Phase II Evaluation of Docetaxel-Modulated Capecitabine in Previously Treated Patients with Non–Small Cell Lung Cancer

Lung cancer is the second most common cancer diagnosed in both men and women in the United States, with an estimated 173,770 new cases diagnosed in 2004 (1). Platinum-based chemotherapy remains the cornerstone of treatment for the non–small cell lung cancer subtype (NSCLC) and results in a small but statistically significant improvement in survival compared with supportive care alone (2–5). The modest contribution of first-line treatment has nevertheless resulted in an increasing number of patients with good performance status available for further treatment.

In the United States, fluoropyrimidines have lost favor in combination chemotherapy regimens for NSCLC despite an increase in the adenocarcinoma histology and the demonstration of a survival advantage in surgically resected patients with NSCLC treated with the fluoropyrimidine UFT (tegafur/uracil), as compared with no treatment in adjuvant trials (6, 7). In addition, UFT in combination with cisplatin for advanced NSCLC compares very favorably to the most commonly used regimens for first-line treatment of NSCLC (2, 8, 9). Although UFT is not available in the United States, another oral fluoropyrimidine, capecitabine is available and commonly used instead of 5-fluorouracil (5-FU). Capecitabine once ingested is modified by a three-step enzymatic cascade to 5-FU (10). The last step in the enzymatic conversion modifies 5′DFUR to 5-FU and is mediated by thymidine phosphorylase which has been observed to be expressed at higher levels in tumor tissue compared with normal tissue.

Docetaxel, a tubulin-interactive agent, increases the expression of thymidine phosphorylase in human colon cancer xenograph studies resulting in synergistic inhibition of tumor growth in colon and breast cancer models (11). In addition, tumor samples from patients with breast cancer treated with docetaxel before surgery showed that docetaxel up-regulated thymidine phosphorylase expression in tumor cells (12). This up-regulation would be expected to translate into clinical synergy. In fact, a phase III trial of docetaxel 75 mg/m² given every 3 weeks in combination with capecitabine 1,250 mg/m² twice daily (2,500 mg per m² per day) on days 1 to 14 of each cycle showed superior overall survival, response rate, and time to progression in patients with locally advanced or metastatic breast cancer compared with single-agent docetaxel (13).

Docetaxel also has activity in NSCLC and has approved indications as a first-line treatment in conjunction with cisplatin as well as a single agent in previously treated patients. Approval for use in previously treated patients was based on two phase III clinical trials (14, 15). The first clinical trial compared docetaxel with best supportive care in patients previously treated with platinum-based chemotherapy (14). Significant prolongation of time to progression, an overall response rate of 7% (intent to treat, 6%) and a 29% 1-year survival was seen for the docetaxel-treated patients. A second study randomized patients to receive docetaxel at two dose levels every 3 weeks or a choice of vinorelbine or ifosfamide (15). The overall response rate and 26-week progression-free survival (PFS) were better for the two docetaxel arms (relative risk, 11% and 7%; 19% and 17% 26-week PFS) than the vinorelbine/ifosfamide group (relative risk, 1%; 8% 26-wk PFS).

Based on the preclinical observation that thymidine phosphorylase up-regulation by docetaxel is transient, with maximal activity observed between 6 and 10 days after treatment (11), we previously conducted a phase I study of docetaxel in combination with capecitabine in a schedule aimed to maximize thymidine phosphorylase up-regulation and thereby optimize potential synergy (16). Docetaxel was given weekly for 3 weeks (days 1, 8, and 15) every 4 weeks, whereas capecitabine was initiated on day 5 of every course and continued for 14 days (days 5-18). Preliminary activity was observed in NSCLC with one patient experiencing a partial response that lasted 8.5 months and two other patients had prolonged disease stabilization. Docetaxel 36 mg/m² on days 1, 8, and 15 and capecitabine 1,250 mg per m² per day divided into two doses (half of the recommended single-agent capecitabine dose) on days 5 to 18 was recommended for evaluation in phase II studies.

This article reports the results of a phase II trial of docetaxel and capecitabine using the optimized schedule in patients with previously treated NSCLC. The primary objective for this study was to evaluate 6-month (26 weeks) PFS and tolerability of the combination in this patient group.

Eligibility Criteria. Patients with histologically confirmed advanced NSCLC who had received at least one but not more than two platinum- or paclitaxel-based chemotherapy regimens as treatment for their NSCLC and had shown disease progression, were eligible to participate. Eligibility criteria also included the following: age ≥ 18; Eastern Cooperative Oncology Group performance status of 0-2; life expectancy ≥ 12 weeks; adequate hematopoietic function (absolute neutrophil count of ≥1,500/mm³, hemoglobin > 9.0 g/dL, platelets ≥100,000/mm³); adequate renal and hepatic function (calculated creatinine clearance ≥ 50 mL/min, serum bilirubin ≤1.5 mg/dL, aspartate aminotransferase/alanine aminotransferase < 1.5 × upper limit of normal, and alkaline phosphatase ≤2.5 × upper limit of normal). Patients with a history of myocardial infarction within the previous 6 months, congestive heart failure requiring treatment, unstable angina, uncontrolled diabetes mellitus (random glucose > 250 mg/dL), baseline corrected serum calcium >11.5 mg/dL, brain metastasis not previously irradiated, prior malignancy within the last 5 years except basal cell/squamous cell skin cancer or carcinoma in situ of the cervix, or a psychiatric disorder that would interfere with consent or follow up were excluded. Due to the potential interactions between capecitabine and coumarin-based anticoagulants, patients requiring therapeutic doses of these drugs were not allowed on the study; however, if a patient required anticoagulation during the study and it was in the best interest of the patient to continue treatment, it was permitted at the discretion of the investigator. All patients provided written informed consent approved by the Ohio State University Institutional Review Board before participation on the clinical trial.

Treatment Plan. Docetaxel 36 mg/m² was given i.v. over 30 minutes weekly for 3 weeks repeated every 4 weeks in the outpatient clinic. Capecitabine 1,250 mg per m² per day divided into two oral doses (625 mg/m² twice a day) was given on days 5 to 18 of every cycle. The precise dose of capecitabine was calculated by body surface area and rounded off to the nearest 100 mg that would allow equal morning and evening doses. Patients were premedicated with 8 mg oral dexamethasone; 12 hours before, immediately before, and 12 hours after the docetaxel infusion (24 mg/wk) on treatment weeks. This dexamethasone regimen is based on the low incidence of peripheral edema and hypersensitivity reactions observed in patients who received a dexamethasone dose of 24 mg/wk in a previous weekly docetaxel study (17) and based on our prior phase I experience (16). Additionally, dexamethasone eye drops were given, one drop to each eye twice daily for 3 days starting the day before each weekly dose of docetaxel to decrease the potential for hyperlacrimation seen with weekly docetaxel. Antiemetics and loperamide could be used at the investigator's discretion. Prophylactic use of hematopoietic cytokines (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and erythropoietin) was not permitted; however, these agents could be used for therapeutic intervention at the investigator's discretion for an absolute neutrophil count of <500/μL for >5 days, febrile neutropenia, sepsis, or anemia.

Dose Modifications. Before starting a new cycle of treatment, an absolute neutrophil count of ≥1,500/mm³; platelet count ≥ 100,000/mm³; and an improvement to grade ≤1 in other treatment related toxicities was required. Different criteria for dose adjustment within a cycle and for subsequent cycles of treatment were provided (Table 1). In general, modifications of docetaxel dose were made for grade 3 to 4 hematologic toxicities, neutropenic fever, grade 4 thrombocytopenia, liver dysfunction, and any other grade 3 to 4 nonhematologic toxicities, whereas capecitabine modifications were made for grade 3 to 4 hematologic toxicities, neutropenic fever, grade 4 thrombocytopenia, grade ≥ 2 hand-foot syndrome, and any other grade 3 to 4 nonhematologic toxicities.

Clinical Benefit Evaluation. Measurable disease was not a requirement for study participation, given the primary objectives of 6-month PFS (26-week PFS) and tolerability. However, baseline computerized tomography scans were done within 4 weeks of starting chemotherapy in all patients and repeated after every two cycles. Response Evaluation Criteria in Solid Tumors (18) for tumor response were used to assess response in patients with measurable lesions. Any previously irradiated lesions were not considered measurable. Minor responses were cataloged as a decrease in the sum of the longest dimensions of ≥15% but <30% compared with baseline. Objective responses from the radiologists' interpretation were confirmed by review of the computerized tomography scans by two medical oncologists. All responding patients were required to have their response confirmed 4 to 6 weeks after the first documentation of response. Time to progression and 1-year survival were calculated from the date of the first docetaxel infusion.

Immunohistochemistry Staining. Paraffin-embedded tissues, when available, were obtained to evaluate expression of thymidine phosphorylase, thymidylate synthase, and dihydropyrimidine dehydrogenase in both normal and tumor tissue by immunohistochemistry staining. Available tumor blocks were cut into 5-μm sections deparaffinized, rehydrated, and steamed for 5 minutes for antigen retrieval before immunohistochemistry staining. Staining was done at Dr. Robert Diasio's laboratory at the University of Alabama-Birmingham (Birmingham, AL). Specimens were blocked in 20% goat serum for 20 minutes and incubated at 4°C overnight with antibodies/antiserum (1:100) to dihydropyrimidine dehydrogenase, thymidine phosphorylase, or thymidylate synthase (Roche Diagnostics, Penzberg, Germany). Secondary peroxidase antibodies (anti-rabbit-dihydropyrimidine dehydrogenase, thymidylate synthase; anti-mouse-thymidine phosphorylase; Dako, Inc., Glostrup, Denmark) were then added to the specimens for 30 minutes. The specimens were developed with liquid 3,3′-diaminobenzidine (Dako) for 20 minutes and counterstained with Mayer's hematoxylin. Specimens stained with dihydropyrimidine dehydrogenase antibody were incubated for 30 minutes with rabbit anti-rat immunoglobulins (1:100; Dako) before the secondary antibody, as previously described (19). A negative control was provided for each patient specimen. The slides were returned to the Ohio State University and subsequently graded by two pathologists who were blinded to patient information. Final immunohistochemistry scores for each case were determined by multiplying staining intensity and the proportion of cell staining at each respective intensity (0-3) and adding the scores.

Patient Characteristics. Thirty-nine patients (20 females and 19 males) with a median age of 61 (range, 35-73) were enrolled between February 1, 2001 and October 31, 2002. Table 2 illustrates the patient demographics of this study. One patient was ineligible due to the presence of brain metastases that had not been irradiated before study initiation and two patients did not receive capecitabine due to an adverse reaction to docetaxel administration (one patient) and withdrawal of consent due to travel requirements by the other individual. These patients were not considered evaluable for clinical benefit or toxicity of the combination. A total of 36 evaluable patients received 104 cycles (range, 1-8) of the combination. Adenocarcinoma (67%) was the most frequent tumor histology seen in our patient population. Twenty-two and 14 patients had received one and two prior chemotherapy regimens, respectively. All patients had received at least one platinum-based regimen and 81% of patients had received paclitaxel. The median number of weeks from prior chemotherapy to the start of therapy on the clinical trial was 12.7 weeks (range, 4.3-143.7). Ten patients had a prior lobectomy or pneumonectomy as part of their NSCLC treatment and 23 patients had prior radiation for their lung cancer.

Toxicity. The most common hematologic toxicities are depicted in Table 3. Moderate to severe hematologic toxicities were fairly infrequent. Grade 2 and 3 anemia was seen in 31% and 8% of patients, respectively, and only one patient experienced grade 2 thrombocytopenia. Grades 3 and 4 neutropenia occurred in four (11%) and one patient, respectively. There was one episode of grade 4 neutropenia lasting for >5 days, but there were no hospitalizations due to neutropenia and no occurrences of neutropenic sepsis.

The principal nonhematologic toxicities are also summarized in Table 3. Nine patients (25%) experienced grade 3 fatigue at some point during treatment and grade 3 and 4 mucositis were seen in six and one patients, respectively. Grade 3 hand-foot syndrome developed in two patients. Other grade 3 toxicities included nausea/vomiting (8%), diarrhea (3%), peripheral edema (3%), peripheral neuropathy (3%), and pleural effusions (8%). Hyperlacrimation and nail changes were also common toxicities seen in patients receiving this regimen. However, these toxicities were transient and no permanent abnormalities developed. Three patients enrolled on the study had thrombotic episodes, but given the presence of an adenocarcinoma subtype, it is not clear if these events were related to the study drugs.

Only one patient developed toxicity necessitating hospitalization. This patient developed grade 2 neutropenia, as well as grade 2 hand-foot syndrome and grade 4 mucositis throughout the upper and lower gastrointestinal tract, as observed by endoscopy. These events, which started on day 11 of capecitabine administration during the first cycle of treatment, resolved without permanent sequelae, and although no further capecitabine was given to this patient (the patient missed four doses during the first cycle), treatment with single-agent docetaxel was continued upon toxicity resolution. A partial response was documented by computerized tomography and positron emission tomography imaging with resolution of one adrenal lesion and of several pulmonary nodules. Disease progression (by positron emission tomography imaging) did not occur until 6.5 months later.

Dose reduction was required by a total of seven patients in subsequent cycles for toxicities including six patients that required dose reductions of both drugs. The most frequent toxicities requiring dose reductions were mucositis (six patients) and hand-foot syndrome (one patient). A total of 290 of 311 (93%) intended doses of docetaxel were delivered and 23 of 36 (64%) patients had one or more doses of capecitabine omitted in accordance with the predetermined, protocol specified dose modification schedule (Table 1).

Antitumor Activity. Relevant details pertaining to the antitumor effects of the combination in all patients who participated in the study are depicted in Table 4. Patients who received at least one dose of capecitabine were considered evaluable. The docetaxel and capecitabine regimen resulted in a 26-week PFS of 25% [95% confidence interval (95% CI), 12-42] with a median time to progression of 66 days (range, 1-23 months) for the 36 evaluable patients. Intent to treat median survival was 9.1 months (range, 23 days to >2 years) and the 1-year survival 37% (95% CI, 22-54).

As measurable disease was not part of the eligibility criteria for study enrollment, five patients with no measurable disease according to the Response Evaluation Criteria in Solid Tumors participated in the study. These include four patients with progression of previously irradiated lung or mediastinal lesions and one patient with new bone metastases. For patients with measurable disease (n = 31) the response rate was 26% (95% CI, 12-45). No complete responses were observed. Eight patients had partial responses including one patient with an unconfirmed partial response (due to an 81-day delay in getting his follow-up computerized tomography scans). Minor responses (17-18% decrease in tumor size) occurred in two patients. Five patients (16%) had stable disease as their best response, whereas progressive disease occurred in 16 patients (52%). The median overall duration of response was 5.9 months (95% CI, 2.2-9.6 months).

The type of prior therapy did not seem to influence antitumor activity, with six patients (24%) with previous paclitaxel exposure achieving a response compared with 33% for patients not receiving prior paclitaxel. The response rate was 33% for patients receiving one prior chemotherapy treatment and 15% for patients receiving two prior therapies. Twelve of the 15 patients (80%) with a partial response, minor response, or stable disease had the adenocarcinoma NSCLC subtype.

Laboratory Correlates. With the aim of identifying potential predictors of antitumor activity, immunohistochemistry analyses were done on available paraffin embedded tumor blocks and adjacent normal tissue, as depicted in Fig. 1, from 16 patients. Table 5 depicts the median scores and ranges for thymidine phosphorylase, thymidylate synthase, and dihydropyrimidine dehydrogenase by tumor compartment and according to patients' response to treatment. The small number of samples available for responding patients made statistical comparison difficult; however, of particular interest are the thymidylate synthase epithelial nucleus data showing median scores for patients with progressive disease (n = 10) and partial response (n = 4) of 35 (range, 0-150) and 5 (range, 0-20), respectively. In addition, thymidine phosphorylase seems to be increased in the cytoplasm of both tumor stroma as well as tumor epithelium in patients who had a partial response to therapy. The median thymidine phosphorylase in tumor epithelium cytoplasm in patients with a partial response or stable disease was approximately twice higher than in patients who did not respond to therapy. When comparing thymidine phosphorylase tumor/normal ratios, there was an increased ratio in stroma cytoplasm and epithelium cytoplasm in patients who had a partial response.

This study addresses the tolerability and efficacy of the combination of the oral fluoropyrimidine capecitabine in combination with docetaxel in patients with previously treated NSCLC. The rationale for the development of this study includes the in vivo (11) and clinical synergistic interactions (13) shown for these two agents when given in combination, and the observation of antitumor activity in heavily pretreated NSCLC patients in a study designed to maximize the synergistic interaction of these agents (16).

Results of this study showed an acceptable safety profile for the combination with only one patient developing toxicity necessitating hospitalization. Notable are the low rate of myelosuppresion and severe hand-foot syndrome (two patients). The notably low myelosuppression rate is likely due to the weekly schedule in which docetaxel was given, whereas the low severity of hand-foot syndrome could potentially be explained by the lower dose of capecitabine used (half of the recommended single agent dose) and/or the proactive dose reduction/omission program used. Despite the tolerability of this regimen, the combination showed efficacy in previously treated NSCLC. Given the phase II, single institution nature of this trial, it is not possible to draw conclusions regarding a potential higher efficacy for the combination, as opposed to the Food and Drug Administration–approved 75 mg/m² single-agent docetaxel every 3 weeks. However, the high response rate (26%), 26-week PFS (25%) and 1-year survival (intent to treat, 37%) are notable, especially in the presence of such low toxicity, making this regimen of interest for study in chemotherapy naive patients and would encourage randomized phase III evaluations in previously treated patients.

In support of the results of this trial is another in which 19 of 36 chemotherapy-naive NSCLC patients achieved antitumor responses (response rate, 53%; 95% CI, 37-69) following treatment with weekly docetaxel and capecitabine (20). A higher dose of capecitabine (1,000 mg/m² twice daily) and day 1 to 14 capecitabine administration may have accounted for the higher rate of hand-foot syndrome (33%) observed in that study compared with ours.

Of interest is also a recently reported trial of the antifolate pemetrexed, in which when compared with standard docetaxel resulted in a similar response rate in previously treated NSCLC patients and better tolerability (21). These findings, when taken alongside the excellent tolerability and improvement in survival shown for UFT in the adjuvant NSCLC setting (7), suggest that thymidylate synthase–interactive agents may have been unfairly tarnished as devoid of activity against NSCLC. It is possible that either the increase in the adenocarcinoma subtype (67% of the patients [80% of partial response/stable disease] in the current trial; 54% in the pemetrexed trial, ref. 21; and 100% in the UFT trial, ref. 7) or the more efficient delivery of the antimetabolites to its target, as featured in the trials discussed above (dihydropyrimidine dehydrogenase inhibition by UFT, polyglutamation by pemetrexed, and increased fluoropyrimidine tumor activation through thymidine phosphorylase up-regulation for capecitabine) may account for the discrepancy with historical single agent 5-FU results. In fact, dihydropyrimidine dehydrogenase activity has been shown to be increased in freshly explanted NSCLC human specimens compared with surrounding noncancerous tissues or to breast, colorectal, and gastric cancer specimens (22). This would likely result in a decreased tumor exposure to 5-FU active metabolites following the administration of plain 5-FU (23, 24).

It is our opinion that efforts aimed to identify subsets of NSCLC more susceptible to antimetabolite treatment are essential in any trial conducted with these drugs given their known mechanisms of action and resistance. Although the analyses of the enzymatic profiles presented here are very preliminary in nature, due to the small numbers, the data is provocative enough to consider thymidylate synthase epithelial nucleus, and thymidine phosphorylase cytoplasmic expression, as well as thymidine phosphorylase tumor/normal ratio worth evaluating in properly powered trials. To this regard, with the support of a National Cancer Institute grant, we are performing a trial with the combination discussed in this manuscript in patients with chemo-naive advanced NSCLC. Availability of tissue to perform tumor analyses to identify predictors of response is a condition for trial eligibility. The adjuvant setting, given the availability of tumor tissue and longer life expectancy of these patients, would be the next logical step to test this notion.

In conclusion, the combination of docetaxel and capecitabine at the doses and schedule studied in this trial is a feasible regimen for NSCLC when taking into consideration both toxicity and antitumor activity. Further investigation of this regimen in chemotherapy naive patients or in the adjuvant setting seems warranted.

We thank the help from the staff of the Tissue Procurement Shared Resource of the Comprehensive Cancer Center, the Ohio State University, Columbus, OH.