A Phase II Study of Gemcitabine, Vincristine, and Cisplatin As Second-Line Treatment for Patients with Advanced Soft Tissue Sarcoma.

Patients with advanced soft tissue sarcoma (aSTS) typically have a poor prognosis. Patients progressing to doxorubicin-based regimen have limited therapeutic options. Monotherapy with cytotoxic drugs appears to have only modest activity in the second-line setting. The purpose of this phase II study was to prospectively evaluate the safety and efficacy of combination regimen with gemcitabine, vincristine, and cisplatin (GVP) as a salvage treatment for patients with aSTS.Eligible patients were female with 18∼75 years old, and had aSTS that had progressed after 1 prior anthracyclines-based chemotherapy regimen. Patients were treated with 1,000 mg/m gemcitabine intravenously (IV) on days 1 and 8, 1.4 mg/m (max 2 mg) vincristine IV on day 1 and 25 mg/m cisplatin IV on days 1 through 3 every 21 days until disease progression, unacceptable toxicity or up to 6 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), over response rate (ORR) and safety. This trial was registered with http://www.clinicaltrials.gov (no. NCT01192633).A total of 26 patients with a median age 47 years (21-72) were recruited. ORR was 23.1% [1 complete response and 5 partial responses]. The median PFS and OS were 4.8 (95% CI, 0.1-9.5) months and 15.0 (95% CI, 6.1-23.9) months, respectively. Grade 3/4 hematologic toxicities included neutropenia (34.6%), leukopenia (23.1%), thrombocytopenia (11.5%) and anemia (3.8%). No febrile neutropenia and grade 3/4 non-hematologic toxicities occurred. The most frequent non-hematologic toxicities were nausea/vomiting (50.0%), fatigue (30.8%), and fever (11.5%).We conclude that GVP regimen is effective with a favorable safety profile as the second-line chemotherapy in aSTS patients, which warrants further investigation in a phase III study.

INTRODUCTION

Soft tissue sarcomas (STSs) are relatively rare and heterogeneous malignancies originating from mesenchymal cell with distinct clinical and pathological features. STSs account for less than 1% of all new cancer cases each year, but have an aggressive biologic behavior and poor prognosis.[1] More than 50 histological subtypes have been identified, including leiomyosarcoma (LMS), liposarcoma, synovial sarcoma, alveolar soft part sarcoma, angiosarcoma, fibrosarcoma, malignant fibrous histiocytoma (MFH) and pleomorphic undifferentiated sarcoma. Approximately, half of STS patients are diagnosed with advanced disease or will develop recurrent metastasis after surgery and/or chemotherapy.[2] In these patients not amenable to surgery, chemotherapy is almost the only available treatment with median survival estimated to be about 12 months from diagnosis of metastasis.[3] Until recently, a limited number of drugs have been available for these patients with advanced soft tissue sarcoma (aSTS). Doxorubicin and/or ifosfamide-based regimens with well-established activity constitute the standard treatment in the first-line setting. Patients progressing to these two drugs have limited therapeutic options.

A small number of drugs have been incorporated into the second-line treatment of sarcomas. Gemcitabine, temozolomide, ifosfamide, dacarbazine, vincristine, taxanes, platinums as well as trabectedin are promising cytotoxic drugs that have shown variable degrees of efficacy in phase II-III studies.[4] All these drugs appear to have only modest activity given as monotherapy. For example, the overall response rates (ORRs) of gemcitabine single agent in second-line treatment of aSTS have been reported from 6% to 22% with the progression free survival (PFS) about [3] months.[4] Therefore it is necessary to identify new combinations to improve therapy for patients with aSTS. Previous preclinical study indicated that the drug combination (gemcitabine plus cisplatin, GP) produced a synergistic response (data not shown). Furthermore, vincristine has a different tumor suppression mechanism which inhibits microtubule dynamics and is less likely to cause bone marrow suppression, which made the new regimen GP plus vincristine (GVP) worthy of being investigated. Here, we aimed to assess the safety and efficacy of combination regimen of GVP as a salvage treatment for patients with aSTS (ClinicalTrials.gov identifier, NCT01192633).

Patients and Methods

Patients

The main inclusion criteria were unresectable or metastatic STS with previous treatment with anthracyclines-based regimen, 18–75 years old, at least one extracranial measurable lesion by MRI or CT according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), Eastern Cooperative Oncology Group performance status of 0–2, ≤ 1 prior regimen of chemotherapy for advanced disease, no anticancer treatment for at least 4 weeks prior to enrollment in the study, a life expectancy ≥3 months, adequate hematologic, renal, and hepatic function, as indicated by hemoglobin ≥8 g/dL, absolute neutrophil count (ANC) ≥1.5 × 109 /L, platelet count ≥80 × 109 /L, total serum bilirubin ≤1.5 × upper limit of normal (ULN), AST/ALT ≤2.5 × ULN (≤5 × ULN if hepatic disease involvement present), alkaline phosphatase ≤2.5 × ULN (≤5 × ULN if hepatic disease involvement present and ≤10 × ULN if bone disease involvement present), serum creatinine ≤1.25 × ULN or calculated creatinine clearance ≥65 ml/min.

Patients with primitive neuro-ectodermal tumor (PNET), Ewing sarcoma, embryonal rhabdomyosarcoma, chondrosarcoma, osteosarcoma, and gastrointestinal stromal tumor were not eligible. Other exclusion criteria included prior exposure to gemcitabine, vincristine or cisplatin, known CNS metastases, participation in any other clinical trials within 28 days of enrollment, previous or concomitant malignant disease (with the exception of cervical carcinoma in situ and cutaneous basal cell carcinoma), grade ≥2 peripheral neuropathy, uncontrolled severe infections, significant cardiac disease, and pregnant or lactating women.

Independent ethics committees of Fudan University Shanghai Cancer Center approved the study protocol. We did the study in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Treatment

Patients were treated with 1,000 mg/m2 gemcitabine intravenously (IV) on days 1 and 8, 1.4 mg/m2 (max 2 mg) vincristine IV on day 1 and 25 mg/m2 cisplatin IV on days 1 through 3 every 21 days until disease progression, unacceptable toxicity or up to 6 cycles (Supplementary Figure 1, http://links.lww.com/MD/A470). Patients were required to have an adequate absolute neutrophil (≥1.5 × 109 /L) and platelet count (≥75 × 109 /L) before day 1 of each cycle. The following recommendations for chemotherapy dose reductions were applied. In patients who experienced grade 4 haematological, grade 3/4 non-haematological, or other protocol-specified toxicities, gemcitabine, vincristine and cisplatin treatment was interrupted. When the toxicity resolved to grade < 2, the dose of gemcitabine and cisplatin was restarted at 75% of the original dose at the first appearance of the respective toxicity and at 50% of the starting dose at the second appearance. Vincristine was reduced only when grade 3/4 non-haematological toxicities occurred. If whole blood count was low, day 8 gemcitabine could be postponed for at most 7 days to allow recovery, otherwise it would be cancelled. Maximum delay for GVP regimen was 14 days. Treatment was permanently discontinued if dose modification of greater than twice was required. Patients would discontinue only one drug if one specific severe adverse event (AE) was judged to be related to that particular drug. Administration of prophylactic G-CSF was not permitted in the study.

Assessment

Pretreatment assessment included a detailed medical history, physical examination, routine laboratory tests and performance status. Laboratory evaluation included a routine blood count, biochemistry including electrolytes, renal and liver function tests, and urinalysis. AEs and concomitant medications were recorded at the end of each cycle throughout the study period until 30 days after the last dose of a study treatment was administered. Toxicity was evaluated and graded according to National Cancer Institute Common Terminology Criteria for AEs, version 4.0.

Radiographic scans (CT scan or MRI) for efficacy evaluation were conducted at baseline and every two treatment cycles until disease progression according to RECIST 1.1. The best overall response was reported. Survival status was assessed every 2 months after disease progression.

Statistical Methods

The primary endpoint was PFS defined as the time from the date of enrollment to progression or death from any cause. Secondary endpoints included overall survival (OS, time from enrollment to death from any cause), over response rate (ORR, complete response and partial response) and safety.

The sample size was based on testing the hypothesis that GVP given for aSTS pretreated with anthracyline-based chemotherapy may be superior to single agent gemcitabine given to comparable set of patients. The median PFS for patients receiving gemcitabine was assumed to be 3.0 months.[5,6] Therefore, the null hypothesis of PFS of 3.0 months or lower was tested against the alternative hypothesis of a true PFS of 4.8 months or higher with GVP regimen. The sample size was calculated as 26 patients, with a two-sided alpha-level of 0.05 and 70% power (48 months enrollment duration, 12 months follow up duration after enrollment).

All statistical analyses were carried out using SPSS 19.0 (SPSS, Inc.). Statistical analysis of 2 × 2 contingency tables of categorical variables was carried out using the Pearson's χ2 test (or Fisher's exact test when appropriate). Time-to-event variables were summarized using the Kaplan-Meier method.

RESULTS

Between Mar 2009 and Jul 2013, 26 patients with aSTS were recruited. Patient characteristics are listed in Table 1. The median age was 47 years (range: 21–72). Six (23.1%) had LMS, 3 (11.5%) liposarcoma, 3 (11.5%) alveolar soft part sarcoma, 2 (7.7%) angiosarcoma, and 12 (46.2%) other histologic types. Only 2 patients (7.7%) had locally advanced disease, and the remainder had relapsed or metastatic diseases. The majority (73.1%) of tumors were histologically grade 3. All patients had been exposed to anthracyclines-based regimen regimens.

TABLE 1

Patient characteristics at baseline

Efficacy

The median number of treatment cycles was 4 (range: 1–6 cycles). The outcome of the patients treated with GVP as salvage chemotherapy was presented in Table 2. Of the 26 patients, 1 (3.8%) achieved complete response (CR), 5 (19.2%) partial response (PR), and 11 (42.3%) stable disease (SD) with the ORR of 23.1% and disease control rate of 65.4%. Both the two patients with angiosarcoma who had progressed to MAID (mesna, anthracycline, ifosfamide and dacarbazine) regimen responded to GVP (one CR and one PR). Of the 8 patients with primary extremity sarcomas, 2 (25.0%) achieved PR and 5 (62.5%) achieved SD. After a median follow-up of 22.6 months, the median PFS and OS were 4.8 (95% CI, 0.1–9.5) months and 15.0 (95% CI, 6.1–23.9) months, respectively (Fig. 1).

TABLE 2

Summary of efficacy

FIGURE 1

Kaplan-Meier estimates of progression-free survival (PFS) (A) and overall survival (OS).

Toxicity

Toxicity profile of the combination was acceptable and manageable. The most common AEs were presented in Table 3. Grade 3/4 hematologic toxicities included neutropenia (34.6%), leukopenia (23.1%), thrombocytopenia (11.5%) and anemia (3.8%). No grade 3/4 non-hematologic toxicities occurred. The most frequent non-hematologic toxicities were nausea/vomiting (50.0%), fatigue (30.8%), and fever (11.5%). Dose adjustment due to AEs occurred in 11 patients (42.3%). There were no treatment-related deaths.

TABLE 3

Adverse events

DISCUSSION

The primary purpose of therapy for aSTS is palliation.[7,8] Current treatment for unresectable or metastatic STS is not only dictated by the histological subtype of sarcoma, but also by location of metastatic sites, tumor size, and the pathological grade.[7-9] Cytotoxic chemotherapy is still the main systemic treatment, with little dedicated biological agents currently available. According to the European Society for Medical Oncology and the National Comprehensive Cancer Network treatment guidelines, anthracycline monotherapy or anthracycline-based regimen (mainly combined with ifosfamide) was recommended as the first-line regimen for most subtypes of aSTS.[8,10] However, after treatment failure of doxorubicin and/or ifosfamide, no standard recognized therapeutic options exist.

The combination of gemcitabine, vincristine, and cisplatin may have a relatively important role for patients with aSTS who have failed to doxorubicin-based regimens. In our study, this regimen has shown a total response rate of 23.1%, a disease control rate of 65.4%, a median PFS of 4.8 months and a median OS of 15.0 months in an unselected cohort of patients with aSTS including different histological subtypes. Both the PFS and OS were particularly promising and these results could be decisive for second-line treatment of patients with pretreated aSTS.

As a limitation, it should be noted that the range of different tumor types included in this study was relatively wide. However, the results of the study suggested which subtypes might better respond to GVP regimen and require further confirmation. Actually, the subtypes comprising the group of STSs differ strongly in their sensitivity to the different drugs or combinations. Selection of cytotoxic chemotherapy for patients with different types of aSTS is increasingly driven by histological subtype considerations.[11-13] Prior experience indicated that LMS and MFH are relatively responsive to gemcitabine-docetaxel (GD) chemotherapy. However, in our study, angiosarcoma was the most sensitive subtype to the treatment of GVP (ORR 100%). On the contrary, no response was found in patients with LMS or MFH when salvage GVP was administered. The reason why angiosarcoma responded better to this combination is unknown. Hence, this subtype should be separately tested in future clinical trials.

GD or GD-based regimens [13-23] had been widely investigated as the salvage treatment for patients with aSTS. The ORR and PFS in our study were almost comparable to those with GD-based regimens, however, the side effect results of our study were relatively lower. In our study, the most common hematologic and non-hematologic toxicities were neutropenia (34.6%) and nausea/vomiting (50.0%), respectively. There was no toxicity related death. The toxicity profile of GVP was as expected, generally self-limiting and well manageable, with no new safety observations.

Recently, in the Phase III PALETTE study, pazopanib, a new oral selective tyrosine kinase inhibitor for the treatment of aSTS (excluding GIST, liposarcoma and other subtypes) has successfully demonstrated significant PFS prolongation compared with placebo (4.6 months vs. 1.6 months, p < 0.001).[24] However, it is not commercially available in China and salvage chemotherapy still remains the standard therapy. The traditional cytotoxic drugs commonly induce hematological toxicities whereas grade 3/4 toxicities seen with pazopanib included fatigue, elevated liver enzymes, and hypertension. The safety profiles of both approaches (chemotherapy versus pazopanib) appear to be distinct and discontinuations due to AEs appear more frequent with pazopanib; this is of particular relevance when discussing the toxicity/benefit ratio with patients.

In conclusion, the GVP combination regimen given as second-line therapy for patients with aSTS resulted in better PFS when compared to the historical data for gemcitabine single agent, - an observation meeting the primary endpoints of our study. Future work could include the validation in a phase III study, expanding the information of our GVP regimen on pre-specific histological subtype (such as angiosarcoma), and the identification of predictive markers for treatment with GVP for patients with aSTS.