All patients provided written informed consent in accordance with federal and institutional guidelines.
Single-agent gemcitabine and vinorelbine have activity in treatment of patients with soft-tissue sarcomas. The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity. This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft-tissue sarcoma.
A single academic center performed this phase II trial. Eligible patients had unresectable or metastatic soft-tissue sarcomas, Eastern Cooperative Group performance status of 0–2, adequate organ function, and ≤1 prior regimen. Gemcitabine 800 mg/m2 was given over 90 minutes on Days 1 and 8 of a 21-day cycle after administration of vinorelbine 25 mg/m2. Dosing schedule was modified for toxicity (doses constant but administered on Days 1 and 15 of a 28-day cycle). Dose reductions were allowed if unacceptable toxicities recurred.
The study accrued 40 patients, and 248 dosing cycles were administered (range, 1–32). No treatment-related deaths occurred. Of 9 episodes of grade 4 toxicities, 8 were hematologic. Of 38 episodes of grade 3 toxicity, 24 were hematologic. Clinical benefit was seen in 25% of patients and was defined as complete response (CR), partial response (PR), or stable disease (SD) at >4 months. There has been 1 CR lasting >1 year in a patient with high-grade pleomorphic spindle-cell sarcoma.
Classic combination regimens for treatment of soft-tissue sarcoma use anthracyclines either alone or in combination with ifosfamide. Responses rates ranging from 5% to 40% have been reported, with no improvement in overall survival when single agents are compared with combination regimens.1–5 Median overall survival remains poor, typically <2 years.5 Novel therapies, which balance disease control with acceptable tolerability and minimal negative impact on patient performance status, are worthy of development for clinical use.
Gemcitabine is a pyrimidine analog with activity in a broad spectrum of solid tumors. Single-agent response rates that use gemcitabine in advanced sarcoma have been reported from 4% to 18%.6–9 Response rates for gemcitabine specifically in leiomyosarcoma have been reported as high as 53% alone or in combination with docetaxel.9–10
Clinical activity of gemcitabine depends on formation of the metabolite gemcitabine triphosphate and data suggest that the rate of gemcitabine triphosphate accumulation is saturated at plasma levels of 10–20 μmol/L of gemcitabine.11–12 This concentration is achieved when gemcitabine is administered at a fixed-dose rate of 6–10 mg/m2 per minute.11, 13 The optimal infusion rate of gemcitabine in clinical practice has yet to be clearly defined. An initial study of a fixed-dose rate of infusion of gemcitabine demonstrated improved outcomes in patients with pancreatic cancer when compared with standard 30-minute infusion.13 A more recent study that evaluated the role of a gemcitabine fixed-dose rate of infusion in pancreatic cancer showed equivalence with standard-rate infusion.14 Experience with single-agent gemcitabine administered at a fixed-dose rate of infusion suggests benefit in treatment of soft-tissue sarcoma.9
Vinorelbine is a semisynthetic derivate of vinblastine, which is well tolerated and has shown activity in soft-tissue sarcoma.15 The combination of gemcitabine with vinorelbine has known activity in treatment of lung and breast carcinomas.16–20 The primary toxicity observed has been myelosuppression, with febrile neutropenia reported infrequently.
To attempt to improve upon response rates of single-agent gemcitabine, without altering the favorable toxicity profile, we have explored the use of gemcitabine in combination with vinorelbine administered at a fixed-dose rate of infusion to patients with advanced soft-tissue sarcomas.
MATERIALS AND METHODS
The following eligibility criteria were required for patient entry, histologically confirmed, unresectable, or metastatic soft-tissue sarcoma; an Eastern Cooperative Group Performance Status of ≤2; no more than 1 prior regimen of chemotherapy for advanced disease; adequate organ function defined as bilirubin <1.8, serum glutamic oxaloacetic transaminase/serum glutamate pyruvate transaminase (SGOT/SGPT) <2.5 × upper limits of normal (ULN) (<5 × ULN if hepatic disease involvement present); creatinine <1.5 × ULN; absolute neutrophil count >1.5 × 109/L; platelets >100 × 109/L; absence of pregnancy or lactation; no other active primary malignancy; and no other severe and/or life-threatening medical condition including classes III or IV cardiac dysfunction as defined by the New York Heart Association.
The Dana-Farber/Harvard Cancer Center institutional review board approved this study. All patients provided written informed consent in accordance with federal and institutional guidelines.
Patients received vinorelbine 25 mg/m2 infused intravenously over approximately 10 minutes and gemcitabine 800 mg/m2 infused intravenously over approximately 90 minutes on Day 1 and Day 8 of a 21-day cycle (or for selected patients, on Day 1 and Day 15 of a 28-day cycle). All patients were assessed within 14 days of enrollment and during treatment by physical examination, by assessment of Eastern Cooperative Oncology Group performance status, by laboratory tests (complete blood cell count with differential, liver function tests, electrolytes, and creatinine). Patients underwent imaging by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and after every 2 cycles to assess their response to treatment. Chemotherapy continued until disease progression or unacceptable toxicity occurred. Patients who required radiotherapy or surgery for additional disease control were removed from the study. Toxicity was graded according to the National Cancer Institute common toxicity criteria (NCICTC).
Dose Modification for Nonhematologic Toxicity
If grade ≥3 nonhematologic toxicity occurred at any point, treatment was held until the patient's condition resolved to grade ≤1, and then treatment was resumed at the same dose and schedule. If grade ≥3 toxicity recurred, then treatment was held until resolution to grade ≤1 and then restarted as follows: the cycle length was changed to 28 days, and treatment was given at the same doses on Day 1 and Day 15. If grade ≥3 toxicity recurred on this new schedule, then the dose of both gemcitabine and vinorelbine was reduced by 25%, and treatment given on Day 1 and Day 15 of a 28-day cycle. If an additional grade ≥3 toxicity occurred, the patient was removed from the study. No dose modification was implemented for grade 1 or grade 2 nonhematologic toxicity.
Dose Modification for Hematologic Toxicity
If grade 3 or 4 neutropenia or thrombocytopenia was present on the day of planned therapy, treatment was held until the absolute neutrophil count recovered to at least 1000 and platelet count recovered to at least 75,000. Treatment could be restarted as follows: the cycle length was changed to 28 days, and treatment was given at the same doses on Day 1 and Day 15. If grade 3 or 4 neutropenia or thrombocytopenia recurred, the dose of both gemcitabine and vinorelbine was reduced by 25%, and treatment was administered on Day 1 and Day 15 of a 28-day cycle. If grade 3 or 4 neutropenia or thrombocytopenia recurred despite this dose and schedule modification, the patient was removed from the study. Hematopoietic cytokine supportive care was allowed at the discretion of the treating physician. No dose modification was required for grade 3 or grade 4 anemia.
Dose Modification for Elevation in Total Bilirubin
If bilirubin elevations were noted, the dose of gemcitabine remained the same, and the dose of vinorelbine was modified as follows: When total bilirubin reached 2.1–3.0 mg/dL, then the vinorelbine dose was decreased to 15 mg/m2, or when total bilirubin reached >3.0 mg/dL, then the vinorelbine dose was decreased to 7.5 mg/m2.
Objective Response was defined as complete response or partial response by Response Evaluation Criteria In Solid Tumors (RECIST).21Clinical Benefit was defined either as objective response or RECIST-defined stable disease for a minimum of 4 months. Progression-free survival at 6 months for first-line therapy and at 3 months for second-line therapy have been proposed as reasonable reference values for clinical benefit in phase II trials in soft-tissue sarcomas.22 Because our patient population was mixed with regard to number of prior therapies, stable disease for 4 months or longer was included in our definition of clinical benefit for this study.
The study was structured with a 2-stage design, as proposed by Simon, that would allow early study closure if the overall clinical benefit rate was unacceptably low.23 In the first stage, 16 patients would be entered. If 3 or more clinical benefit responses (CBRs) were seen, then an additional 24 patients would be entered into the study for a total of 40. If 10 or more CBRs were observed among the 40 eligible patients, then the conclusion would be that the CBR with combined gemcitabine and vinorelbine was consistent with a rate of 35%. In selecting this design, we reasoned that if the true response rate was 35%, the probability of stopping early and rejecting combined gemcitabine and vinorelbine as a promising regimen was 0.05, and the probability of declaring it promising was 0.91. An exact 2-stage binomial confidence interval for the overall response rate was determined according to the method of Atkinson and Brown.24 Exact binomial confidence intervals were provided for the overall hematological and nonhematological toxicity rates. Progression-free survival (PFS) was defined as the length of time from the date when study treatment began to the date of documented progression or date of death, whichever occurred first. Overall survival (OS) was defined as the length of time from the date when study treatment started to the date of death from any cause. PFS and OS percentages and standard errors were obtained by using the Kaplan-Meier method and Greenwood formula, respectively.
Patient Characteristics and Time of Reporting
This phase II study was activated on February 19, 2003 and closed to further accrual on April 13, 2005, with a final accrual of 40 eligible patients. Details of baseline characteristics, including number of prior regimens, grade, and histology, with leiomyosarcoma as the most common (47.5%), are shown in Table 1. Results are reported at a median follow-up of 6.9 months for survivors.
Table 1. Baseline Characteristics
All 40 patients no. (%)
Includes 1 patient with malignant solitary fibrous tumor and 1 patient with carcinosarcoma.
Other histology includes carcinosarcoma (n = 1); desmoplastic small round cell tumor (DSRCT) (n = 1); metastatic malignant epithelioid and spindle cell neoplasm (n = 1); high-grade pleomorphic sarcoma (n = 1); small round blue cell tumor (n = 1); dedifferentiated liposarcoma (n = 1); dermatofibrosarcoma protuberans (DFSP) (n = 1); myoepithelioma (n = 1); and malignant solitary fibrous tumor (n = 1).
Tolerability of Gemcitabine + Navelbine in This Population
Treatment-related toxicities are summarized in Table 2. Twenty (50%; 90% CI, 36% to 64%) patients experienced grade 3 or 4 hematological toxicities. The most common toxicity was grade 3 neutropenia. Febrile neutropenia was uncommon, occurring in <5% of cycles administered.
Table 2. Toxicities Reported During Treatment
Type of toxicity
Leukocytes (total WBC)
Total hematological toxicities
Patients with grade 3 or grade 4 hematological toxicity
Febrile neutropenia (fever of unknown origin w/o infection)
Infection without neutropenia
Abdominal pain or cramping
Irregular menses (change from baseline)
Total nonhematological toxicities
Patients with grade 3 or grade 4 nonhematological toxicity
Patients with grade 3 or grade 4 toxicity
Nine (23%; 90% CI, 12% to 36%) patients experienced grade 3 to 4 nonhematological toxicities. Ten (25%) patients had their treatment schedules changed from days 1, 8 to days 1, 15. Five of these 10 (50%) patients underwent schedule change because of hematological toxicities. No treatment-related deaths were seen.
The rate of clinical benefit response was defined as the proportion of patients with complete or partial objective responses or patients with stable disease for ≥4 months. All 40 patients were assessable for efficacy.
As of June 1, 2006, 248 cycles had been administered, with a median of 3 cycles per patient (range, 1–32 cycles). Table 3 presents the response rate for all 40 enrolled patients. One patient (Case 14) of the first 16 withdrew from the study after a single cycle of study drug administration but is included in the denominator as a nonresponder for response rate calculations.
Table 3. Summary of Efficacy-Clinical Benefit Rates
Of the 40 total patients, 10 (25%; 90% CI, 15% to 40%) achieved from amongst a complete response (n = 1), partial response (n = 4), or sustained stable disease for at least 4 months (n = 5). Of the 5 patients with objective response, 3 patients had metastatic leiomyosarcoma, 2 of these of uterine origin. The other 2 responders were a 71-year-old female with high-grade myxofibrosarcoma of the thigh with pulmonary metastasis and a 25-year-old male with metastatic small round blue cell malignancy, which originated in the soft tissues around the knee and spread to the lungs and pelvic lymph nodes. The latter patient had previously received ifosfamide and Adriamycin-based chemotherapy in the adjuvant setting and developed pulmonary metastasis within 4 months of completing adjuvant therapy. Gemcitabine with vinorelbine was first-line therapy for advanced disease in all 5 of these patients.
Of the 5 patients with prolonged stable disease, 1 patient had metastatic leiomyosarcoma of uterine origin. The remaining 4 patients had had a variety of histologic diagnoses as follows: unclassified high-grade spindle cell sarcoma, high-grade myxofibrosarcoma, high-grade malignant fibrous histiocytoma, and malignant peripheral nerve sheath tumor. One of these 5 patients had received prior chemotherapy for advanced disease. The median duration of clinical benefit for the 10 responding patients was 12.6 months (range, 4.1 months to 29.9 months). The median duration of clinical benefit for the 5 patients who achieved a complete or partial response was 16.1 months (range, 5.3 months to 29.9 months). The median duration of clinical benefit for the 5 patients who achieved stable disease sustained for at least 4 months was 9.6 months (range, 4.1 months to 20.9months). The median time to progression for the entire cohort was 3.4 months. The 6-month and 12-month progression-free survival (PFS ± SE[standard error]) rates were 27% ± 8% and 18% ± 7%, respectively (Fig. 1). The 6-month and 12-month overall survival (OS ± SE) was 90% ± 5% and 75% ± 9%, respectively. Figure 2 presents the overall survival curve for all 40 enrolled patients.
In the continuing challenge to find new effective treatments for patients with advanced or metastatic soft-tissue sarcomas, the combination of gemcitabine and vinorelbine may have a role. In the current study, this regimen has shown a clinical benefit rate of 25% in a heterogeneous group of patients with various histopathologic subtypes of metastatic soft-tissue sarcomas; importantly, this outpatient regimen has been overall well tolerated. The high rates of overall survival are particularly interesting, making these results encouraging for this population of patients with pretreated soft-tissue sarcomas.
Gemcitabine administered as a single agent has been previously studied in patients with metastatic soft-tissue sarcoma, with reported response rates ranging from 4% to 18%.6–8 In these studies, gemcitabine was administered by means of a standard infusion rate of 30 minutes, independent of dose. Pharmacokinetic data9 suggest that there may be a pharmacologic advantage to dose-adjusted infusion of 6 mg/m2 to 10 mg/m2. At this rate, the accumulation of the active metabolite, gemcitabine triphosphate, appears to be maximal, thus suggesting an pharmacologic advantage to this regimen. When used as a single agent administered at this dose rate, gemcitabine has very encouraging rates of benefit and objective response, particularly in leiomyosarcomas of uterine origin or those arising outside the gastrointestinal tract.9 The combination of gemcitabine and docetaxel has shown promise in leiomyosarcomas and other histopathologic subtypes of soft-tissue sarcomas.10, 25 In studies of the gemcitabine and docetaxel combination reported to date, gemcitabine has been administered by a fixed-dose rate of infusion. Response rates for leiomyosarcoma (LMS) were reported to be 47% to 53% with a median duration of response of just over 5 months. When histologies other than LMS were included, response rates were lower, (40% versus 10%), with a median duration of response for patients responding noted to be 7 months.26 An early report comparing gemcitabine alone with gemcitabine plus docetaxel suggested activity for both regimens, with patients experiencing a better overall response rate to the combination regimen.27
Our current study adds to data that support the activity of a fixed-dose rate of infusion for a gemcitabine-based regimen for patients with soft-tissue sarcoma. The combination of gemcitabine plus vinorelbine was associated with an observed clinical benefit rate of 25% when we included patients with durable stable disease on treatment. This regimen was well tolerated and readily managed with adjustments to the dose schedule without compromising the dose. Although the observed response rate with the combination of gemcitabine and vinorelbine is comparable to that with single-agent gemcitabine, the median duration of response in this study of 12.6 months (range, 4.1 months to 29.9 months) for patients achieving clinical benefit is promising. This study was not statistically powered to draw any definitive conclusions on the relative benefit of this treatment in specific histologic subtypes; however, responses were seen in a variety of high-grade tumors. The optimal regimen to balance antitumor efficacy and toxicity in patients with these incurable diseases will require additional studies. It will also be important to identify subsets of sarcomas that may be particularly sensitive to these agents, given the fact that this regimen has induced durable objective responses in a notable subset of patients. Further molecular characterization of these sensitive sarcomas will be required, as routine histopathology has not yielded any clues that would help clinicians accurately prognosticate an outcome for individual patients.
The authors gratefully acknowledge the generous participation and encouragement of all the patients and families who supported this work.