Dacarbazine for Metastatic Soft Tissue and Bone Sarcoma

• The primary endpoint is to determine the overall best tumor anatomic response rate to dacarbazine given until disease progression as assessed by RECIST criteria using CT and clinical examination in patients with metastatic sarcoma. [ Time Frame: response to treatment ] [ Designated as safety issue: No ]
  

• To determine the overall risk of nausea/emesis (any grade) and neutropenia (grade 3 or 4) with up to six cycles of dacarbazine given with current antiemetic agents and with pegfilgrastim [ Time Frame: 30 days post last treatment ] [ Designated as safety issue: Yes ]
  
• To compare the SUV at up to three target tumor sites as assessed by FDG-PET/CT performed at baseline and then after every three cycles of treatment with dacarbazine [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
  
• To determine the overall tumor metabolic response as assessed by FDG-PET/CT performed at baseline and then after every three cycles of dacarbazine [ Time Frame: response ] [ Designated as safety issue: No ]
  
• To correlate the tumor metabolic response to dacarbazine as assessed by PET/CT with the tumor anatomic response rate by RECIST criteria performed after every three cycles of dacarbazine [ Time Frame: response to treatment ] [ Designated as safety issue: No ]
  
• To determine the overall disease control rate by RECIST criteria to dacarbazine given until disease progression [ Time Frame: response to treatment ] [ Designated as safety issue: No ]
  
• To determine the time-to-progression and overall survival in patients treated with dacarbazine [ Time Frame: disease progression and overall survival ] [ Designated as safety issue: No ]
  
• To correlate the overall best tumor metabolic response to dacarbazine as assessed by FDG-PET/CT and to correlate the overall best tumor anatomic response to dacarbazine by RECIST criteria to TTP and OS [ Time Frame: response to treatment ] [ Designated as safety issue: No ]
  

The two reasons why dacarbazine was eliminated from treatment options for patients with metastatic sarcoma included inability to effectively address the drug's major toxicities (emesis and neutropenia) and the prevailing opinion that the drug was less effective than other chemotherapeutic agents.

Specific Aim #1: The primary endpoint of this study is to determine the overall best tumor anatomic response rate (CR- complete response, PR - partial response, SD - stable disease, or PD - progressive disease) to dacarbazine given until disease progression as assessed by RECIST criteria using CT and clinical examination in patients with metastatic sarcoma.

The prevailing opinion that dacarbazine was less effective than other chemotherapeutic agents in this setting was not based on data from controlled randomized clinical trials. Indeed, we are not aware of a single randomized trial that was conducted and reported which compared the anti-tumor activity of single agent dacarbazine to that of other active single agents in this patient population. However, phase two trials clearly established that dacarbazine had anti-tumor activity in the treatment of metastatic sarcoma, and our personal experience at this institution has confirmed that this is true. In addition, randomized trials demonstrated that the addition of dacarbazine to doxorubicin increased tumor response rates over doxorubicin alone.12 The literature supports the conclusion that dacarbazine has anti-tumor activity in the treatment of metastatic sarcoma.

Historically, in most studies, tumor response to dacarbazine was assessed by WHO criteria. However, current assessment of tumor response usually is based on RECIST criteria, which differ from the WHO criteria, as shown:

Studies have not been performed to determine the tumor anatomic response rate of single agent dacarbazine using RECIST criteria. This study will determine the tumor anatomic response rate as assessed by RECIST criteria to dacarbazine in patients with metastatic sarcoma. Modern methods of CT scans will be used to assess tumor response which contrasts with the earlier methods to assess tumor response to dacarbazine used in most of the published reports. These methods included physical examination and conventional X-ray or first generation, lower resolution CT scans. The current methods of radiologic assessment of tumor response are superior to those used over 15 years ago. The latest generation of CT scans more accurately measure and image a tumor mass, which may better assess tumor response to therapy.

Specific Aim #2: To determine the overall risk of nausea/emesis (any grade) and neutropenia (grade 3 or 4) with dacarbazine when given with current antiemetic agents (5-hydroxytryptamine-3 serotonin antagonist, dexamethasone, and aprepitant) and with pegfilgrastim.

Historically, dacarbazine-induced toxicities such as emesis and myelosuppression were common and led to significant dose reductions and delays which could have negatively impacted the drug's anti-tumor activity. When dacarbazine was initially identified as a potentially effective agent for the treatment of sarcoma, the anti-emetic drugs available had limited efficacy. Also, there were no measures available to prevent chemotherapy-induced neutropenia. Today, there are very effective drugs that can prevent and reduce the frequency of both chemotherapy-induced emesis and neutropenia.

Dacarbazine carries the risk of emesis (all grades) of >90% of cases when administered without antiemetics13. A three-drug anti-emetic combination of a 5-hydroxytryptamine-3 serotonin antagonist, dexamethasone, and aprepitant is the current recommendation from ASCO when administering highly emetogenic chemotherapy drugs13. Hesketh, et al reported that the risk of emesis (all grades) following highly emetogenic chemotherapy (cisplatin) and pre-medication with this three drug anti-emetic regimen was 27% compared to a two drug regimen of ondansetron and dexamethasone in which the risk was 48% (p< 0.001)14.

Prior studies showed that the risk of grade 3 or 4 neutropenia following dacarbazine given without granulocyte- colony stimulating factors was 36%15. Granulocyte- colony stimulating factors (pegfilgrastim or neupogen) are effective agents in preventing chemotherapy-induced neutropenia. Crawford, et al showed in a randomized trial that risk of chemotherapy- induced grade four neutropenia was one day with G-CSF compared to six days with placebo15. Subsequent randomized trials showed equivalent efficacy of pegfilgrastim compared with neupogen16. Vogel, et al reported in a phase three double blinded randomized trial of patients with breast cancer receiving docetaxel 100 mg/m2 that pegfilgrastim compared to placebo reduced the incidence of febrile neutropenia ( 1% vs 17%, p< 0.001) and febrile neutropenia-related hospitalization (1% vs 14%, p< 0.001)17.

In this trial, we hypothesize that the implementation of these newer anti-nausea agents (5-hydroxytryptamine-3 serotonin antagonist, dexamethasone, and aprepitant) and granulocyte-colony stimulating factor (pegfilgrastim) as a primary prophylactic strategy will reduce the frequency of dacarbazine-induced nausea/emesis (any grade) and neutropenia (grade 3 or 4).

Specific Aim #3: To compare the SUV at up to three target tumor sites and to determine the overall tumor metabolic response (complete metabolic response, partial metabolic response, stable metabolic disease or progressive metabolic disease (CMR, PMR, SMD, or PMD) as assessed by FDG-PET/CT performed at baseline and then after every three cycles of treatment with dacarbazine.

Studies have not been performed to determine the changes in FDG uptake by PET imaging following dacarbazine in patients with metastatic sarcoma. There is limited published data about changes in FDG uptake by PET imaging following other chemotherapy agents in patients with metastatic sarcoma. However, there is an emerging body of data showing the prognostic impact of early tumor response to targeted agents (imatinib or sunitinib) as assessed by FDG-PET in patients with metastatic GIST18. In this trial, we will determine the tumor metabolic response to dacarbazine as assessed by FDG-PET/CT and correlate this to the tumor anatomic response as assessed by CT scans.