Please select the eligibility criteria that correspond to the clinical trial below.
Title: Localized High-Risk Soft Tissue Sarcomas Of The Extremities And Trunk Wall In Adults: An Integrating Approach Comprising Standard Vs Histotype-Tailored Neoadjuvant Chemotherapy
Brief Summary: This is a randomized Phase III clinical trial in the setting of localized high-risk soft tissue sarcomas (STS). This study will compare a standard neoadjuvant chemotherapy with epirubicin plus ifosfamide versus a histology-driven chemotherapy, i.e. a chemotherapy tailored to the specific histology within the family of adult STS. Chemotherapy will be administered for 3 cycles. There will be five histological groups (representing 80% of STS), as follows: leiomyosarcoma, myxoid liposarcoma with hypercellularity (round cell MLPS), synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma. The histology-driven chemotherapy for these groups will be, respectively, gemcitabine plus dacarbazine, trabectedin, high-dose ifosfamide, ifosfamide plus etoposide, gemcitabine plus docetaxel. Other histological groups will also be included and registered, but treated only by standard chemotherapy. Patients who have already undergone definitive surgery will receive treatment post-operatively and patients needing a re-excision after inadequate surgery will be treated as patients in the two groups, but of course will not be evaluable for response. A centralized pathological review will be performed. Radiological response will be evaluated according to RECIST and to Choi criteria. Pathological response will also be recorded.

The endpoint will be disease-free survival (DFS) and, secondarily, overall survival (OS) of patients receiving standard chemotherapy versus those receiving histotype-tailored chemotherapy. Additional aims will be to compare the probability of response of standard vs histotype-tailored chemotherapy and to determine the radiological and pathological response with standard chemotherapy vs tailored chemotherapy in each different histological group. Another aim will be to validate the response (both radiological and pathological) to preoperative chemotherapy as a surrogate endpoint for DFS and OS.

Three hundred patients will be randomized over a 3-years period, from a pool of 400-450 registered patients.

Translational research will be performed. Areas of research will include identification and validation of the potential predictive markers for each histological subgroups.

The study is designed to verify the statistical hypothesis that histotype-tailored approach is associated, overall, with a 30% reduction in the hazard of relapse. However, in each different histological group, the effect of histotype-tailored chemotherapy, as compared to standard chemotherapy, can be different. To address this weakness an orthogonal study of response to chemotherapy as a surrogate of DFS and OS has been introduced into the trial. This study intends to extensively investigate the response (radiological and pathological) to preoperative chemotherapy and to validate it as a surrogate endpoint by showing that it correlates with disease free survival and overall survival.


Options:
A: Inclusion Criteria:

* Endoscopically and histologically confirmed cancer of esophagus
* Progressive dysphagia caused by esophageal cancer, and the dysphagia grade of level Ⅲ or level Ⅳ\[STOOLER stand\]
* In barium meal of esophagus, severe stricture of the cancer make the barium difficult to pass through and the superior normal esophagus broaden
* The bulk and shape of the oesophageal cancer displayed by CT three-dimensional reconstruction
* Patients with clear consciousness，Cooperation，ECOG performance status of 0,1 and 3
* Informed consent: authorization and signature

Exclusion Criteria:

* Poor general status,ECOG performance status of 4,
* Dysphagia not caused by esophageal cancer,
* Noncooperation or no authorization and signature.
* The superior border of cancer higher than the seventh cervical vertebrae
* Ulcerative esophageal carcinoma
* Esophageal fistulas,
* WBC less than 3000/mm3

  * Severe hepatic inadequacy or renal inadequacy,
B: Inclusion Criteria:

1. Soft tissue sarcoma of adults, primary or locally recurrent, with spindle-cell or pleomorphic histology, belonging to one of the following for the randomization (Group1):

   myxoid-Round Cell liposarcoma (cellular component \>5 %), leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheat tumor, undifferentiated pleomorphic sarcoma (ex Malignant fibrous histiocytoma)

   Or belonging to one of the following for the registration (Group 2):

   myxofibrosarcoma, unclassified Spindle Cell, pleomorphic liposarcoma, pleomorphic rabdomiosarcoma Or belonging to either group but not being evaluable for response (re-excision after previous inadequate resection or primary definitive surgery) (Group3).

   The histological diagnosis must be made according to the WHO criteria and will have to be centrally reviewed before randomization.
2. High malignancy grade: grade 3 of 3, according to Coindre, or grade 2 at biopsy with a radiological evidence of more than 50% of necrosis in the tumor mass.
3. Deep seated extremities, girdles and/or superficial trunk (thoracic or abdominal wall)lesion.
4. Size of primary tumor (visible or previously inadequately resected) \>5 cm at instrumental staging (CT, MRI), or locally recurrent of any size.
5. Age \> 18 years.
6. ECOG performance status \<1.
7. Adequate bone marrow function:

   WBC \>3.500/mm3 neutrophil \>1.500/mm3 platelets \>150.000/mm3 hemoglobin \>11 g%.
8. Adequate renal (creatinine \<1.3 mg%), and hepatic function (bilirubin \<1.5 mg% and transaminases \<2 x n.v. If ALP \> 2.5 x ULN, ALP LF and/or GGT \< ULN).
9. Adequate cardiac function (FE \>50%).
10. Signed informed consent.
11. Complete compliance of the participating center with the protocol requirements.

Exclusion Criteria:

1. Pregnancy or lactation.
2. Distant metastasis.
3. Other malignancies within past 5 years, with the exception of carcinoma in situ of cervix and basocellular skin cancers treated with eradicating intent.
4. Sarcoma histotypes other than those mentioned in the inclusion criteria.
5. Prior CT and/or RT.
6. Serious psychiatric disease that precludes informed consent or limits compliance.
7. Medical disease limiting survival to less than two years, limiting compliance or which in the physician's opinion might interfere significantly with the toxicity of the treatments.
8. Cardiovascular diseases resulting in a New York Heart Association Functional Status \> 2.
9. Uncontrolled bacterial, viral or fungal infection.
10. Impossibility of ensuring adequate follow-up.
11. Failure to comply with the requirements of the present protocol leading to exclusion of the participating center.
C: Inclusion Criteria:

* Histologically proven, unresectable, locally advanced or metastatic liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) or leiomyosarcoma. Participants must have a pathology report indicating the diagnosis of liposarcoma or leiomyosarcoma that has been reviewed by the sponsor before randomization may occur
* Treated in any order with at least: an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen
* Measurable disease at baseline in accordance with RECIST Version 1.1
* Pathology specimens (example \[e.g.\], tumor blocks or unstained slides) for potential centralized pathology review and biomarker studies
* ECOG Performance Status score of 0 or 1
* Adequate recovery from prior therapy, all side effects (except alopecia) have resolved to Grade 1 or less according to the National Cancer Institute - Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 4.0
* Adequate organ function as evidenced by the following peripheral blood counts or serum chemistry values: hemoglobin 9 gram per deciliters (g/dL), absolute neutrophil count (ANC) 1,500/L, platelet count 100,000/L, serum creatinine 1.5\*the upper limit of normal (ULN), creatine phosphokinase (CPK) 2.5 Upper Limit of Normal \[ULN\]
* Adequate hepatic function as evidenced by the following serum chemistry values: total bilirubin, ULN. If total bilirubin is greater than (\>) ULN, measure indirect bilirubin to evaluate for Gilbert's syndrome (if direct bilirubin is within normal range, participant may be eligible) ALP 2.5 x ULN; Trabectedin: if the ALP is \>2.5 x ULN, then an ALP liver fraction or 5-nucleotidase must be obtained and ULN, AST and ALT 2.5 ULN
* Negative pregnancy test (urinary or serum beta-HCG) at screening (applicable to women of child bearing potential who are sexually active)
* Female participants must be postmenopausal (no spontaneous menses for at least 2 years), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent (at the discretion of the investigator), or if sexually active, be practicing an effective method of birth control. Male participants must agree to use an adequate contraception method as deemed appropriate by the investigator (e.g., vasectomy, double-barrier, partner using effective contraception) and to not donate sperm for a minimum of 5 months after treatment discontinuation

Optional Extension Phase (OEP) Phase:

* Documentation for inclusion criteria histologically proven, unresectable, locally advanced or metastatic liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) or leiomyosarcoma. Participants must have a pathology report indicating the diagnosis of liposarcoma or leiomyosarcoma that has been reviewed by the sponsor before randomization may occur and treated in any order with at least: an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen do not need to be reviewed by the Sponsor
* Collection of the specimen: Pathology specimens (example (e.g.), tumor blocks or unstained slides) for potential centralized pathology review and biomarker studies is not applicable
* Documentation of inclusion criteria adequate organ function as evidenced by the following peripheral blood counts or serum chemistry values: hemoglobin 9 gram per deciliters (g/dL), absolute neutrophil count (ANC) 1,500/L, platelet count 100,000/L, serum creatinine 1.5\*the upper limit of normal (ULN), creatine phosphokinase (CPK) 2.5\*ULN and adequate hepatic function as evidenced by the following serum chemistry values: total bilirubin, ULN. If total bilirubin is greater than (\>) ULN, measure indirect bilirubin to evaluate for Gilbert's syndrome (if direct bilirubin is within normal range, participant may be eligible) ALP \<= 2.5\*ULN; Trabectedin: if the ALP is \>2.5\*ULN, then an ALP liver fraction or 5-nucleotidase must be obtained and ULN, AST and ALT 2.5 ULN will be reviewed by the Sponsor before enrollment in the OEP may occur

Exclusion Criteria:

* Potential participants who meet any of the following criteria will be excluded from participating in the study: Prior exposure to trabectedin or dacarabazine, less than 3 weeks from last dose of systemic cytotoxic therapy, radiation therapy, or therapy with any investigational agent, other malignancy within past 3 years. Exceptions: basal or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, or Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage 1 carcinoma of the cervix
* Known central nervous system metastasis
* Known significant chronic liver disease, such as cirrhosis or active hepatitis (potential participants who test positive for hepatitis B surface antigen or hepatitis C antibodies are allowed provided they do not have active disease requiring antiviral therapy)
* Myocardial infarct within 6 months before enrollment, New York Heart Association Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities
* Uncontrolled intercurrent illness including, but not limited to, poorly controlled hypertension or diabetes, ongoing active infection, or psychiatric illness/social situation that may potentially impair the participant's compliance with study procedures
* Unwilling or unable to have a central venous catheter
* Known allergies, hypersensitivity, or intolerance to trabectedin, dacarbazine, dexamethasone, or their excipients
* Pregnant or breast-feeding
* Any condition that, in the opinion of the investigator, would compromise the well-being of the participant or the study or prevent the participant from meeting or performing study requirements

OEP phase:

* Potential participants who meet any of the following criteria will be excluded from Participating in the study: Prior exposure to trabectedin, less than 3 weeks from last dose of systemic cytotoxic therapy, radiation therapy, or therapy with any investigational agent, other malignancy within past 3 years. Exceptions: basal or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, or Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage 1 carcinoma of the cervix does not apply
* Treated in any order with at least: an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen with less than 3 weeks from last dose of systemic anticancer therapy, radiation therapy, or therapy with any investigational agent
* Known allergies, hypersensitivity, or intolerance to dacarbazine does not apply
D: DISEASE CHARACTERISTICS:

* Histologically proven soft tissue sarcoma that is amenable to definitive surgery no more than 8 weeks after biopsy or inadequate surgery

  * Eligible subtypes:

    * Alveolar soft part sarcoma
    * Angiosarcoma
    * Fibrosarcoma
    * Leiomyosarcoma
    * Malignant fibrous histiocytoma
    * Liposarcoma (round cell and pleomorphic)
    * Miscellaneous sarcoma (including pelvic mixed mesodermal tumors)
    * Malignant paraganglioma
    * Neurogenic sarcoma
    * Rhabdomyosarcoma
    * Synovial sarcoma
    * Unclassifiable sarcoma
  * Ineligible subtypes:

    * Chondrosarcoma
    * Dermatofibrosarcoma
    * Embryonal rhabdomyosarcoma
    * Ewing's sarcoma
    * Kaposi's sarcoma
    * Liposarcoma (myxoid and well differentiated)
    * Malignant mesothelioma
    * Neuroblastoma
    * Osteosarcoma
* Confirmed high-grade tumor (i.e., Trojani Grade II or III)
* No metastases on staging with chest x-ray and thoracic CT scan
* No regional lymph node involvement
* Locally recurrent disease allowed

  * Interval of 3 months or more between definitive surgery and recurrence

PATIENT CHARACTERISTICS:

Age:

* 16 to 69

Performance status:

* WHO 0-1

Life expectancy:

* Not specified

Hematopoietic:

* WBC greater than 4,000/mm\^3
* Platelet count greater than 120,000/mm\^3
* No bleeding disorders

Hepatic:

* Bilirubin no greater than 1.25 times normal
* No severe hepatic dysfunction

Renal:

* Creatinine less than 1.6 mg/dL OR
* Creatinine clearance greater than 60 mL/min

Cardiovascular:

* No clear history of angina
* No documented myocardial infarction
* No existing cardiac failure

Other:

* No serious infection
* No other malignancy except adequately treated carcinoma in situ of the cervix or basal cell or squamous cell skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Not specified

Chemotherapy:

* No prior systemic chemotherapy

Endocrine therapy:

* Not specified

Radiotherapy:

* No prior radiotherapy to affected area

Surgery:

* See Disease Characteristics

Answer: B