Phase II Trial of Cytoreduction + Hyperthermic Intraperitoneal Mitomycin-C+ Standard Systemic Therapy In Patients With Peritoneal Carcinomatosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Completeness of Cytoreduction
研究概览
简要总结
This is a clinical study investigating the new treatment of surgery combined with intraperitoneal mitomycin-C for patients with gastrointestinal cancer that has spread to the peritoneal (abdominal cavity) surface. Mitomycin-C to be used in this procedure is approved by the U.S. Food and Drug Administration (FDA)for many different cancers including gastrointestinal cancer. Giving mitomycin C via the intraperitoneal route is not FDA approved and is an investigation therapy. Cytoreductive surgery plus intraperitoneal chemotherapy can be offered as standard of care outside of a clinical trial. However, since this is an unproven and potentially more effective but a more toxic approach, the investigators are performing this procedure under an IRB approved clinical trial in order to better evaluate the risks and benefits of this approach.
A standardized, evidence-based approach is currently lacking for patients with peritoneal surface malignancy from gastrointestinal origin. A clinical trial with surgical quality assurance and modern hyperthermic intraperitoneal chemotherapy incorporating critical assessment of disease burden, determinants of complete cytoreduction, treatment-related toxicity, quality of life and survival is imperative. Theoretically, cytoreductive surgery is performed to treat macroscopic disease, and hyperthermic intraperitoneal chemotherapy is used to treat microscopic residual disease with the objective of removing disease completely in a single procedure.
详细描述
Patients with peritoneal surface malignancy from gastrointestinal (GI) cancers almost uniformly succumb to advanced locoregional disease in the form of intractable ascites, malignant visceral obstruction and cancer cachexia. The natural history of peritoneal carcinomatosis from GI malignancies is inexorably lethal with median overall survival of approximately 5 months 7, as patients with disease confined to the peritoneum remain at increased risk of synchronous occult hematogenous metastases. While systemic therapy improves outcome in patients with hematogenous disease spread, improvements are needed in the control of peritoneal surface malignancy, which is known to be relatively resistant to systemic agents owing principally to the presence of a peritoneal-plasma partition. Moreover, the results of surgical resection alone for peritoneal dissemination of GI cancer have been disappointing given the difficulty in clearing surgically all microscopic disease foci. The infusion of chemotherapy into the peritoneal cavity provides distinct pharmacokinetic advantages. The addition of hyperthermia potentiates the effect of intra-peritoneal chemotherapy through anti-tumor synergism, without systemic drug absorption.
Mitomycin- C is the cytotoxic agent of choice for this purpose, one that has been studied most extensively for hyperthermic intra-peritoneal chemotherapy in patients with peritoneal carcinomatosis of gastrointestinal origin. Mitomycin- C has also been shown to demonstrate consistent pharmacokinetics, favorable toxicity profile, and hyperthermia-facilitated tumor cytotoxicity, which is enhanced under conditions of tumor hypoxia; furthermore, Mitomycin- C contributes to improved outcomes after optimal cytoreduction. Hence, the delivery of intra-peritoneal heated chemotherapy has the advantage of dose-dense regional delivery of cytotoxic agents with relatively little systemic toxicity. Current clinical experience suggests that adding cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy to modern systemic chemotherapy regimens may significantly improve oncological outcomes.
The Montefiore-Einstein Center for Cancer Care has an on-going cooperative Cancer Bio-specimen Repository and correlative/translational research program to identify prognostic factors for patients with malignant tumors, as well as factors predictive of response to and toxicity of treatment. To support this important scientific work, tissue block submission [primary tumor and peritoneal surface malignancy] along with serum specimens will be mandatory for all patients providing informed consent for bio-specimen submission so that complete tissue microarrays (TMA) may be studied. These inquiries will establish molecular profiles of biomarkers of prognostic and predictive value in patients with gastrointestinal carcinomatosis undergoing treatment in the context of this trial.
The primary endpoint for analysis is to evaluate the technical parameters including completeness of cytoreduction, achievement of hyperthermia, morbidity and mortality in patients with peritoneal carcinomatosis undergoing CRS and hyperthermic intraperitoneal chemotherapy (HIPEC) with Mitomycin- C. Patients who have satisfied the inclusion criteria will be taken to the operating room for exploration and cytoreductive surgery. We will record the completeness of cytoreduction (CC 0 - CC 3) as described below. Complete cytoreduction will be defined as a CC 0 or CC 1. Ability to achieve adequate hyperthermia will be defined as target intraperitoneal temperature of 41-43º C. Adverse events will be assessed through enrollment following study treatment. The severity of adverse events will be evaluated using NCI-CTCAE version 4. Adverse events which are assessed as possibly, probably, or definitely related to study treatment will be followed until the AE is resolved or the subject is clinically stable. Other safety data including physical examinations, vital signs, hematology, clinical chemistry, and urinalysis will be collected from time of informed consent signed up through subject discontinuation or 12 months after initial study treatment, whichever occurs first.
For every multi-modality (CRS-HIPEC) case, the following will be required in the context of this clinical trial:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Capable of providing informed consent.
- •The patient who has not previously received hyperthermic intraperitoneal chemotherapy must have histopathologically or cytologically confirmed cancer of colorectal, appendiceal, peritoneal mesothelioma, pseudomyxoma or gastric origin with known synchronous or metachronous disease dissemination limited to the peritoneal surfaces.
- •The patient must have documented disease limited to the peritoneal surface, amenable to complete cytoreduction indicated by:
- •Disease confined to the peritoneal surfaces
- •No parenchymal liver metastases
- •No evidence of clinical, biochemical or radiological biliary obstruction
- •Small volume of disease in the gastro-hepatic ligament defined by a < 5cm mass in the epigastric region on cross-sectional imaging
- •No clinical or radiological evidence of hematogenous or distant nodal metastasis
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
- •Absolute neutrophil count (ANC) > 1200/mm3, white blood cell count (WBC) > 4000/mm3 and platelet count > 150,000/mm3
- •An international normalized ratio (INR) ≤ 1.5 (patients who are therapeutically anticoagulated for unrelated medical conditions such as atrial fibrillation and whose antithrombotic treatment can be withheld for operation will be eligible).
- •Adequate hepatic function must be met as evidenced by total serum bilirubin ≤ 1.5 mg/dl (patients with total bilirubin > 1.5 mg/dL eligible only with Gilbert's syndrome);
- •alkaline phosphatase < 2.5 times the upper limit of normal; and/or
- •AST < 1.5 times upper limit of normal (alkaline phosphatase and AST cannot both exceed the upper limit of normal
- •Serum renal functional parameters, blood urea nitrogen (BUN) and creatinine are within normal limits
- •Satisfactory cardiopulmonary function (no history of severe congestive heart failure or severe pulmonary disease, as indicated by clinically acceptable risks to undergo major abdominal - cytoreductive surgery).
- •Patients who have met the above criteria and who have undergone CRS and HIPEC in the past 18 months for the beforementioned disease processes without evidence of recurrence will be eligible for participation in this study for analyzing ability to achieve complete cytoreduction, morbidity, progression and survival.
排除标准
- •The patients have documented disease beyond the peritoneal surfaces, which prevent achieving complete cytoreduction as indicated by:
- •Evidence of distant hematogenous metastatic disease or distant nodal metastases
- •Evidence of parenchymal hepatic metastases
- •Evidence of clinical, biochemical or radiological biliary obstruction
- •Evidence of gross disease of the small bowel mesentery characterized by distortion, thickening or loss of mesenteric vascular clarity which limits ability to obtain complete cytoreduction
- •Significant history of a medical problem or co-morbidity that would preclude the patient from undergoing a major abdominal operation such as a history of severe congestive heart failure or active ischemic heart disease.
- •Active systemic infections, coagulation disorders, or other major medical illnesses precluding major surgery.
- •Childs B or C cirrhosis or with evidence of severe portal hypertension by history, endoscopy or radiologic studies.
研究组 & 干预措施
HIPEC + Mitomycin C
HIPEC + 40mg of Mitomycin C. Mitomycin C, 30 mg, will be administered into the inflow line of the perfusion circuit once target temperature is reached. At the 60 minute time point of the perfusion, Mitomycin C, 10 mg, will be administered into the inflow line of the perfusion circuit. Once the 90-minute perfusion period has elapsed, the perfusate will be drained into the waste reservoir. The peritoneal cavity will be rinsed/washed-out.
干预措施: HIPEC (Procedure)
HIPEC + Mitomycin C
HIPEC + 40mg of Mitomycin C. Mitomycin C, 30 mg, will be administered into the inflow line of the perfusion circuit once target temperature is reached. At the 60 minute time point of the perfusion, Mitomycin C, 10 mg, will be administered into the inflow line of the perfusion circuit. Once the 90-minute perfusion period has elapsed, the perfusate will be drained into the waste reservoir. The peritoneal cavity will be rinsed/washed-out.
干预措施: Mitomycin C (Drug)
结局指标
主要结局
Completeness of Cytoreduction
时间窗: Up through study discontinuation or 12 months after study treatment, whichever occurs first
Completeness of cytoreduction will be estimated and recorded using a complete cytoreduction (CC) which corresponds to a residual disease (RR) score. Completeness of Cytoreduction (CC) scores range from CC0 - CC3 and correlate to residual disease as follows: CC0 = R0: No Disease, complete removal of all visible tumor with negative cytology or microscopic margin CC1 = R1: \<= 0.25 cm; complete removal of all visible tumor with positive cytology or microscopic margin CC2 = R2a: 0.25-2.5 cm; minimal residual tumor, nodule(s) ≤ 0.5 cm CC3 =R2b: \>=2.5 cm; gross residual tumor, nodule(s), \> 0.5, but ≤ 2 cm CC3 =R2c: \>=2.5 cm; extensive disease remaining, nodule(s) \> 2 cm
Perioperative and Postoperative Morbidity and Mortality
时间窗: Up to 30 days following surgery
Perioperative and Postoperative morbidity and mortality will be determined in patients with peritoneal carcinomatosis of colorectal, gastric, appendical, pseudomyxoma peritonei and peritoneal mesothelioma origin undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with Mitomycin- C. The number of peri/postoperative deaths up to 30 days following the time of surgery will be recorded.
次要结局
- Progression-free Survival (PFS)(Up to 5 years)
- Overall Survival (OS)(Up to 5 years)