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Clinical Cancer Research 13, 515-522, January 15, 2007. doi: 10.1158/1078-0432.CCR-06-1058
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

Tanguy Y. Seiwert1, Philip P. Connell2, Ann M. Mauer1, Philip C. Hoffman1, Christopher M. George1, Livia Szeto1, Ravi Salgia1, Katherine E. Posther3, Binh Nguyen3, Daniel J. Haraf2 and Everett E. Vokes1

Authors' Affiliations: 1 Section of Hematology/Oncology, Department of Medicine; 2 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois; and 3 Eli Lilly and Company, Indianapolis, Indiana

Requests for reprints: Everett E. Vokes, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-9306; Fax: 773-702-3002; E-mail: evokes{at}medicine.bsd.uchicago.edu.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy.

Experimental Design: Patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m2); regimen 2 was pemetrexed (500 mg/m2) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower).

Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m2). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m2; AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase II dose-range was established (pemetrexed 500 mg/m2 and carboplatin AUC = 5-6).

Conclusions: The combination of pemetrexed (500 mg/m2) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.

Lung cancer is the leading cause of cancer-related death in the United States and Europe for both men and women. Non–small cell lung cancer (NSCLC) accounts for ~87% of all lung cancers. About one third of patients present with locally advanced stage III NSCLC, the majority of whom have unresectable bulky disease or extensive mediastinal lymphadenopathy, making curative treatment a challenge (1). The 5-year survival rate for these patients remains low (1).

For patients with locally advanced unresectable disease, concurrent chemoradiotherapy offers a greater survival advantage than sequential chemotherapy and radiation. Concurrent chemoradiotherapy is now considered the standard therapeutic approach (2–8). However, both locoregional and distant failure remain a problem (8–11). Following treatment with chemoradiotherapy, 70% to 75% of patients will develop recurrent or progressive disease (failure of therapy): Roughly one third of patients fail in the radiation field (local failure); one third of patients fail outside the irradiated field (distal failure); and one third of patients fail both locally and distally (10–13). For patients with stage IV disease, radiotherapy is also appropriate to relieve symptoms related to bulky chest disease (6).

The combination of carboplatin, paclitaxel, and radiotherapy (widely used in the United States) yielded disappointing results in a recent randomized cooperative group trial [Cancer and Leukemia Group B (CALGB) 39801], with median survival times of 11.4 and 13.7 months (concurrent chemoradiotherapy ± induction chemotherapy; ref. 14). The Radiation Therapy Oncology Group 98-01 trial used the same chemotherapy plus accelerated, hyperfractionated radiotherapy and reported better results (median survival time of 16 months; ref. 15). Nevertheless, a clear need remains to explore novel therapies to improve survival in patients with locally advanced NSCLC.

Pemetrexed, a novel antimetabolite, acts as a multitargeted antifolate by inhibiting several key enzymes involved in nucleotide synthesis: thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase (16). Pemetrexed has activity in a wide range of cancers (17) and was approved by the U.S. Food and Drug Administration for second-line, single-agent therapy in metastatic NSCLC (18) as well as first-line treatment of inoperable malignant mesothelioma in combination with cisplatin (19). Pemetrexed shows single-agent activity similar to other active agents in NSCLC (20, 21). In clinical trials for chemo-naive patients with advanced NSCLC, pemetrexed was evaluated in combination with cisplatin, gemcitabine, vinorelbine, oxaliplatin, and carboplatin (22–28).

In two phase II studies [one in Europe (N = 39) and one in the United States (N = 50)] in patients with locally advanced or metastatic NSCLC, the combination of pemetrexed (500 mg/m2) and carboplatin (AUC = 6) given every 3 weeks produced response rates of 32% and 24%, median survival times of 10.5 and 13.5 months, and 1-year survival rates of 44% and 56% (25, 29).

Furthermore, in preclinical studies, the combination of pemetrexed with concurrent radiation showed synergistic activity (30). An enhancement ratio of 1.6 was reported for a lung cancer line (1.2-1.8 for other tumor types), with a tendency towards higher ratios with increasing pemetrexed concentrations. Based on these preclinical data, as well as the evident activity of pemetrexed in NSCLC, we conducted a phase I dose-finding study to determine the maximum tolerated dose (MTD) of pemetrexed as a single agent and in combination with carboplatin given with concurrent radiotherapy in patients with locally advanced or locally symptomatic metastatic NSCLC or esophageal cancer. Secondary objectives were to determine the dose-limiting toxicities (DLT) and the recommended phase II dose of pemetrexed plus carboplatin and radiotherapy for subsequent studies.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Eligibility criteria. Inclusion and exclusion criteria are listed in Table 1 . This study was conducted according to good clinical practice guidelines and the Declaration of Helsinki. The local ethical review board approved the study, and patients gave written informed consent before enrollment.


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  		Table 1. Eligibility/exclusion criteria and definition of DLT

 
Treatment plan. This phase I trial was an open-label, nonrandomized, dose-finding cohort study using two sequential pemetrexed regimens and concurrent radiotherapy. Initially, patients with NSCLC or esophageal cancer (regimen 1 only) received single-agent pemetrexed with concurrent radiotherapy (regimen 1). Subsequently, the trial was amended to limit the inclusion criteria to NSCLC patients and combine pemetrexed 500 mg/m2 with escalating doses of carboplatin plus concurrent radiotherapy (regimen 2).

Pemetrexed (Alimta, LY231514, Eli Lilly and Company, Indianapolis, IN) was administered as a 10-min i.v. infusion on day 1 every 21 days for a maximum of two cycles or until disease progression or unacceptable toxicity occurred. In regimen 1, the initial dose level was pemetrexed 200 mg/m2, which was escalated in 100-mg/m2 increments. During the conduct of the trial, published results established the pemetrexed dose for second-line treatment in NSCLC at 500 mg/m2 (18). The pemetrexed dose was therefore capped at 500 mg/m2, and regimen 2 was started with an initial carboplatin dose of AUC = 4, which was escalated in increments of 1. For patients on regimen 2, a 30-min infusion of 100 mL saline was administered between the pemetrexed and carboplatin therapy, followed by a 30-min infusion of carboplatin.

Radiotherapy started 30 to 60 min following chemotherapy on day 1. Patients received daily fractions of 2 Gy (using megavoltage equipment with a nominal energy of usually 6 and 18 MV if necessary to achieve adequate dose homogeneity), 5 days per week to the isocenter of the treatment field until the total cumulative dose of 40 to 70 Gy was reached. Lower radiation doses were used in the palliative setting (stage IV disease; typically between 40 and 55 Gy), whereas higher doses of radiation were used in locally advanced disease (mean radiation dose: 61 Gy). The treatment volume generally consisted of two parts that were irradiated sequentially: the original volume (included the primary lesion with a 2-cm margin and draining lymphatics for primary thoracic tumors) and the boost volume (included the entire pre-therapy radiologically defined primary tumor volume and clinically involved regional hilar and/or mediastinal nodes). Elective nodal regions were included in the "original volume" in most patients with IIIB NSCLC, but this was not mandatory for all patients. Supraclavicular nodal regions were radiated only in a few selected patients due to concern for esophageal toxicity. Computed tomography–based planning and three-dimensional dosimetry were used routinely, and dose-volume histograms for dose-limiting organs were established for all patients.

All patients had custom immobilizations constructed and underwent computed tomography–based simulation (with 3- to 5-mm image slices). Formal three-dimensional planning was done in all patients, and this was typically done using the PLUNC software package. Corrections for tissue density inhomogeneity were not used in the majority of cases. Weekly quality assurance port films were taken and reviewed by treating physicians. The initial treatment was delivered using an AP/PA technique. Oblique field arrangements to boost the mediastinum and areas with gross disease were instituted at the appropriate times to minimize the dose to normal lung and to keep the dose to the spinal cord under 46 Gy. The total radiation dose to grossly uninvolved mediastinum, supraclavicular fossa, or hilum was 40 to 50 Gy. The total radiation dose to areas of gross disease was 40 to 70 Gy. No more than 40% of normal lung (with PTV subtracted) received a dose >20 Gy based on three-dimensional dosimetry and dose-volume histograms.

Patients were allowed to receive full supportive care. All patients were premedicated with oral dexamethasone 4 mg twice a day for 5 days, starting the day before treatment to reduce potential hypersensitivity reactions and nausea. Granulocyte colony-stimulating factor was used for patients with absolute neutrophil count <0.5 x 109/L for at least 5 days, neutropenic fever, or documented infections with neutropenia. It was discontinued at least 24 h before the start of the next cycle. All patients received vitamin supplementation (31): a vitamin B12 injection (1,000 µg) and folate supplementation (350-600 µg) were given ~1 to 2 weeks before the first pemetrexed dose. Folate was continued daily until the patient discontinued therapy.

For both regimens, the absolute neutrophil count had to be above 1.5 x 109/L, and platelets had to be above 100 x 109/L, before the start of any cycle; treatment was delayed up to a maximum of 3 weeks to permit recovery. Pemetrexed was delayed until the patient received vitamin B12 and folate for at least five of the 7 days before cycle 1, or until the patient took folate for at least 14 of the 21 days before cycle 2. Pemetrexed was also held for creatinine clearance <45 mL/min. Both pemetrexed and carboplatin were held for Common Toxicity Criteria grade 3 or 4 mucositis or esophagitis and would not be restarted until recovery to grade ≤2. Any patient experiencing a pulmonary or esophageal Common Toxicity Criteria grade 3 or 4 toxicities did not receive cycle 2 treatment, unless it was considered to be in the patient's best interest to continue chemotherapy; if retreated, both study drugs were reduced by 50%. Radiotherapy was interrupted for grade 4 esophagitis and was restarted when the patient recovered to grade 2.

Dose-escalation schema. For regimen 1, five dose levels of pemetrexed were tested, starting at 200 mg/m2 (Table 2 ). The initial dose was given to the first three patients enrolled in the study. If none of the first three patients experienced a DLT, then escalation proceeded to the next dose level. If one of the first three patients experienced a DLT, then enrollment continued until six patients were enrolled, or a third DLT occurred, whichever came first. If no or one additional DLT occurred (≤2 DLTs in six patients), dose escalation continued. If ≥2 of the first three patients or ≥3 of the six patients had DLTs, the MTD was reached, and dose escalation stopped.


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  		Table 2. Treatment administration

 
For regimen 2, pemetrexed was fixed at 500 mg/m2, and three dose levels of carboplatin were tested, starting at an AUC = 4 and increasing by 1 (Table 2). The protocol was amended to allow discontinuation of dose escalation once systemic doses of both pemetrexed and carboplatin were achieved.

DLTs. All toxicities were assessed using the National Cancer Institute-Common Toxicity Criteria 2.0 before each cycle.4 Following the expansion of the trial, the definition of DLT was broadened for regimen 2. The definition of DLTs for regimens 1 and 2 are shown in Table 1.

Baseline and treatment assessments. The assessment of disease status of each patient included medical history and physical examination, evaluation of performance status, tumor measurement of palpable or visible lesions, chest + abdomen computed tomography scan, electrocardiogram, and vital signs. Positron emission tomography scanning at the time of the initial study planning was not standard of care and was not included in staging studies. Mediastinoscopies were done when clinically indicated, in particular, before surgical treatment when the study treatment was used neoadjuvantly.

Follow-up assessments included weekly hematology and blood chemistry monitoring (±3 days and up to 4 days before each cycle). Creatinine clearance was calculated (modified Cockcroft-Gault formula; ref. 32) within 4 days before the start of each cycle. Vitamin metabolites were measured up to 4 days before both pemetrexed doses. In addition, an outside laboratory (Covance, New York, NY) did blood chemistries and homocysteine levels and calculated creatinine clearance. All patients who received at least one dose of chemotherapy were included in the analysis. Patients were then followed every 3 months until death, or until data was censored for disease progression, chemotherapy, surgery, and other treatments. Patients were closely followed for delayed toxicity for at least 30 days after completing therapy.

Although efficacy was not an end point of this study, response was assessed per Southwest Oncology Group criteria (33). Baseline computed tomography (chest + abdomen) was done within 4 weeks before starting therapy, and subsequent scans were obtained every 4 to 6 weeks. All patients with bidimensionally measurable disease, who received at least one dose of chemotherapy and radiotherapy, were evaluable for the efficacy analysis. Local response was assessed by applying response criteria to lesions within the radiation field. Patients who underwent surgery had pathologic response assessment.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics. A total of 30 patients were treated: 18 on regimen 1 and 12 on regimen 2 (Table 3 ). The median age was 65 years, and 60% of the patients were male. On regimen 1, the patient population was more heterogeneous, with 3 patients having esophageal cancer and 15 NSCLC. All patients on regimen 2 had advanced NSCLC. Overall, locally advanced disease was reported in 60% of patients. On regimen 2, the population was significantly more homogeneous, with 83.3% having locally advanced disease. Only two patients had metastatic disease (first and third patient enrolled). All nine patients on the highest two dose levels had locally advanced NSCLC (stages IIIA and B; Table 3).


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  		Table 3. Patient characteristics

 
Recommended dose and DLTs. For both regimens, dose escalation was discontinued when full single-agent doses were reached; accordingly, per the definition, the MTD was not reached for either regimen (Table 4 ). However, two DLTs occurred: one on each regimen. On regimen 1, at dose level 500 mg/m2, one DLT (grade 4 esophagitis/anorexia) occurred in a patient with metastatic NSCLC (radiation dose: 66 Gy). This patient had a resected solitary brain metastasis and, in the absence of metastatic disease, was treated with curative treatment doses for his remaining thoracic disease. This patient also experienced non-DLT toxicities of grade 3 dehydration, fatigue, and pain secondary to the esophagitis. Three additional patients were enrolled, and pemetrexed was subsequently escalated to 600 mg/m2. Parallel studies established the standard dose of single-agent pemetrexed for second-line treatment of NSCLC as 500 mg/m2 (18). Therefore, we chose 500 mg/m2 as the recommended dose for single-agent pemetrexed combined with radiotherapy and used this dose as the basis for regimen 2. On regimen 2, one DLT (grade 3 esophagitis) occurred in a patient with locally advanced NSCLC at the highest dose level (pemetrexed 500 mg/m2 and carboplatin AUC = 6; radiation dose, 66 Gy). Accordingly, six patients were enrolled at this dose level. Further dose escalation was discontinued at this point for multiple reasons (i.e., achievement of systemically active doses, increased incidence of non-DLT toxicities, and absence of literature supporting higher AUCs; see Discussion for further detail). Pemetrexed 500 mg/m2 with carboplatin with an AUC = 6 or potentially 5 was recommended for phase II testing.


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  		Table 4. DLTs and selected treatment-related toxicities

 
Other non-DLT toxicities. Treatment-related grade 3 and 4 toxicities are shown in Table 4. Overall, all dose levels were well tolerated. On regimen 1, one patient at the 300 mg/m2 dose level developed grade 4 respiratory failure (radiation dose; 60 Gy), which occurred within the first 30 days after the end of radiotherapy. The precise etiology remained unclear. Nevertheless, the clinical and radiological picture was suggestive of an infectious etiology leading to acute respiratory distress syndrome; therefore, the event was not primarily attributed to study treatment or determined to qualify as a DLT.

At 500 mg/m2, one patient developed grade 3 dehydration, fatigue, and pain [secondary to esophagitis (DLT, see above), 66 Gy], and three patients had decreased blood counts (leukopenia or neutropenia). Furthermore, one case of grade 2 radiation pneumonitis occurred shortly after completion of radiation at the 500 mg/m2 dose level (70 Gy). At 600 mg/m2, one patient developed grade 3 esophagitis (66 Gy), which per definition (for regimen 1) was not a DLT.

On regimen 2, at the 500 mg/m2 and AUC = 6 dose level, two patients had radiation pneumonitis [one grade 1 (58 Gy) and one grade 2 (66 Gy)], which manifested in the month following radiation. After completion of therapy, the patient with grade 2 pneumonitis had progressive disease and received docetaxel and dexamethasone within 30 days after the last study drug administration. Withdrawal of dexamethasone led to immediate worsening of the previously stable symptoms (grade 3). Exacerbation was considered related to the docetaxel and steroid withdrawal by the treating physician and the primary investigator; therefore, it was not considered to qualify as a DLT for the previous study treatment. Although a remote possibility, the fulminant respiratory failure could also have been caused by pemetrexed and radiation. Careful further testing in a larger cohort is necessary to clarify this further. In the other patient, grade 1 radiation pneumonitis resolved over a period of 2 months, and the patient subsequently underwent curative intent surgery.

There was no treatment discontinuation due to adverse events. In regimen 1, the weekly mean dose intensity for pemetrexed was 99.6% of the protocol planned dose intensity. One patient died due to disease progression before completing therapy. Five of 30 patients experienced dose delays due to adverse events: decreased creatinine clearance in one patient on regimen 1 and hyperglycemia, dehydration, pulmonary embolism, and atrial flutter each in one patient on regimen 2. On regimen 2, one patient had cycle 2 doses reduced (both pemetrexed and carboplatin were reduced, by 50%) due to pulmonary embolism (radiation dose: 54 Gy). In regimen 2, the weekly mean dose intensity for both pemetrexed and carboplatin was 94.4% of the planned dose intensity. A total of three patients (two on regimen 1 and one on regimen 2) developed pulmonary emboli (radiation doses: 60, 70, and 54 Gy); the patient on regimen 2 developed atrial fibrillation as a consequence.

Efficacy. Although this was a phase I study, early signs of efficacy were visible. Four patients had a complete response: one on regimen 1 (dose level: 500 mg/m2) and three on regimen 2 (one on each dose level). Two of these patients had a pathologically confirmed complete response after surgery without any residual cancer cells (dose levels: 500 mg/m2, AUC = 5/6). One patient had an unclear initial assessment of partial response versus complete response by imaging; subsequent pathologic examination of the specimen confirmed complete response, which was noted as the final response. After 2 years of follow-up, this patient continues to be free of disease.

A total of five patients with borderline resectable disease underwent curative intent surgery after neoadjuvant chemoradiotherapy (all on regimen 2).

Overall tumor response and in-field response are shown in Table 5 . The overall response rate for both regimens combined was 43%; this included two partial responders with esophageal cancer on regimen 1. All responders on regimen 2 had locally advanced NSCLC. The overall in-field response rate was higher at 61% (63% for regimen 1 and 58% for regimen 2).


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  		Table 5. Overall response and in-field response rates

 
The median survival time was 12.6 months (95% confidence interval, 6.9-18.8) overall. On regimen 2, seven of 12 patients (58.3%) are still alive.


   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
This phase I trial shows the tolerability of combining pemetrexed with thoracic radiotherapy as well as combining pemetrexed, with carboplatin, and chest radiotherapy in patients with NSCLC. Although limited by the small number of patients, our data suggest that pemetrexed can be administered at systemically active doses in combination with radiotherapy, which is in contrast to several other active agents in NSCLC [e.g., gemcitabine with prominent acute pulmonary toxicity (34)], but similar to cisplatin/etoposide (35).

Overall, the toxicity profile seems favorable, in particular, given the enrollment of poor risk patients. Primarily hematologic toxicities were noted (i.e., grade 3/4 leukopenia/neutropenia) in up to one third of patients. On the other hand, in-field complications were mild. Radiation pneumonitis or esophagitis were not a clinically significant problem with only three low-grade occurrences of pneumonitis (one grade 1 and two grade 2) and three cases of radiation esophagitis (two grade 3 and one grade 4; Table 4).

The incidence of esophagitis as well as hematologic, skin, and pulmonary toxicities is low in comparison with other established chemoradiotherapy platforms (14, 36). Two additional cases of pulmonary failure were not attributed to study treatment. In the first case, the clinical picture was more suggestive of infectious origin, and in the second case, complications associated with docetaxel consolidation and steroid withdrawal were the likely cause. We caution that these pulmonary complications could remotely be attributed to pemetrexed and radiation. Careful testing in a larger phase II cohorts is necessary to establish the safety profile of this regimen.

A limitation of this study is the heterogeneity with respect to tumor types enrolled (esophageal and NSCLC), NSCLC stages (stages IIIa, IIIb, and IV), and differences in radiation doses for curative (high dose) and palliative (lower dose) intent. This is particularly true for regimen 1, where general tolerability in thoracic malignancies was examined. Specifically, three patients (10%) with esophageal cancer were enrolled for regimen 1, and there were several patients with metastatic disease (56%). In contrast, regimen 2 enrollment was limited to NSCLC, and all patients treated at the two highest dose levels had locally advanced NSCLC.

The average radiation dose for second highest dose level was 60.7 Gy (all locally advanced NSCLC) and for the highest dose level was 57.0 Gy (all locally advanced NSCLC). There was only one patient with locoregionally advanced disease (stage IIIb) who received <50 Gy on the highest dose level. This was due to an unfavorable tumor location and large tumor burden. Tumor coverage with high doses of radiotherapy would have been prohibitively toxic and would have exceeded the tolerance of the normal lung tissue (no more than 40% of normal lung could receive >20 Gy). All other radiation doses on the highest two dose levels were consistent with curative intention.

Given the overall study size and heterogeneity of this study population, its results are to be reviewed with caution. However, the apparent absence of severe toxicities when administering pemetrexed and radiation (+/– carboplastin) is encouraging and supports further testing in phase II trials in locally advanced NSCLC. Indeed, there are several ongoing phase I and II trials examining regimens combining concurrent pemetrexed, carboplatin or cisplatin, and radiation therapy as well as testing this combination with induction or consolidation chemotherapy. Specifically, the CALGB phase II study 30407 is currently enrolling patients (see Fig. 1 ).


Figure 1
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  		Fig. 1. Future direction. A follow-up phase II study (CALGB 30407: a randomized phase II study of radiotherapy, pemetrexed, and carboplatin with or without cetuximab in stage III NSCLC). *, Cetuximab dose: week 1, 400 mg/m2; weeks 2 to 7, 250 mg/m2.

 
Doublet chemotherapy has been shown to prolong survival more than single-agent chemotherapy in metastatic NSCLC (37–41), and as mentioned earlier, the doses, systemic efficacy, and tolerability of pemetrexed/carboplatin without radiotherapy are substantiated in two phase II trials in stage IIIB and IV NSCLC (25, 29). In regimen 1, further dose escalation of pemetrexed beyond 500 mg/m2 was not pursued. Instead, we amended the protocol to determine if systemic doses of both pemetrexed and carboplatin could be administered with concurrent radiation in regimen 2.

Dose escalation of either agent beyond their recommended single-agent doses was considered to be of questionable value. There is no data currently to support that doses of pemetrexed higher than 500 mg/m2, or carboplatin higher than AUC = 6 (alone, in combination, or with radiotherapy), would be more efficacious in a similar NSCLC patient population. Similarly, the authors are not aware of any chemotherapeutic agent with radiosensitizing properties that is administered at a higher dose with concurrent radiation than the standard dose used in single-agent administration for the treatment of NSCLC. The protocol was amended to allow discontinuation of dose escalation once systemic doses of both pemetrexed and carboplatin were achieved.

Overall, the here presented data support phase II testing of the highest dose level: pemetrexed 500 mg/m2 and carboplatin AUC = 6. However, the limited number of patients treated on each dose level (typical for the phase I design) prevents us from drawing a final conclusion that carboplatin at an AUC = 6 is optimal. Additional data in a larger and homogenous cohort are needed, evaluating both AUC = 5 and 6. Evidence of activity was noted in several patients in this small phase I trial, with four complete responses, two of which were based on the absence of tumor on pathology review of the surgical specimens. Furthermore, five patients with borderline resectable disease underwent curative-intent surgery after chemoradiotherapy. This suggests a good in-field activity, which is also supported by the in-field response rate of 61%.

The choice of the second agent for combination with pemetrexed (carboplatin versus cisplatin) can be debated. Carboplatin may have inferior efficacy when compared with cisplatin-based combinations, although most studies suggest similar efficacy for such doublet combinations (42–44). We chose carboplatin over cisplatin as it offers a markedly better nonhematologic toxicity profile and showed good activity in combination with pemetrexed in the previously mentioned studies (25, 29). Furthermore, our results show activity with four complete responses, which is encouraging, and support phase II testing of this combination of pemetrexed with carboplatin and radiation (CALGB 30407).

We conclude that the combination of pemetrexed, carboplatin, and radiotherapy is promising for further testing as it seems tolerable and achieves systemically active doses of chemotherapy, and preliminarily shows early signs of activity in the treatment of locally advanced NSCLC. Careful monitoring of pulmonary toxicity is advised as this regimen is further tested in phase II studies with locally advanced NSCLC, due to the two, likely unrelated cases, of pulmonary failure reported here.

The recommended phase II dose range is pemetrexed 500 mg/m2 and carboplatin AUC = 5 or 6. It is currently being evaluated in a multicenter, randomized phase II trial (CALGB 30407; schema outlined in Fig. 1). CALGB 30407 and other future trials will need to determine the optimal dose within the given dose range and whether the systemic activity of this regimen will translate into lower rates of distal failure.


   Acknowledgments
 
We thank the wonderful support of Noelle Gasco, Susan Sutton, Takashi Nakamura, and Laura Oberthur (MedFocus consultant before publication) of Eli Lilly and Company as well as Julie Stein of the University of Chicago.


   Footnotes
 
Grant support: Eli Lilly and Company, Valda and Robert Svendsen Foundation, and the University of Chicago Cancer Research Center.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented in part at the American Society of Clinical Oncology 2005 Annual Meeting, May 13-17, 2005, Orlando, Florida and the 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain.

Conflict of interest: E. Vokes has received research funding and honoraria from Eli Lilly and Company. K.E. Posther and B. Nguyen were employed by Eli Lilly and Company at the time of preparation of this article.

4 http://ctep.cancer.gov/forms/Hndbk.pdf (accessed July 25 2002). Back

Received 5/ 1/06; revised 10/12/06; accepted 10/26/06.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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