 mg/m², and concurrent carboplatin therapy (to an AUC of 2 mg/ml•min) was started with docetaxel 20 mg/m² in a fourth cohort. The docetaxel dose was subsequently raised to 30 mg/m² in a fifth cohort, with concurrent radiotherapy being given in all groups. Two complete responses were obtained in the docetaxel/carboplatin cohorts (Fig. 2), and the authors recommended a weekly schedule of docetaxel, 20 mg/m², with carboplatin, to an AUC of 2 mg/ml•min, and with standard radiation therapy to a total dose of 60 Gy over 6 weeks.

View larger version (13K): [in this window] [in a new window]   Figure 2. Complete and partial responses to treatment with docetaxel alone or with carboplatin weekly for 6 weeks, with concurrent radiotherapy to 60 Gy over 6 weeks, in patients with inoperable stage III NSCLC [57]. Docetaxel doses are shown in mg/m2 and carboplatin doses are shown as AUCs.

The other studies listed in Table 3 were basically neoadjuvant studies [75, 76], with surgery following chemoradiotherapy in patients without disease progression. Preoperative response rates are shown in Table 3. In the Japanese trial, all 27 patients with stages IB-IIB disease were subsequently radically resected and remained disease free after a median follow-up of 14 months [76]. Similarly, resection was performed in 11 of 15 stage IIIA patients studied by Skarin et al. [75]. In that small series, downstaging was documented in 73% of patients, with three pathologic complete responses. Sakai et al. [74] administered six courses of chemotherapy in a 2-week schedule, concurrently with radiation therapy over the first 6 weeks. Phase I data showed good tolerability, with early phase II data (Table 3) indicating efficacy. Overall, these early data suggest that 20 mg/m² docetaxel with carboplatin to an AUC of 2 mg/ml•min and radiotherapy to 60 Gy over 6 weeks is likely to be a well-tolerated treatment in locally advanced NSCLC.

	INDUCTION CHEMORADIOTHERAPY FOLLOWED BY CONSOLIDATION CHEMOTHERAPY

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
Efforts to optimize therapeutic gains through manipulation and sequencing of chemoradiotherapy combinations include the use of consolidation chemotherapy after chemoradiotherapy to maximize tumor responses. The rationale underlying this approach lies in the improvements in survival seen with sequential chemoradiotherapy coupled with the apparent superiority of concurrent therapy over sequential regimens.

In this area, a range of phase II and III studies are ongoing, with early data (median follow-up of 28 months) being available from the trial (9504) of the Southwest Oncology Group (SWOG) in 83 patients with stage IIIB NSCLC [77], in which a regimen consisting of cisplatin, 50 mg/m² on days 1 and 8 in weeks 1, 2, 5, and 6, with etoposide, 50 mg/m² on days 1–5 during weeks 1 and 5, was given in conjunction with radiotherapy to 61 Gy over 6 weeks. This combined therapy was then followed by consolidation docetaxel, 75–100 mg/m² every 21 days for three cycles. The reported median survival time from that study is 27 months—remarkably better than the 15 months previously reported in SWOG 9019, a study in 50 patients (purportedly similarly staged) treated with cisplatin/etoposide and concurrent radiation followed by two consolidation cycles with cisplatin and etoposide [77, 78]. The latest available comparative survival results from these two studies are illustrated in Figure 3. The predominant toxicity during docetaxel consolidation in the SWOG 9504 trial was neutropenia (56% grade 4), and three patients (4%) died of pulmonary complications (two from pneumonitis, one from aspiration pneumonia). Currently, the Hoosier Oncology Group is testing the two consolidation regimens proposed by SWOG trials in a phase III randomized trial (cisplatin/etoposide, as in SWOG 9019, versus docetaxel, as in SWOG 9504) following concurrent chemoradiotherapy treatment.

View larger version (14K): [in this window] [in a new window]   Figure 3. Survival rates after 1, 2, and 3 years of treatment with concurrent cisplatin/etoposide chemoradiotherapy followed by consolidation chemotherapy in the SWOG 9019 (cisplatin/etoposide consolidation) and 9504 (docetaxel consolidation) studies in a total of 133 patients with stage IIIB NSCLC [77].

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 
Management of stage III NSCLC has many variations, and the optimum management remains one of the subjects of investigation, but the outcome for patients presenting with mediastinal lymph nodes remains desperately poor despite efforts to integrate all modalities and new drugs. Docetaxel has proven efficacy in front-line therapy of advanced NSCLC, and its therapeutic role in second-line therapy is well established. This report describes current efforts in locally advanced NSCLC using docetaxel (both alone and in combination with other drugs) as part of a multimodality approach together with surgery and radiotherapy. Although toxicities are predominantly granulocytopenia and esophagitis with such docetaxel-based therapies, occasional pulmonary toxicity has been recognized. It remains low in frequency, but, judiciously, one should probably use targeted volumes to spare normal lung tissue, standard fractionations, and select patients with reasonably good pulmonary reserves. Concurrent chemoradiotherapy seems to offer the best chance for favorable interactions, and both laboratory and clinical data support this methodology with docetaxel and radiotherapy. Neoadjuvant chemotherapy followed sequentially by radiotherapy or concurrent chemotherapy may be alternative strategies. The use of elective nodal irradiation in standard treatments, as reviewed in this report, may or may not be related to the observed pulmonary toxicity, but is of uncertain value and necessarily exposes more normal tissues to both chemotherapy and radiotherapy. Using therapy targeted to sites of known disease seems to be a logical strategy, particularly with an agent that might produce pulmonary toxicity; however, information on correlations between this toxicity and lung volume is required from future studies. While altered fractionation schemes have improved survival in comparison with standard fractionation alone, adding concurrent radiotherapy to the effective accelerated schemes may be difficult to accomplish, and the benefits of the often-used hyperfractionated scheme, 69.9 Gy with or without chemotherapy, have never been proven in randomized prospective trials—it always has been second best to concurrent once-daily treatment. Trials changing one variable seem to make more sense than conglomerates where contributions from each variable are hard to isolate. Docetaxel possesses sufficiently interesting rationale and clinical benefit to warrant its investigation in further trials against conventional therapy.

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Top Learning Objectives Abstract Introduction Radiotherapy Schedules Rationale for Chemotherapy and... Rationale for Combined Modality... Induction Chemotherapy Followed... Concurrent Chemoradiotherapy Induction Chemoradiotherapy... Conclusions References

 

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