PROCLAIM: A Phase III Study of Pemetrexed, Cisplatin, and Radiation Therapy Followed by Consolidation Pemetrexed Versus Etoposide, Cisplatin, and Radiation Therapy Followed by Consolidation Cytotoxic Chemotherapy of Choice in Locally Advanced Stage III Non–Small-Cell Lung Cancer of Other than Predominantly Squamous Cell Histology


Everett E. Vokes; Suresh Senan; Joseph A. Treat; Neill A. Iscoe


Clin Lung Cancer. 2009;10(3):193-198. 

In This Article

Abstract and Introduction


This clinical trial summary provides the background and rationale for a randomized trial examining the benefits of pemetrexed/cisplatin chemotherapy combined with radiation followed by consolidation pemetrexed in patients with unresectable stage IIIA/B non–small-cell lung cancer. The rationale for the selection of the control arm is provided, and study design limitations are discussed. The primary outcome is survival, and secondary outcomes include progression-free survival, toxicities, and 1-, 2-, and 3-year survival rates. Radiation quality control is a key component of the trial.

Introduction and Rationale

Lung cancer is the most common cancer in the world, both in terms of incidence (1.2 million new cases or 12.3% of the world, total) and mortality (1.1 million deaths or 17.8% of the world, total).[1] Non–small-cell lung cancer (NSCLC) constitutes 75%-80% of lung cancer cases, and one third of these patients will present with stage III disease.[2] Depending on tumor and patient characteristics, standard treatment options for patients with locally advanced, inoperable or unresectable stage III NSCLC are radiation therapy (RT), chemotherapy, or combinations of these modalities.

A meta-analysis based on individual data from 3033 patients from 22 trials demonstrated a statistically significant benefit of combining chemotherapy with radiation for these patients.[3] The greatest difference in efficacy was seen in the 12 cisplatin-based trials involving 1780 patients. The hazard ratio (HR) in favor of cisplatin 0.87 (P = .005) corresponded to an absolute reduction in the risk of death of 4% at 2 years and 2% at 5 years.

A recently updated individual patient-based meta-analysis examined the results of randomized trials comparing concurrent chemotherapy and radiation (ChRT) with sequential chemotherapy and radiation.[4] Data from 6 trials encompassing a total of 1205 patients were assessed; 97% of patients had stage IIIA or IIIB disease, with 97% having performance status of 0 or 1. Although there was no difference seen in pulmonary toxicity between the sequential and concurrent groups, the relative risk of grade 3 or 4 esophagitis was higher in the group treated with concurrent therapy (relative risk [RR] = 4.9; P < .0001). Improved survival was seen in patients in the concurrent group (HR = 0.84; P = .004). Compared with the sequential group survival rate of 10.6% at 5 years, the survival rate of 15.1% at 5 years in the concurrent group represented an absolute increase of 4.5%. These benefits seem primarily attributable to a decrease in locoregional progression in the concurrent group, albeit at the expense of increased esophageal toxicity.

Most commonly used chemotherapy regimens administered to patients with metastatic disease cannot be administered at full doses safely with radical doses of thoracic radiation. It is possible to hypothesize that the lack of improvement in systemic control seen in the meta-analysis reported by Auperin and colleagues[4] could be either a reflection of the undertreatment of occult systemic disease by outdated regimens given at full dose or the use of standard chemotherapy regimens at suboptimal doses.[5]

The conclusion arising from these efforts is that concurrent ChRT produces the highest cure rates as measured by 5-year survival but with an increased level of toxicity during a period when relatively large fields were used to encompass uninvolved mediastinal regions.

Although it is clear that concurrent ChRT produces improved survival for appropriately selected patients compared with sequentially administered chemotherapy and radiation, there have been no studies specifically addressing the question of the optimal chemotherapy regimen to be given with radiation. The majority of information available supports the use of a platinum-based treatment program in this setting. There are few randomized trials that have addressed the question of whether additional chemotherapy given outside the setting of the concurrent phase of therapy enhances the overall efficacy of the treatment. Table 1A and Table 1B summarizes the results of individual studies in locally advanced NSCLC discussed in this article.[6,7,8,9,10,11,12,13,14,15,16,17,18,19]

Current practice commonly consists of patients receiving induction chemotherapy before concurrent therapy or consolidation chemotherapy given after concurrent therapy. There is one randomized phase II trial and one randomized phase III trial that have examined the role of induction chemotherapy before concurrent therapy. The randomized phase II trial compared 2 cycles of induction chemotherapy with paclitaxel and carboplatin followed by 63 Gy radiation with a similar 2 cycles of the same induction therapy followed by weekly paclitaxel and carboplatin given with 63 Gy radiation. A third arm within this study allocated patients to immediate weekly paclitaxel and carboplatin and 63 Gy radiation followed by 2 cycles of consolidation chemotherapy with paclitaxel and carboplatin.[6] The most effective treatment observed was the immediate concurrent therapy arm, though this was associated with greater toxicity, notably esophagitis. Vokes and colleagues in the Cancer and Leukemia Group B (CALGB) randomized 366 patients to immediate concurrent ChRT with weekly paclitaxel and carboplatin or to an arm in which the same therapy was preceded by 2 cycles of full-dose paclitaxel and carboplatin chemotherapy.[7] Although the median survival of the patients allocated to induction chemotherapy was 14 months compared with 12 months in the control arm, the differences in survival were not statistically significant. The relative similarity of the results was also shown by very similar failure-free survival times of 8 months in the induction group versus 7 months in the control group. It must also be pointed out that studies evaluating the roles of single-agent carboplatin[8,9] and taxanes[10,11] as radiosensitizers in locally advanced NSCLC have not shown any significant survival benefits.

A randomized phase III trial examined the role of single-agent docetaxel as consolidation therapy after chemotherapy with etoposide/cisplatin and concurrent thoracic RT versus an arm that received no consolidation therapy.[12] The study was closed by the data monitoring committee (DMC) before the target accrual had been reached, after the DMC concluded that the trial could not show a difference in favor of the more toxic docetaxel arm with the projected sample size for the trial. Of the 203 patients who began the concurrent therapy, 147 were randomized to consolidation docetaxel or observation. Consolidation docetaxel did not improve survival and was associated with significant toxicity, including an increased rate of hospitalization and premature death. The investigators concluded that docetaxel consolidation does not improve overall survival (OS) and should no longer be used for patients with unresectable stage III NSCLC.

Despite these negative studies, there remains considerable uncertainty about the role of chemotherapy outside the concurrent phase of treatment, with many physicians unwilling to abandon more treatment in a potential curative setting when distant relapse rates approach 50% or more in patients who relapse.[4,13,14]

In attempting to identify an appropriate standard of care for the concurrent phase of therapy without the benefit of randomized trial data that compare chemotherapy regimens, data from phase II trials were examined. To date, the most promising results were reported from the multicenter phase II trial examining the Southwest Oncology Group (SWOG) 9504 regimen in patients with stage IIIB disease.[15] The investigators reported a median survival of 26 months and a 3-year survival rate of 37% among the 83 eligible patients. This trial used etoposide/cisplatin with radiation, followed by docetaxel consolidation. As already noted, Hanna and colleagues[12] found no benefit from the addition of docetaxel consolidation, which was associated with notable toxicity compared with the nonconsolidation arm. The median survival in the docetaxel arm was 21.2 months compared with 23.2 months in the arm without consolidation, with 3-year survival rates of 27.1% and 26.1%, respectively.

The predecessor to the SWOG 9504 program was SWOG 9019, which used etoposide and cisplatin both with the radiation and as consolidation and reported a median survival of 15 months and 3-year survival rate of 17% in 50 eligible patients.[16] Considering the survival reported in the Hanna trial,[12] it seems likely that the difference in the improved median survival was a consequence of patient selection because of stage migration resulting from positron emission tomography (PET) scans used in their initial assessment of patients.

The SWOG 9019 regimen has been studied more completely in a randomized trial in which definitive ChRT was compared with preoperative concurrent therapy in patients with resectable stage IIIA disease (Lung Intergroup Trial 0139).[13] Of 429 patients randomized, 411 were eligible for analysis and showed a median survival of 21.7 months for the patients randomized to definitive ChRT with a 3-year survival of 33%. The only toxicity that was significantly higher in the definitive ChRT arm was grade 3/4 esophagitis.

Based on the cumulative information available, concurrent therapy with cisplatin and etoposide plus radiation is an appropriate treatment regimen for the concurrent phase of therapy, as this regimen has a known, predictable, and acceptable side effect profile. Based on limited information, the preferred order of administration appears to favor commencing therapy with concurrent ChRT and then adding consolidation treatment.

There is no single consolidation treatment regimen that can be recommended, based on available data. A number of consolidation therapies have been used following a program of combined ChRT and include additional etoposide and cisplatin,[13,16] vinorelbine and cisplatin,[17,18] paclitaxel and carboplatin,[7] docetaxel,[15] and paclitaxel.[19] When either taxane was used alone, excessive toxicity was noted, though the use of single-agent paclitaxel was in a poorer risk population. Given the lack of consensus about a standard of consolidation treatment, this current trial will permit investigation sites to select 1 of 3 platinum-based doublet regimens to be used as consolidation ChRT for the patients entered in the control arm: etoposide/cisplatin, or vinorelbine/cisplatin, or paclitaxel/carboplatin.


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