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Laboratory and Clinical Evidence of Synergistic Cytotoxicity of Sequential Treament With Gemcitabine Followed by Docetaxel in the Treatment of Sarcoma

From the Department of Medicine, Division of Hematology/Oncology; the Pharmacology Department; the Department of Surgery; the Department of Orthopedic Surgery; and the Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI

Address reprint requests to Laurence H. Baker, DO, University of Michigan Comprehensive Cancer Center, 7216 CCGC, Ann Arbor, MI 48109; bakerl{at}umich.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: A recent report of the combination of gemcitabine and docetaxel described favorable results in patients with uterine leiomyosarcoma. The objective of this report is to describe experience with this combination in a variety of histologic subtypes of sarcoma. Additionally, cell-culture studies were performed to assess the effect of the sequence of drug administration on colony formation.

PATIENTS AND METHODS: A medical record review of 35 patients receiving the gemcitabine/docetaxel combination was undertaken. Gemcitabine 675 mg/m² intravenously was administered over 90 minutes on days 1 and 8, and docetaxel 100 mg/m² intravenously was administered over 60 minutes on day 8 of a 21-day cycle. Cell culture studies using the SAOS-2 osteosarcoma cell line and MCF-7 breast cancer cell line were also performed. Gemcitabine and docetaxel were added to cells either simultaneously for 24 hours, gemcitabine for 24 hours followed by docetaxel for 24 hours, or the reverse sequence.

RESULTS: Thirty-five patients were treated. Five complete responses and 10 partial responses were observed for an overall response rate of 43%. Responses occurred in uterine, extremity, and retroperitoneal leiomyosarcoma, osteosarcomas, angiosarcomas, malignant fibrous histiocytomas, malignant peripheral-nerve sheath tumors, and Ewing's sarcoma. In the cell culture studies, gemcitabine followed by docetaxel provided synergy. In contrast, the administration of drugs simultaneously resulted in antagonism, and docetaxel followed by gemcitabine provided mixed results.

CONCLUSION: The combination of gemcitabine and docetaxel seems to be active in a variety of sarcomas. A multicenter, randomized clinical trial in soft tissue sarcoma comparing gemcitabine alone with this combination, is ongoing.

	INTRODUCTION

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Soft tissue and bone sarcomas remain a challenging group of diseases for the oncology community. An estimated 8,300 cases of soft tissue sarcoma and approximately 2,400 cases of malignancy of bones and joints will be diagnosed in the United States this year.¹ Half as many patients will die from this group of diseases within this same period.¹ Multimodality treatment is the standard of care for primary lesions and limited metastatic disease, with adjuvant chemotherapy offering 10% improvement in relapse-free survival for patients with soft tissue sarcoma at 10 years.^2,3 Effective chemotherapeutic options for the adjuvant treatment of sarcoma and for the treatment of metastatic disease remain limited beyond first-line treatment with doxorubicin- and ifosfamide-based regimens. Some patients are not candidates for these agents due to their substantial adverse effect profiles. Thus, additional chemotherapeutic options are needed.

Gemcitabine (2',2'-difluorodeoxycitidine) is a difluorinated analog of deoxycytidine. It is an S-phase-specific drug that requires intracellular transport and activation to exert its cytotoxic effects.⁴ The active diphosphate form is a potent inhibitor of ribonucleotide reductase leading to perturbations in the deoxynucleotide pools.^4,5 In contrast, the active triphosphate form is incorporated into DNA, resulting in interference with DNA chain elongation and disruption of cell growth.^4,6,7 The reported response rates of single-agent gemcitabine in patients with soft tissue and bone sarcoma are 3%, 3%, 5.5%, 11%, and 18%, respectively, with a median of 5.5%, based on five phase II trials.^8–12

Docetaxel is a semisynthetic taxane synthesized from the needles of the European yew tree. This agent promotes microtubule assembly and inhibits microtubule depolymerization.¹³ The reported response rates of single-agent docetaxel in patients with sarcoma are 0%, 6%, 15%, 17%, and 18%, respectively, with a median of 15%, based on five phase II trials.^14–18

The combination of gemcitabine and docetaxel has been evaluated in a variety of malignancies, with activity demonstrated in non-small-cell lung cancer, breast cancer, esophageal cancer, and others.^19,20 A recent report by Hensley et al documented an impressive 53%response rate in patients with predominantly uterine leiomyosarcoma (LMS).²¹ Given the paucity of effective second-line treatments available for the treatment of soft-tissue and bone sarcomas, we have been treating patients with this combination who either are not candidates for, have disease following, or have disease resistant to, treatment with doxorubicin and/or ifosfamide. The purpose of this retrospective review is to describe this experience with the combination of gemcitabine and docetaxel in patients with a variety of histologic subtypes of sarcoma.

Based on the clinical observation of synergy, we subsequently performed laboratory investigations of this combination in vitro, with specific attention to the effect of sequence of drug administration. The purpose of these studies was to determine the in vitro effects of sequence of drug administration on cytotoxicity.

	PATIENTS AND METHODS

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Patients
A medical record review of 35 patients with a variety of bone and soft tissue sarcomas treated with the combination of gemcitabine and docetaxel was performed. These patients had previously received doxorubicin and/or ifosfamide, or were patients for whom gemcitabine and docetaxel was preferable for medical reasons. Following a discussion of the rationale for using this combination of chemotherapeutic agents, patients were offered this regimen as innovative care rather than in the context of a clinical trial. The appropriate institutional review board at the University of Michigan approved our request to summarize this data for publication.

Medical Record Review Process and Definitions
All patient cases were initially presented to the University of Michigan multidisciplinary sarcoma tumor board. Patients' electronic and paper records were reviewed; chemotherapy administration schedules and dosages were verified. Note was made of any dosage delay or modification, and of any significant toxicity. Radiographic studies and/or reports were reassessed, and responses were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria when measurements were available.²² Response was assessed based on a single scan for each time point for each patient; confirmatory scans were not available. Pathology assessment was confirmed by a sarcoma pathologist. Best overall response was defined as the best response designation recorded from the start of treatment until disease progression. Response rate is reported on an intention-to-treat basis. Time to progression was defined as the time from first treatment until clinical or radiographic progression. Survival was determined from the date of first treatment.

Treatment Regimen
Patients received gemcitabine 675 mg/m² intravenously over 90 minutes on day 1 and day 8, and docetaxel 100 mg/m² over 60 minutes on day 8 of a 21-day cycle. All patients received either filgrastim 300 µg subcutaneously once per day on days 9 to 15, or pegfilgrastim 6 mg subcutaneously on day 9. Standard prophylactic premedications were provided on day 1 and day 8 with diphenhydramine and dolasetron or its equivalent. In addition, patients received dexamethasone 8 mg orally twice daily on days 7 to 9. Response was assessed every two to three cycles.

Statistical Analysis
Response rates were reported with point estimate and 95% exact binomial CI. The Kaplan-Meier method was used to estimate the survival function and time to progression.²³ The median survival rate and time to progression were also reported with 95% CIs.

Cell Culture Studies
Gemcitabine and docetaxel were added to exponentially growing SAOS-2 osteosarcoma and MCF-7 breast cancer cell lines, either simultaneously for 24 hours, gemcitabine for 24 hours followed by docetaxel for 24 hours, or the reverse sequence. Cells were then plated in triplicate for assessment of colony formation. Three concentrations of each drug were used to create dose-response curves. Isobologram analysis was applied to these dose-response curves. Each experiment was performed at least three times.

	RESULTS

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Patient Characteristics
Thirty-five patients (11 men, 24 women) were treated between April 2001 and August 2002 with this regimen. The median age was 53 years (range, 20 to 73 years). Histologic subtypes are indicated in Table 1. Of note, two of the LMS were of uterine origin, two were of the extremity, six were retroperitoneal, and two were from other or unknown primary sites. Nine patients had locoregional disease, and 26 had metastatic disease. Of the nine patients with locoregional disease, three were newly diagnosed, whereas six had recurrent disease. Of the 35 patients, seven had received no prior systemic therapy for their sarcoma. Four of these patients were chemotherapy-naive but were judged not able to receive doxorubicin and/or ifosfamide owing to underlying medical issues (two patients were elderly and frail; two patients had renal insufficiency). One patient with LMS received first-line treatment with gemcitabine and docetaxel based on the recently published phase II data, and two had received doxorubicin with or without ifosfamide for a prior malignancy. Of the 28 patients previously treated, 18 had received one prior chemotherapy regimen, seven had received two prior regimens, and three patients had received three to five prior regimens. In total, 27 patients had previously received doxorubicin and/or ifosfamide for the current malignancy; one had received a non-doxorubicin/ifosfamide-containing regimen. Of note, one patient with osteosarcoma who had received five prior systemic treatment regimens received gemcitabine in combination with docetaxel as adjuvant treatment, with subsequent recurrence and lack of alternative treatment options, prompting re-treatment with this regimen.

Antitumor Effect
Antitumor effect is reported on an intention-to-treat basis. Of the 35 patients reviewed, one with malignant fibrous histiocytoma was considered nonevaluable, as she discontinued treatment after one cycle due to severe rash and did not have subsequent imaging performed until after she had received additional therapy. For the purpose of this review, she was considered to have a best response of PD. Responses, catalogued according to histologic subtype, are presented in Table 1. Among the 35 treated patients, five (14%) had a complete response (CR), 10 (29%) had a partial response (PR), 13 (37%) had a best response of stable disease (SD), and seven (20%) had PD. Thus, an overall response rate of 43% was observed (95% CI, 26% to 61%). Eighty percent of patients had either a response or stabilization of disease.

In 26 patients with metastatic disease, two (8%) had a CR, eight (31%) had a PR, 10 (38%) had SD, and six (23%) had PD (Table 2). Thus, a response rate of 38% was observed in patients with metastatic disease (95% CI, 20% to 59%). In comparison, the response rate for the nine patients with locoregional disease was 55% (95% CI, 21% to 86%).

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve.

Cell Culture Studies
The optimal sequence for combining gemcitabine and docetaxel was evaluated in SAOS-2 sarcoma cells and MCF-7 breast cancer cells (Fig 2). Isobologram analysis demonstrated that the simultaneous addition of gemcitabine and docetaxel produced primarily additive to antagonistic interactions in both cell lines. The sequence of docetaxel followed by gemcitabine was mostly antagonistic in the SAOS-2 cells, while MCF-7 cells showed primarily an additivity interaction with a few conditions suggestive of synergy. The sequence of gemcitabine followed by docetaxel produced synergy with some evidence of additivity in SAOS-2 cells, with strong synergy observed in MCF-7 cells. The addition of docetaxel after gemcitabine resulted in a significant decrease in IC50 values for gemcitabine—from 60.0 ± 17.0 nmol/L (gemcitabine alone) to 7.9 ± 0.5 nmol/L (gemcitabine followed by docetaxel) in MCF-7 cells (P = .049), and from 26.0 ± 0.5 nmol/L to 14.5 ± 6.1 nmol/L (P = .032) in SAOS-2 cells. Only this sequence of drug administration resulted in a significant decrease in IC50 values for gemcitabine in both cell lines.

View larger version (30K): [in this window] [in a new window]   Fig 2. Isobologram analysis of SOAS-2 sarcoma cells and MCF-7 breast cancer cells, and effect of sequence of administration of gemcitabine and docetaxel in (A) SAOS-2 osteosarcoma and (B) MCF-7 breast cancer cell lines. Simultaneous administration of both drugs resulted in antagonism, docetaxel followed by gemcitabine produced mixed results, and gemcitabine followed by docetaxel resulted in synergy. The curve represents an additive interaction, while the area above the curve represents an antagonistic interaction, and the area below the curve represents synergy. (), 75%; (•), 50%; (), 30%; (), 15%.

	DISCUSSION

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The overall response rate of 43% observed in this retrospective review compares quite favorably with that of doxorubicin/ifosfamide-based therapies, and this regimen is clearly less toxic. The present report carries with it the foibles of a retrospective review, including possible observer bias, patient selection bias, and the lack of systematic recording of toxicities. However, the histologic subtypes of sarcoma represented in this trial are representative of a typical sarcoma practice, and most patients had been heavily pretreated. RECIST criteria were not rigorously applied in real-time during treatment, but reports and films were reviewed as extensively as possible in an effort to accurately define each patient's best response. Confirmatory scans were not routinely available. All patients were treated by three physicians (K.M.L., M.Z., and L.H.B.), and chemotherapy dosing was consistent among the patients.

As noted previously, gemcitabine as single-agent therapy has been evaluated as second-line therapy in the treatment of soft tissue sarcoma. Five phase II trials reported response rates of single-agent gemcitabine in patients with soft tissue, and bone sarcoma of 3% to 18%.^8–12 Doses generally ranged from 1,000 to 1,250 mg/m² and were administered over 30 minutes,^8,9,12 though one study utilized a schedule of 200 to 250 mg/m² administered over 360 minutes on days 1, 8, and 15 of a 28-day cycle, without any improvement in response rate.¹¹

Docetaxel has also been evaluated as second-line therapy in the treatment of soft tissue sarcoma. The response rate of single-agent docetaxel at a dose of 100 mg/m² administered over 60 minutes once every 3 weeks in patients with soft tissue sarcoma has varied from 0% to 18% in five phase II trials.^14–18

The overall response rate of 43% observed in this retrospective review compares favorably to that of single-agent gemcitabine and single-agent docetaxel to a degree, suggesting synergy rather than simple, additive effect. This response rate is consistent with that of 53% in predominantly uterine LMS, as reported by Hensley et al.²¹ Two factors may be responsible for the improved response rate of this regimen, including the longer duration of gemcitabine infusion and the sequence in which the drugs are administered.

The rate of gemcitabine administration may be crucial to maximizing the antitumor activity of this drug. The intracellular accumulation of gemcitabine triphosphate, the active form of the drug, is saturated at gemcitabine dose rates that produce plasma gemcitabine concentrations of 10 to 20 µmol/L.^27,28 Hensley et al compared plasma levels of gemcitabine using a 90-minute infusion versus a standard 30-minute bolus infusion.²¹ While the mean area under the curve did not differ between the two administration rates, the duration at which the plasma gemcitabine concentration remained above the 10 umol/L threshold was approximately 50% longer with the 90-minute infusion as compared with the 30-minute bolus infusion (P = .0008).²¹

In addition, the sequence in which the two drugs are administered may also contribute to the efficacy of this regimen. In vitro studies demonstrated that the sequence of gemcitabine followed by docetaxel was most consistently synergistic in a sarcoma and a breast carcinoma cell line. This data contrasts in vitro data evaluating the combination of gemcitabine and paclitaxel, as well as in vitro data using gemcitabine and docetaxel in gastric cancer cell lines. Theodossiou et al and Kroep et al have reported not more than additive cytotoxicity for any sequential exposure to gemcitabine and paclitaxel, and antagonism for concomitant exposure to both drugs.^29,30 In fact, the administration of paclitaxel before gemcitabine increased the accumulation of gemcitabine triphosphate in non-small-cell lung cancer cells, increased the incorporation of gemcitabine into RNA, and increased the apoptotic index, leading to the conclusion that perhaps paclitaxel before gemcitabine might be favorable.³⁰ Thus, the effect of administration sequence on cytotoxicity is not generalizable across the taxanes.

In addition, Ricotti et al³¹ recently published a series of in vitro investigations of gemcitabine and docetaxel in gastric cancer cell lines, with the conclusion that docetaxel followed by gemcitabine produces synergy, while gemcitabine followed by docetaxel results in antagonism. Cell growth, rather than colony formation, was assessed, which may partially account for the discrepancy. In addition, our results suggest that under certain conditions, docetaxel followed by gemcitabine may be synergistic. The preferred sequence for addition of these drugs may also be cell-line specific. If the synergy reported here depends on the ability of docetaxel to block cells in G2/M, then other mitotic inhibitors may have similar results, though the study by Kroep et al³⁰ would argue against this. Furthermore, docetaxel was reported to have higher toxicity when added to cells in S phase, the cell-cycle phase in which cells gemcitabine produces cytotoxicity. Future studies will determine whether cell-cycle interactions contribute to the synergistic observed here with gemcitabine and docetaxel.

While toxicity data were not collected in a rigorous, prospective fashion, this regimen was fairly well-tolerated in this heavily pretreated population. Adverse effects that were noted include those that are commonly associated with either agent alone, including myelosuppression, fatigue, weight gain, and peripheral edema, with edema requiring diuretic treatment more commonly occurring with cycles four to eight. In addition, 20% of patients in this review developed a vague pulmonary syndrome as described previously,²¹ requiring dose modification or delay. These symptoms were not associated with any flulike syndrome and were not due to radiation recall. Prior studies of this combination, primarily in non-small-cell lung cancer, have occasionally reported pulmonary symptoms.³² However, two studies have reported a high incidence of lung toxicity. Dunsford et al³³ reported severe lung toxicity in 3 of 5 patients with metastatic transitional cell carcinoma treated with gemcitabine and docetaxel, and Kouroussis et al³⁴ reported such toxicity in five of 26 patients with non-small-cell lung cancer. Thus, clinicians should remain vigilant in monitoring for pulmonary symptoms when using this combination.

In conclusion, the combination of gemcitabine administered over 90 minutes on day 1 and day 8, followed by administration of docetaxel on day 8, has demonstrated a 43%response rate and 37% SD in patients with sarcomas of various histologic subtypes. This regimen may have synergistic antitumor effect secondary to both the prolonged gemcitabine infusion, resulting in a longer time above the 10-µmol/L threshold concentration, as well as to sequence of administration. These results need to be validated in a prospective manner, with close monitoring for pulmonary toxicity. We are currently enrolling patients in a multi-institutional, randomized clinical trial comparing this regimen with a 120-minute infusion of gemcitabine alone in patients with soft-tissue sarcoma. A multi-institutional, phase II clinical trial evaluating this regimen in patients with bone sarcomas is under development.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 6, 2003; accepted December 22, 2003.

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