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Gemcitabine and Docetaxel in Patients With Unresectable Leiomyosarcoma: Results of a Phase II Trial

From the Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to David R. Spriggs, MD, Memorial-Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Few chemotherapy agents are active in leiomyosarcoma (LMS), particularly LMS that has progressed after doxorubicin treatment. We sought to determine the response to gemcitabine plus docetaxel among patients with LMS.

PATIENTS AND METHODS: Patients with unresectable LMS of uterine (n = 29) or other (n = 5) primary sites who did not respond to zero to two prior chemotherapy regimens were enrolled onto a phase II study of gemcitabine 900 mg/m² intravenously (IV) on days 1 and 8 plus docetaxel 100 mg/m² IV on day 8 with granulocyte colony-stimulating factor given subcutaneously on days 9 to 15, delivered every 21 days. Patients with prior pelvic radiation received 25% lower doses of both agents. Gemcitabine was delivered over 30 or 90 minutes in cycles 1 and 2 and by 90-minute infusion in all subsequent cycles. Pharmacokinetic studies assessed in vivo differences in gemcitabine concentrations with different rates of infusion.

RESULTS: Thirty-four patients (median age, 55 years; range, 32 to 74 years) have enrolled. Fourteen had received prior pelvic radiation. Sixteen of 34 patients had progressed after doxorubicin-based therapy; 18 had no prior chemotherapy. Among 34 patients, complete response was observed in three patients and partial response in 15, for an overall response rate of 53% (95% confidence interval, 35% to 70%). Seven patients had stable disease. Fifty percent of patients previously treated with doxorubicin responded. Hematologic toxicity was common (neutropenia: grade 3, 15%; grade 4, 6%; thrombocytopenia: grade 3, 26%; grade 4, 3%), but neutropenic fever (6%) and bleeding events (0%) were rare. The median time to progression was 5.6 months (range, 4 to 10 months).

CONCLUSION: Gemcitabine plus docetaxel is tolerable and highly active in treated and untreated patients with LMS.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CURRENT TREATMENT options for recurrent or advanced leiomyosarcoma (LMS) of uterine or other organ origin are limited. Although approximately 60% of women with uterine LMS present with disease that is limited to the uterus, cure rates range from 20% to 60%.^1,2 Patients who present with advanced-stage LMS and patients whose disease recurs after initial resection have a poor prognosis. Except for rare cases of resectable, isolated pulmonary metastases,³ such patients are not considered curable. In addition, few chemotherapy agents have been identified with activity against LMS.⁴

Negligible activity was observed in phase II trials that tested the following single agents: cisplatin,⁵ mitoxantrone,⁶ amonifide,⁷ oral etoposide,⁸ diazoquone,⁹ and trimetrexate.¹⁰ Single agents that demonstrate moderate activity in LMS include ifosfamide (response rate, 17%),¹¹ intravenous (IV) etoposide (11%),¹² and doxorubicin (25%)¹³ Combination chemotherapy regimens with activity in previously untreated patients include hydroxyurea, dacarbazine and etoposide (overall response rate 18%)¹⁴ and doxorubicin plus ifosfamide (response rate 30%).¹⁵ No standard second-line chemotherapy therapy agents have been identified. We sought to determine the clinical activity of docetaxel plus gemcitabine in previously treated or untreated patients with LMS of uterine or other organ of origin who disease was not amenable to resection for cure.

Both gemcitabine and docetaxel have mechanisms of action that differ from previous agents tested in LMS. Gemcitabine is an analog of the nucleoside deoxycytidine. Gemcitabine is inactive in its parent form. Intracellular phosphorylation of the parent drug yields the active di- and triphosphate metabolites. The diphosphate form inhibits ribonucleotide reductase (an enzyme important for DNA biosynthesis),¹⁶ whereas the triphosphate form is incorporated into DNA, in competition with the normal nucleotide base deoxycytidine, as a fraudulent base.¹⁷ Once the gemcitabine triphosphate metabolite is incorporated into DNA, one additional nucleoside is incorporated, after which DNA chain synthesis is terminated. This "masked chain termination"¹⁸ leaves the fraudulent base relatively resistant to excision repair by DNA repair enzymes and thus may overcome a key mechanism for the development of drug resistance.¹⁹ Docetaxel functions by stabilizing tubulin, which results in inhibition of mitotic and interphase cellular functions.²⁰ Activity of docetaxel has been demonstrated in patients with breast cancer whose tumors were resistant to anthracycline-based therapy.^21,22 Docetaxel induces phosphorylation of bcl-2, promoting apoptosis. The combination of DNA synthesis termination by gemcitabine and promotion of apoptosis by docetaxel may lead to a synergistic effect of these two agents in vivo.

Gemcitabine, like other nucleoside analogs, is active only after entry into cells and subsequent phosphorylation to the fraudulent nucleoside triphosphate.²³ The ability of cells to accumulate gemcitabine triphosphate is saturable at gemcitabine dose rates that produce plasma gemcitabine levels of 20 to 25 µmol/L.^24-26 DNA synthesis rates decrease in inverse proportion to the intracellular gemcitabine triphosphate concentration,²⁷ and cell viability decreases in direct proportion to the amount of gemcitabine triphosphate incorporated into DNA.²⁸ We postulated that controlled-rate gemcitabine infusions over 90 minutes, compared with standard bolus infusion over 30 minutes, would result in more sustained periods of time during which plasma gemcitabine levels are above the 10 µmol/L threshold and thus result in longer duration of saturated intracellular gemcitabine triphosphate levels. Given that cell viability correlates with gemcitabine triphosphate incorporation into DNA, increasing the time that cells have saturated gemcitabine triphosphate levels may result in higher tumor response rates with the same dose of gemcitabine delivered. With individual patients serving as their own controls, we sought to determine whether the duration of time during which plasma gemcitabine levels remained above 10 µmol/L was significantly longer after a 90-minutes infusion, compared with the duration of time above that threshold after a 30-minutes infusion.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patients with histologically confirmed LMS of the uterus or of other primary site with measurable disease that was considered unresectable for cure and who had received zero to two previous chemotherapy regimens for treatment of LMS were eligible if they met the following criteria: adequate organ function (defined as absolute neutrophil count [ANC] 1,000/µL, platelet count 100,000/µL, total bilirubin 1.5 mg/dL, serum creatinine 2.0 mg/dL) and Karnofsky performance status 60%. Patients must have completed any previous chemotherapy at least 3 weeks before enrollment, and they must have completed any previous radiation at least 6 weeks before enrollment. Pregnant or lactating women and patients with active uncontrolled infection, history of malignancy, a history of grade 3 or 4 neuropathy were excluded. All patients provided written informed consent. The protocol was approved by the institutional review board and was reviewed annually.

Treatment Plan
Participants who had not previously received radiation received gemcitabine 900 mg/m² on days 1 and 8 IV over either 30 or 90 minutes in cycles 1 and 2 (for pharmacokinetic assessments), followed immediately by docetaxel 100 mg/m² on day 8 IV over 1 hour. Gemcitabine was given over 90 minutes in all subsequent cycles. Participants who had previously received radiation therapy received gemcitabine 675 mg/m² on days 1 and 8 IV over either 30 or 90 minutes in cycles 1 and 2, followed by docetaxel 75 mg/m² on day 8 IV over 1 hour. Gemcitabine was given over 90 minutes in all subsequent cycles.

The recommended premedication for the docetaxel was dexamethasone 8 mg administered orally for two doses the day before chemotherapy, and 8 mg administered orally twice daily for the next 2 days. Patients who developed peripheral edema as a side effect of docetaxel were treated with diuretics at the discretion of the treating physician.

Recombinant human granulocyte colony-stimulating factor 150 µg/m² (dose rounded to 300 µg or 480 µg) was given subcutaneously to all patients with each cycle on days 9 to 15 as primary neutropenia prophylaxis. It was permitted for granulocyte colony-stimulating factor to be stopped before day 15 if the absolute neutrophil count was more than 1,200/µL on two separate occasions, although patients were not required to have routine complete blood counts performed before day 15.

Treatment cycles were administered in the outpatient setting every 3 weeks. Treatment duration was planned for six cycles, unless there was evidence of disease progression or unacceptable toxicity. Patients with continued response after six cycles could receive two additional cycles of therapy.

Evaluations During Treatment
Pretreatment evaluations included the following: history and physical examination; complete blood count with differential and platelet count; biochemical profile; electrocardiogram; chest x-ray, computed tomography (CT) scan of the chest, abdomen, and pelvis; and documentation of tumor measurements. During treatment, complete blood cell counts were performed weekly. History and physical examinations and assessment of toxicities were performed before each cycle of treatment. Biochemical profiles were performed approximately every 3 weeks. CT scans were repeated after cycle 3 to assess response. Patients with stable disease (SD), complete response (CR), or partial response (PR) continued on study and underwent repeat CT scan after cycle 6. Patients who continued on study underwent a CT scan again after cycle 8. All patients with SD, CR, or PR subsequently underwent CT scans approximately every 3 months until there was evidence of disease progression. At the discretion of the treating physician, CT scans were permitted to be performed earlier than required by protocol. If such a scan demonstrated progression of disease, the date of that scan was used as the date of disease progression in the analysis. Treatment toxicities were graded by National Cancer Institute common toxicity criteria.²⁹

Dose Adjustments
Dose adjustments were required in the following situations.¹ If patients experienced febrile neutropenia or had platelet count of less than 25,000/µL lasting more than 5 days, doses of both gemcitabine and docetaxel were reduced to 75% of the previous dose in all subsequent cycles. If at day 1 of the treatment cycle the ANC was less than 1,000/µL or if the platelet count was less than 100,000/µL, treatment was delayed 1 week. Patients in whom the ANC or platelet counts had not recovered after a 2-week delay were removed from the study. If on day 8 the ANC was 500 to 999/µL or the platelet count was 50,000 to 99,000/µL, docetaxel and gemcitabine were provided at 75% of the day 1 doses. If at day 8 the ANC was less than 500/µL or if the platelet count was less than 50,000/µL, docetaxel and gemcitabine at the day 8 dose were not provided in that cycle. If the patient experienced grade 3 or 4 neurotoxicity, treatment was delayed for 1 week. If neurotoxicity has resolved to grade 2, treatment resumed with the docetaxel dose decreased to 75% of the previous dose for all subsequent cycles. If the patient’s bilirubin level was more than 1.5 mg/dL, the docetaxel treatment was held for that cycle. If bilirubin returned to 1.5 mg/dL, docetaxel treatment was resumed in the subsequent cycles. If patients experienced other grade 3 or 4 nonhematologic toxicities (except alopecia), treatment held for up to 2 weeks; treatment resumed if nonhematologic toxicity had resolved to grade 2.

Pharmacokinetic Studies
Plasma samples were collected immediately before gemcitabine infusion on day 1 of cycles 1 and 2 and at six subsequent times over 24 hours to determine gemcitabine concentration (µmol/L) by use of high-performance liquid chromatography.^30,31 Tetrahydrouridine was added immediately to the Vacutainer tube to stop degradation of gemcitabine in plasma.

Response Criteria
In order to be considered assessable for response, a patient must have received at least one cycle of the treatment regimen and must have had one assessment for response. Responses were assessed by CT scan. Response Evaluation Criteria in Solid Tumors criteria were used to determine best overall response.³² For patients with multiple metastases, the five largest lesions were followed up for measurements on response evaluations. CR was defined as disappearance of all measurable and nonmeasurable lesions. PR was defined as at least 30% decrease in the sum of the longest diameter of measurable lesions, taking as a reference the baseline sum of the longest diameters of the measurable lesions. Progressive disease (PD) was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as a reference the smallest sum longest diameter recorded since treatment started, or the appearance of new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Radiographic responses were confirmed by review by an independent radiologist (GG). Best response was defined as the most CR achieved by a patient (thus, each patient had a single best response: CR, PR, SD, or PD), and the date of best response was the date that best response was first detected. All participants underwent CT scan for response approximately every 6 weeks while undergoing the protocol treatment and approximately every 3 months after completion of protocol treatment. These follow-up evaluations were used to determine duration of response and date of progression of disease. The date of progression of disease was the date that progression was first detected.

Statistical Analysis
A Simon two-stage phase II study design was used,³³ where the unacceptable and promising response rates were designated as 5% and 15%, respectively. The error rates used are 5% for accepting a poor regimen and 30% for rejecting a promising regimen. Nineteen patients were to be treated in the first stage, and if one response was observed, the study would have been stopped and the regimen declared ineffective. Because two or more responses were seen, accrual of an additional 24 patients (for a total of 43) was planned. The regimen was to be declared promising if five or more responses were seen. The unexpectedly high response rates observed prompted this interim report of first 34 assessable patients.

The proportion of responses and 95% confidence intervals (95% CIs) were determined. Progression-free and overall survival were determined by Kaplan-Meier methodology. Progression-free survival was defined as the time from registration on study to the date of documentation of progression by CT scan. If the patient died before repeat imaging could be performed, the date of death was used at the date of progression.

Mean area under the curve (AUC) and estimates of the duration of time with gemcitabine concentration more than 10 µmol/L were made with the trapezoid rule.³⁴ Mean AUCs and the mean time in hours above the threshold concentration of 10 µmol/L gemcitabine, achieved with 90-minute gemcitabine infusion and 30-minute gemcitabine infusions, were compared by two-sided t tests, with alpha < 0.05 considered to be statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Thirty-four patients with LMS were enrolled onto the study, and all received at least one cycle of chemotherapy. Patient characteristics are listed in Table 1. The median age of the patients was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 90%. Thirty-three of the participants were women. The majority of patients (85%) had uterine LMS. The other LMS were of pelvic or retroperitoneal³ or gastrointestinal (nongastrointestinal stromal tumors) origin.² Fifteen patients (47%) had progressed on or after treatment with doxorubicin with or without ifosfamide for LMS. One patient had been treated with ET-743 (an experimental cytotoxic agent) and one with medroxyprogesterone. Two patients had received two previous cytotoxic regimens. Forty-one percent of patients had received previous pelvic radiation therapy. The median number of cycles delivered was six (range, one to eight cycles).

View larger version (12K): [in this window] [in a new window]   Fig 1. Duration of best response, measured from date of best response to date of disease progression, among leiomyosarcoma patients achieving complete or partial response to gemcitabine plus docetaxel (n = 18).

View larger version (12K): [in this window] [in a new window]   Fig 2. Progression-free survival in patients with leiomyosarcoma treated with gemcitabine plus docetaxel (n = 34).

View larger version (11K): [in this window] [in a new window]   Fig 3. Overall survival in patients with leiomyosarcoma treated with docetaxel plus gemcitabine (n = 34).

Pharmacokinetics
For the pharmacokinetic end point of this study, each patient served as her or his own control. Thus, a patient who received gemcitabine over 30 minutes in cycle 1 received gemcitabine over 90 minutes in cycle 2; and a patient who received gemcitabine over 90 minutes in cycle 1 received the drug over 30 minutes in cycle 2. The concentration of gemcitabine was determined in both cycles, and comparisons of the mean AUC for gemcitabine 30- v 90-minute infusion and the duration of time that the gemcitabine concentration remained above a threshold level of 10 µmol/L for gemcitabine 30- v 90-minute infusion could be determined for each patient. Results are listed in Table 4.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The combination of gemcitabine plus docetaxel is highly active in patients with LMS, with an overall response rate of 53%. Seven PRs and one CR were observed among the 16 patients who had received previous doxorubicin-based chemotherapy (overall response rate, 50%). The 6-month progression-free rate has been suggested as an alternative end point for assessing treatment activity in phase II trials in sarcoma. Among 531 patients with LMS treated with first-line chemotherapy, the 3-month progression-free rate was 58%.³⁵ The 6-month progression free rate was 56% for patients with synovial sarcoma and 38% for patients with malignant fibrous histiocytosis, although the 6-month progression-free rate was not provided for patients with LMS. The 47% 6-month progression-free rate observed in this study supports the conclusion that gemcitabine plus docetaxel is an active regimen in LMS. The regimen was well tolerated, with acceptable and uncomplicated hematologic toxicity.

The results observed with the combination of gemcitabine plus docetaxel may be surprising in light of previous studies assessing the activity of these drugs given as single agents for soft tissue sarcoma. The activity of docetaxel as second-line, single-agent therapy for soft tissue sarcoma was reported to be 17% in a phase II study.³⁶ However, in a subsequent randomized phase II study of docetaxel versus doxorubicin as first- or second-line therapy, zero responses were observed among the 43 patients randomized to receive docetaxel, compared with 13 (30%) of 43 of doxorubicin-treated patients.³⁷ Gemcitabine as a single agent achieved an 18% overall response in 56 patients (17 gastrointestinal LMS and 39 other soft tissue sarcoma histologies), with median response duration of 3.5 months. Among the subgroup of 10 patients with nongastrointestinal LMS, four responses were observed; there were no objective responses among 17 patients with gastrointestinal LMS.³⁸

There are several potential explanations for the superior response rates observed in our study, compared with the single-agent response rates observed in other studies. It is possible that LMS is more sensitive to these chemotherapy agents than other soft tissue sarcoma histologies, or that uterine LMS (84% of our study population) is more sensitive than other sarcomas. Indeed, the response to gemcitabine as a single agent was greatest among patients with uterine LMS in the Patel study detailed above.³⁸

Another possible explanation for the superior response rate observed is that the response to 90-minute infusions of gemcitabine is superior to 30-minute bolus infusion. We demonstrated that in vivo, 90-minute infusions result in approximately 50% longer periods of time above the gemcitabine concentration threshold of 10 µmol/L, compared with 30-minute bolus infusions. Others have demonstrated that, in vitro, tumor-cell kill is greater with greater DNA incorporation of gemcitabine,²³ which correlates with duration of time above gemcitabine concentration of 10 µmol/L. The issue of whether prolonged-infusion gemcitabine (10 mg/m²/min) results in higher clinical response rates compared with bolus infusions has been addressed in a randomized trial in pancreatic cancer. Among 67 assessable patients, response rates and 1-year survival were better among the 30 patients who received gemcitabine at 10 mg/m²/min, compared with the 37 patients who received gemcitabine as a 30-minute bolus infusion (16.6% v 2.7% overall response rate, respectively).³⁹

An additional explanation for the high response rates observed may be that gemcitabine and docetaxel exhibit true in vivo synergy. In a phase II trial of gemcitabine plus docetaxel in chemotherapy-naive non–small-cell lung cancer (NSCLC) patients, PR was observed in 37.5% of patients (95% CI, 24% to 50%).⁴⁰ Responses to single-agent gemcitabine in NSCLC range from 20% to 23%^41,42; and responses to single-agent docetaxel range from 19% to 38%.^43-45 In an additional phase I study of gemcitabine given at 800 mg/m² on days 1, 8, and 15, in combination with docetaxel at doses escalating from 45 to 100 mg/m², responses were observed in nine of 21 NSCLC patients, four of seven breast cancer patients, and one patient with esophageal cancer, with a total of 40 patients treated on study.⁴⁶ Determining whether combination therapy yields significantly higher response rates than single agent therapy would require a randomized trial.

As with most phase II, single-institution studies, the favorable results observed in this trial may not be generalizable to the multi-institution setting or to patients who would not have met the fairly rigorous eligibility criteria. Nevertheless, we have demonstrated that the combination of gemcitabine plus docetaxel is highly active in the first- and second-line setting for patients with LMS. The fact that that eight of 16 patients previously treated with doxorubicin-based chemotherapy therapy achieved objective responses with gemcitabine plus docetaxel suggests that this regimen is a reasonable treatment option for patients with this disease. The promising activity observed in this study should be confirmed in the multi-institution setting for LMS, and the regimen should be investigated in patients with other soft tissue sarcoma histologies.

	ACKNOWLEDGMENTS

 
Supported in part by National Institutes of Health/National Cancer Institute grant no. 5P01 CA 52477-09, American Cancer Society Clinical Research Training Grant no. CRTG-00-281-01-PBP, and Lilly Research Laboratories, Indianapolis, IN (M.L.H.).

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Submitted November 12, 2001; accepted March 19, 2002.

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