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Phase II Study of Area Under the Plasma-Concentration-Versus-Time Curve–Based Carboplatin Plus Standard-Dose Intravenous Etoposide in Elderly Patients With Small-Cell Lung Cancer

From the Yokohama Municipal Citizen's Hospital, Yokohama; National Cancer Center Hospital East, Kashiwa; Tochigi Cancer Center, Tochigi; Niigata Cancer Center, Niigata; Cancer Institute, Tokyo; Nihon University School of Medicine, Tokyo; Toranomon Hospital, Tokyo; National Nishi-Gunma Hospital, Shibukawa; National Sapporo Hospital, Sapporo; and National Cancer Center, Tokyo; Japan.

Address reprint requests to Hiroaki Okamoto, MD, Division of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa 240-0062, Japan; email scyooka{at}alles.or.jp

	ABSTRACT

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PURPOSE: The target area under the plasma-concentration-versus-time curve (AUC)–based dosing of carboplatin using Calvert's formula is expected to result in more acceptable toxicity and greater efficacy in elderly patients with small-cell lung cancer (SCLC) than the body surface area–based dosing strategy. This phase II study was designed to determine the toxicity and efficacy of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC.

PATIENTS AND METHODS: Carboplatin, dosed to a target AUC of 5 x (24-hour creatinine clearance + 25), was given intravenously on day 1 and etoposide 100 mg/m² was given intravenously on days 1, 2, and 3. Patients aged 70 years old with a performance status of 0 to 2 were eligible.

RESULTS: Thirty-six patients were enrolled onto the study. The patient characteristics were as follows: median age, 73 years; limited disease (LD), 16 patients; and extensive disease (ED), 20 patients. Grades 3 and 4 leukopenia occurred in 57% and 3% of patients, and grades 3 and 4 thrombocytopenia occurred in 40% and 11% of patients, respectively. There was one treatment-related death due to hemoptysis. Other toxicities were relatively mild. There were two complete responses and 25 partial responses, for a response rate of 75%. The median survival time was 10.8 months (LD, 11.6 months; ED, 10.1 months), and the 1-year survival rate was 47%.

CONCLUSION: This carboplatin/etoposide combination chemotherapy is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that the combination may be suitable for randomized controlled trials.

	INTRODUCTION

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LUNG CANCER IS THE leading cause of cancer mortality worldwide, and small-cell lung cancer (SCLC) accounts for approximately 20% of these cases. Commonly used combination chemotherapy regimens for SCLC are cyclophosphamide, doxorubicin, and vincristine (CAV), etoposide and cisplatin (EP), and alternating CAV/EP.^1,2 However, as many investigators have arbitrarily excluded elderly patients from clinical trials, no standard chemotherapeutic regimen has been established for elderly patients with SCLC. Approximately 25% of the patients with SCLC are over the age of 70,³ and treatment of elderly patients is becoming increasingly important.

Carboplatin and etoposide are active agents against SCLC.^4-7 Treatment with a combination of these two agents is associated with less renal, neurologic, and gastrointestinal toxicity than EP therapy, and both combinations are equally effective.⁸ Carboplatin is an antineoplastic agent, for which the desired area under the plasma-concentration-versus-time curve (AUC) can be controlled on the basis of individual renal function, and dosing can be individualized using Calvert's formula, ie, dose (mg/body) = AUC · (glomerular filtration rate [GFR] + 25).⁹ The AUC of carboplatin is well correlated with the degree of myelosuppression, especially thrombocytopenia, and with the response rate in ovarian cancer.^10,11 In elderly patients with SCLC, AUC-based dosing of carboplatin is a reasonable strategy for ensuring constant drug exposure, reducing the risk of unnecessary toxicity, and possibly improving the response rate.¹² Furthermore, AUC-based dosing of carboplatin may allow coadministration of a standard dose of intravenous etoposide with additional myelosuppression in elderly patients with SCLC. Therefore, we conducted a phase II study of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC. The objectives of this study were to detect and quantify the clinical toxicities of this combination and to assess its therapeutic activity in elderly patients with SCLC.

	PATIENTS AND METHODS

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Patient Selection
Patients with any stage of histologically or cytologically confirmed SCLC were eligible for this phase II study. Eligibility criteria included an expected survival 2 months, age 70 years, an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2, measurable or assessable lesions, previously untreated SCLC, no active concomitant malignancy, adequate hematologic function (leukocyte count 4,000/µL, platelet count 10 x 10⁴/µL, and hemoglobin level 9.0 g/dL), adequate renal function (blood urea nitrogen and serum creatinine levels less than twice the upper limit of the normal range and creatinine clearance [Ccr] 30 mL/min), and adequate hepatic function (total serum bilirubin level < 1.5 mg/dL and AST and ALT less than twice the upper limit of the normal range). Staging procedures included chest x-ray, computed tomography scans of the chest and brain, computed tomography or ultrasound of the abdomen, and isotope bone scanning. Limited disease (LD) was defined as disease limited to one hemithorax, the mediastinal lymph nodes, and ipsilateral and/or contralateral supraclavicular lymph nodes. Extensive disease (ED) was defined as disease beyond that included above. Patients with pleural effusions were classified as having ED. Written informed consent was obtained from all patients.

Treatment Protocol
Treatment consisted of carboplatin administered intravenously on day 1 plus etoposide 100 mg/m² intravenously on days 1, 2, and 3. The carboplatin dose was calculated using Calvert's formula, in which the target AUC was 5 mg·min/mL. The dose was determined by multiplying the targeted AUC by the sum of the GFR plus 25. The 24-hour Ccr was substituted for GFR. The target AUC of carboplatin was based upon the finding that an AUC of 5 mg·min/mL was the minimum value that produced a tumor response with manageable toxicity in ovarian cancer.¹⁰ Carboplatin was administered by 60-minute infusion before etoposide infusion, and then etoposide was sequentially administered by 60-minute infusion. Patients received antiemetic therapy consisting of dexamethasone (8 mg) and granisetron (40 µg/kg) by intravenous injection before administration of the anticancer drugs on days 1 through 3. Cycles were repeated every 4 weeks for up to four courses. Recombinant human granulocyte colony-stimulating factor 2 µg/kg was administered when grade 3 leukopenia/neutropenia occurred. Patients who experienced grade 4 leukopenia/neutropenia after administration of recombinant human granulocyte colony-stimulating factor or who experienced grade 4 thrombocytopenia received reduced doses of etoposide (75% of the previous dose, ie, 75 mg/m² on days 1, 2, and 3) for the next cycle. If the same hematologic toxicity was observed after dose reduction, the patient was taken off study at that point but was still included in the analysis. Subsequent courses of chemotherapy were started when the leukocyte count was 3,000/µL, with a platelet count 75,000/µL, after day 28. If the leukocyte and platelet counts did not return to normal levels by the first day of the next course of chemotherapy, treatment was withheld until full recovery. If more than 6 weeks passed from the time of the last treatment before these criteria were satisfied, the patient was taken off study at that point but was still included in the analysis. Patients with LD received thoracic irradiation after chemotherapy. Palliative radiotherapy was permitted to control persistent pain associated with bone metastasis during the study period.

Evaluation
Tumor responses were evaluated according to World Health Organization criteria.¹³ A complete response (CR) was defined as the complete disappearance of all evidence of tumor for at least 4 weeks. A partial response (PR) was defined as a 50% reduction in the sum of the products of the two greatest perpendicular diameters of all indicator lesions or a reduction of more than 50% in assessable disease for at least 4 weeks, with no appearance of new lesions or progression of any existing lesions. Progressive disease (PD) was defined as a 25% increase in the tumor area or the appearance of new lesions. All other outcomes were classified as no change (NC). Duration of response was calculated as the time from the first documentation of major response to first documentation of PD or start of subsequent treatment of the target lesion (eg, radiotherapy). Toxicities were evaluated according to Japan Clinical Oncology Group criteria.¹⁴

Study Design
We chose a 80% response rate as a desirable target level and a 60% response rate as undesirable. The study design had a power to detect response greater than 80%, with a less than 5% error. Therefore, we required 13 assessable patients in first stage and 22 in second stage, according to the mini-max design of Simon. We decided to stop the study if fewer than eight patients responded in the first stage. The institutional review board of each institute reviewed and approved the protocol before commencement of the study.

Statistics
Survival, determined from the first day of chemotherapy to death or the last follow-up evaluation, was calculated using the method of Kaplan and Meier. Statistical differences in survival distributions between stage (LD v ED) and age groups (< 75 years v 75 years) were compared using the log-rank test. Multivariate analysis was performed using Cox's proportional hazards model to evaluate the importance of six selected variables (age [< 75 years v 75 years], stage [LD v ED], sex, PS [0 to 1 v 2], lactate dehydrogenase level [normal v abnormal], and hemoglobin level [normal v abnormal]) in predicting survival. All P values in this report are of the two-sided type. The relationship between toxicity and age (< 75 years v 75 years) was analyzed using the ² test.

	RESULTS

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Patient Characteristics
Between January 1995 and August 1996, 36 patients were registered for the study, and all received chemotherapy. Patient characteristics are listed in Table 1. The patients included four women and 32 men, with a median age of 73 years (range, 70 to 80 years) and a median 24-hour Ccr of 75 mL/min (range, 37 to 119 ml/min). Twenty-seven patients (75%) had an Eastern Cooperative Oncology Group PS of 0 or 1. Twenty patients had ED and 16 had LD. The median carboplatin dose actually delivered was 320 mg/m² (range, 229 to 434 mg/m²).

Treatment Delivery
Eight patients (22%) received two courses of treatment, six (17%) received three courses, and 22 (61%) received four courses. Seventy-eight percent of the patients received three to four courses of chemotherapy. The reasons for termination of treatment included completion of four courses of chemotherapy (22 patients, 61%), PD/NC (eight patients, 22%), patient refusal (four patients, 11%), toxicity (one patient, 3%), and treatment-related death (one patient, 3%). None of the four patients who refused subsequent chemotherapy experienced severe toxicity. Only one patient experienced the same grade 4 neutropenia after dose reduction and was taken off study.

Toxicity
There was one treatment-related death due to hemoptysis during grade 3 thrombocytopenia in the second course. One patient developed severe pneumonia after registration but before treatment. Nonetheless, this patient was started on the treatment protocol with coadministration of antibiotics. One other patient received carboplatin reduced by 20% because of protocol violation in all four courses. Therefore, these two patients were ineligible for toxicity evaluation and the other 34 patients were assessable for toxicity. Toxicities are listed in Table 2. Grades 3 and 4 leukopenia occurred in 56% and 3% of patients, grades 3 and 4 neutropenia occurred in 47% and 44%, and grades 3 and 4 thrombocytopenia occurred in 41% and 12%, respectively. Although grades 3 and 4 neutropenia occurred in 91% of the patients, only one patient experienced grade 4 infection and was easily rescued by administration of antibiotics. Although three patients experienced grade 4 hyponatremia caused by worsening of the syndrome of inappropriate secretion of antidiuretic hormone after chemotherapy, all three patients received adequate supportive care and recovered fully from hyponatremia with tumor regression. Other toxicities were relatively mild.

Course intervals and dose reductions are listed in Table 3. The median interval of each chemotherapy course was 28 days. Eight percent to 15% of the patients received dose reduction because of hematologic toxicities during prior chemotherapy. The main cause of dose reduction was grade 4 neutropenia.

When the relationships between the main toxicities (leukopenia, neutropenia, anemia, thrombocytopenia, gastrointestinal, renal and hepatic toxicities, and infection) and age (< 75 years v 75 years) were analyzed using the ² test, there were no differences in any toxicity between patients younger than 75 years old and those 75 or older (data not shown).

Response and Survival
Chemotherapeutic responses are listed in Table 4. Among the 36 patients, there were two CRs and 25 PRs, giving a response rate of 75% (95% confidence interval, 61% to 89%). Among the 27 responders, the median duration of response was 192 days (range, 52 to 851+ days). Among the 16 patients with LD, eight received thoracic radiotherapy after chemotherapy. One partial responder achieved CR and one patient classified as having NC achieved PR after radiotherapy. Therefore, the final response rate was 77.8%. Figure 1 shows the overall survival curve of all patients, and Fig 2 shows the survival curves by stage. The median survival time (MST) was 10.8 months (LD, 11.6 months; ED, 10.1 months). The 1-year and 2-year survival rates of all patients were 47.2% and 15.4%, respectively. In log-rank tests, no significant differences in survival rates were found between stage (LD v ED, P = .336) or age (< 75 years v 75 years, P = .977). When multivariate analysis was performed on the six selected variables, the most important factors associated with poor prognosis were high lactate dehydrogenase level (P = .001), PS of 2 (P = .002), anemia (P = .027), and ED (P = .033). The relative risks of these variables (with 95% confidence intervals in parentheses) were 12.99 (3.48 to 48.47), 6.22 (2.15 to 18.02), 5.83 (1.32 to 25.77), and 2.73 (1.14 to 6.59), respectively. However, age was not an independent prognostic factor in multivariate analysis

View larger version (12K): [in this window] [in a new window]   Fig 1. Overall survival.

View larger version (12K): [in this window] [in a new window]   Fig 2. Survival curves by stage.

	DISCUSSION

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Although oral etoposide has been widely used for elderly or poor-risk patients with SCLC,¹⁵ two recent randomized controlled clinical trials have shown that oral etoposide results in higher toxicity and poorer quality of life and shows lower survival in elderly or poor-risk patients with SCLC than standard combination chemotherapy.^16,17 Therefore, oral etoposide alone should no longer be used in the treatment of elderly or poor-risk patients. However, although the combination chemotherapy regimens used in these two trials were either etoposide/vincristine, CAV, or alternating CAV/EP regimens, the MST of patients treated with combination chemotherapy regimens in the two trials was only approximately 6 months. Therefore, new therapeutic strategies are clearly needed to prolong survival in elderly or poor-risk patients with SCLC.

Because carboplatin/etoposide therapy is associated with less renal, neurologic, and gastrointestinal toxicity than the EP regimen,^4-8 several phase II studies have been conducted to evaluate this combination therapy in the treatment of elderly patients with SCLC. Evans et al¹⁸ treated 47 elderly patients (median age, 69 years) with SCLC with carboplatin plus oral etoposide and reported an MST of 11.5 months for patients with ED and 14.8 months for those with LD. However, there was a high frequency of septic death (8.5%) in their study. Similarly, Matsui et al¹⁹ treated 38 elderly patients (median age, 78 years) with SCLC with carboplatin plus oral etoposide and reported an excellent MST of 15.1 months for patients with LD. However, the MST of their patients with ED was 8.6 months.

Recently, Westeel et al²⁰ treated 66 elderly (> 65 years old) patients with SCLC with a regimen consisting of cisplatin, doxorubicin, vincristine, and etoposide, with 3-week intervals between treatments. Patients with LD received thoracic irradiation delivered concurrently with EP at the time of the second chemotherapy cycle. They reported response rates of 87% for patients with ED and 92% for those with LD and an MST of 46 weeks for patients with ED and 70 weeks for those with LD. These favorable results, especially in patients with LD, may have been due to the use of the EP regimen with concurrent irradiation.

This is the first study of the combination of AUC-based carboplatin and the standard dose of intravenous etoposide for elderly patients with SCLC. The response rate of 75% and the MST of 10.8 months for all 36 patients are encouraging, since the median age was 73 years old and nine of the 36 patients had a PS of 2. Notably, the MST of 10.1 months in patients with ED compared favorably with the MSTs reported by other investigators.

Carboplatin produces less nonhematologic toxicity compared with cisplatin, and its principal toxicity, unlike that of cisplatin, is thrombocytopenia. The carboplatin AUC is well predicted by the Calvert formula, based upon individual renal function,⁹ and correlates well with toxicity and tumor response in ovarian cancer.^10-12 Although it remains unknown whether a similar correlation between AUC and tumor response exists in SCLC, more acceptable toxicities are clearly to be expected when carboplatin dosing is AUC-based rather than body surface area–based. In our study, although a standard dose of intravenous etoposide and a modest dose of carboplatin were coadministered in elderly patients with SCLC, hematologic toxicity, although requiring careful management and supportive care, was acceptable, and compliance was relatively good. In addition, the survival and response rate were encouraging. These favorable results may have been due to the AUC-based carboplatin dosing strategy. Furthermore, the median dose of carboplatin actually administered was 320 mg/m². Compared with the standard body surface area–based dosing strategy (350 to 400 mg/m²), 10% to 20% dose reduction of carboplatin was successfully obtained with more acceptable toxicity and greater efficacy in elderly patients with SCLC.

Although dose adjustment based on isotopic determination of GFR has been proposed in Calvert's formula, it has not been widely applied because an inconvenient, invasive, and expensive method is required to determine the GFR. Therefore, 24-hour Ccr was substituted for the GFR in this study. When using the Calvert formula, several investigators have reported that use of the 24-hour Ccr caused an over- or underestimation of the GFR.^21-23 Although no pharmacokinetic analysis was performed in this study, we recently reported two other studies describing carboplatin pharmacokinetics.^24,25 In summary, when combination chemotherapy consisting of AUC-based carboplatin and etoposide or irinotecan was used, the actual carboplatin AUCs observed, after using the Calvert formula based upon the 24-hour Ccr to calculate the dose, indicated expected values with a small and acceptable bias compared with the values predicted from the dosing formula. This result also suggested that carboplatin pharmacokinetics are not influenced by the prior administration of etoposide or irinotecan. Ccr calculated by the Cockcroft and Gault formula²⁶ is also often substituted for the GFR in clinical practice and in clinical trials. In our previous pharmacokinetic study,²⁵ the pharmacokinetics of carboplatin were accurately predicted by the Calvert formula based upon either Ccr calculated using the Cockcroft and Gault formula or 24-hour Ccr, and the precision of these two formulas was almost identical. In fact, if the GFR had been calculated using the Cockcroft and Gault formula in this phase II study, the median dose of carboplatin would have been 301 mg/m² (range, 211 to 436 mg/m²), comparable to the median dose actually administered in this study.

Interestingly, in our study, there were no differences in any toxicity or survival between patients aged 75 years and those younger than 75, although the number of patients in our study was relatively small. In other words, survival and toxicity are similar in patients aged 75 years and those younger than 75 with SCLC and with good PS who are eligible for treatment according to our protocol. Similarly, multivariate analysis of data from two multicenter randomized trials that included 608 patients with LD-SCLC conducted by the National Cancer Institute of Canada showed that age was not a significant prognostic factor up to 75 years of age.²⁷ In our study, the survival of the patients with LD was relatively poor (11.6 months) compared with the survival times of other studies.^19,20 Two recent retrospective studies have found that elderly patients tolerate combined-modality therapy as well as younger patients do.^28,29 Had chemotherapy with concurrent chest irradiation been used for the patients with LD, better survival might have been achieved in this study.

In conclusion, the combination of AUC-based carboplatin and a standard dose of intravenous etoposide is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that this combination may be suitable for randomized controlled trials. On the basis of results of recent clinical trials indicating that combination chemotherapy including reduced or split doses of cisplatin can be safely and effectively administered in elderly or poor-risk patients with SCLC, reported by Souhami et al¹⁷ and Westeel et al,²⁰ we are now conducting a prospective randomized comparison of AUC-based carboplatin plus etoposide and a split dose of cisplatin plus etoposide in elderly or poor-risk patients with SCLC.

	ACKNOWLEDGMENTS

 
Supported in part by a Grant-in Aid from the Ministry of Health and Welfare (Tokyo, Japan) and from the Second Term Comprehensive 10-Year Strategy for Cancer Control.

We thank the entire staff of the Japan Clinical Oncology Group Data Center for their help with data collection.

	NOTES

 
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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5. Smith IE, Evans BD, Gore ME, et al: Carboplatin (paraplatin: JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer. J Clin Oncol5:185-189, 1987[Abstract]

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Submitted April 5, 1999; accepted June 21, 1999.

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