Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Bochner BH, Sjoberg DD, Laudone VP. A randomized trial of robot-assisted laparoscopic radical cystectomy. N Engl J Med 2014;371: DOI: /NEJMc

2 This supplement contains the following items: 1. Original protocol, including original statistical analysis plan 2. Final protocol, including final statistical analysis plan 3. Summary of amendments

3 MEMORIAL SLOAN-KETTERING CANCER CENTER A Prospective, Randomized Trial Comparing Robotic and Open Radical Cystectomy MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL Principal Investigaor/Department: Vincent Laudone, MD Dept. of Surgery-Urology Service Co-Principal Investigator(s)/Department: Bernard Bochner, MD Dept. of Surgery-Urology Service Investigator(s)/Department: Bertrand D. Guillonneau, MD Jonathan Coleman, MD Guido Dalbagni, MD S. Machele Donat, MD Harry Herr, MD Raul Parra, MD Paul Russo, MD Jaspreet Sandhu, MD Karim Touijer, MD Angel Cronin, MS Andrew Vickers, PhD Victor Reuter, MD Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Epidemiology- Biostatistics Dept. of Epidemiology- Biostatistics Dept. of Pathology Consenting Professional(s)/Department: Approved: Vincent Laudone, MD Bernard Bochner, MD Bertrand D. Guillonneau, MD Jonathan Coleman, MD Guido Dalbagni, MD S. Machele Donat, MD Harry Herr, MD Raul Parra, MD Paul Russo, MD Jaspreet Sandhu, MD Abdelkrim Touijer, MD Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Dept. of Surgery-Urology Service Please Note: A Consenting Professional must have completed the mandatory Human Subjects Education and Certification Program. Memorial Sloan-Kettering Cancer Center 1275 York Avenue Page 1 of 28

4 MEMORIAL SLOAN-KETTERING CANCER CENTER New York, New York Approved: Page 2 of 28

5 MEMORIAL SLOAN-KETTERING CANCER CENTER Table of Contents 1.0 PROTOCOL SUMMARY AND/OR SCHEMA OBJECTIVES AND SCIENTIFIC AIMS BACKGROUND AND RATIONALE OVERVIEW OF STUDY DESIGN/INTERVENTION Design Intervention THERAPEUTIC/DIAGNOSTIC AGENTS CRITERIA FOR SUBJECT ELIGIBILITY Subject Inclusion Criteria Subject Exclusion Criteria RECRUITMENT PLAN PRETREATMENT EVALUATION TREATMENT/INTERVENTION PLAN EVALUATION DURING TREATMENT/INTERVENTION TOXICITIES/SIDE EFFECTS CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT CRITERIA FOR REMOVAL FROM STUDY BIOSTATISTICS RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES Research Participant Registration Randomization DATA MANAGEMENT ISSUES Quality Assurance Data and Safety Monitoring PROTECTION OF HUMAN SUBJECTS Privacy Serious Adverse Event (SAE) Reporting INFORMED CONSENT PROCEDURES Research Authorization REFERENCES APPENDICES Approved: Page 3 of 28

6 MEMORIAL SLOAN-KETTERING CANCER CENTER 1.0 PROTOCOL SUMMARY AND/OR SCHEMA This is a prospective, randomized study comparing robotic-assisted radical cystectomy (RARC), pelvic lymph node dissection and urinary diversion to open radical cystectomy (ORC), pelvic lymph node dissection and urinary diversion for bladder cancer. Our primary aim is to compare the perioperative morbidity, defined as intraoperative and 90 day postoperative complications, between the two techniques. The secondary aims are to assess the pathologic findings at surgery and bladder cancer recurrence outcomes after RARC and ORC. The patient population involves 210 patients with bladder cancer. We expect to enroll 4 patients per month to each treatment arm until we achieve an accrual of at least 105 patients per arm. 2.0 OBJECTIVES AND SCIENTIFIC AIMS Aim 1: To compare surgical complications of robotic-assisted radical cystectomy and open radical cystectomy. Primary Endpoints: a) Perioperative grade 2 to 5 complications (MSKCC grading system) Aim 2: To examine clinical and pathological outcomes of robotic-assisted radical cystectomy and open radical cystectomy. Secondary Endpoints: a) Intra-operative performance (surgical time, blood loss) b) Pathologic findings, including the stage specific, soft tissue surgical margin rate and number of lymph nodes removed. c) Bladder cancer recurrence (local, upper tract and distant disease) The primary efficacy analysis will be based on aim 1a, with the outcome of perioperative grade 2 to 5 complications. We hypothesize that the robotic-assisted procedure will be associated with a lower rate of complications and similar oncologic outcomes. 3.0 BACKGROUND AND RATIONALE Invasive bladder cancer is a potentially lethal disease and one of the single most costly cancers to treat. The primary treatment modality, radical cystectomy (RC) with pelvic lymph node dissection (PLND) and urinary diversion, can be associated with a high rate of perioperative morbidity in the typical elderly patient with bladder cancer. Managing severe complications in patients with significant comorbidities is associated with considerable cost and intense utilization of valuable hospital resources. Incorporation of emerging technologies that potentially decrease perioperative complications, while maintaining a similar ability to control the disease, would provide significant patient benefit and substantial cost savings. Approved: Page 4 of 28

7 MEMORIAL SLOAN-KETTERING CANCER CENTER Advanced surgical robotic technologies hold great promise in advancing patient care and have rapidly been introduced into use for both benign and malignant conditions. Compared with open surgery, robotic assistance allows for tenfold magnification of the surgical field, scaling of motion by 50% to 70%, elimination of hand tremor, smaller instrumentation for easier manipulation within confined spaces, the hemostatic tamponade of a pneumoperitoneum, and the ability to perform surgery through small external incisions. It is presumed that by the use of robotic assistance, surgical efficacy can be maintained while providing decreased morbidity and improved patient outcomes.(1, 2) Given the added expense, can the use of robotic assistance be justified? Currently, there is a large information gap between the presumed benefits of robotic surgery and prospective data that establish its incremental benefits. Significant market pressure, largely driven by patient perception and direct seller-to-purchaser interaction, has accelerated clinical use of the robot. While improvements in patient care have been reported by both clinicians and vendors, the data justifying the use of this technology remain scant, largely as a result of the paucity of level 1 evidence and the plethora of non-comparative or poorly comparative series.(3, 4) Current open RC techniques represent the standard of care and provide excellent cancer control for patients with organ-confined and extravesical invasive bladder cancer (80% and 60% 5-year progression-free survival, respectively), and even for a significant minority of patients with concomitant lymph node involvement (30% 5-year progression-free survival).(5, 6) Introducing a new technique that might compromise cancer control, could not only increase the need for secondary treatments, such as systemic chemotherapy, but also ultimately prove fatal for the patient. The need for additional treatments, with their associated toxicities, may result in substandard care and would certainly negate any patient benefit or cost-savings related to the surgical procedure. Surgical Complications The surgical treatment of bladder cancer at highly experienced centers is associated with perioperative complications in 64% of patients (intraoperative and 90-day postoperative). (7, 8) Careful and meticulous reporting of adverse events is critical to understanding the impact of surgery on the perioperative recovery experience of patients who require this life-saving operation. Researchers at MSKCC have set the standard for the evaluation of perioperative surgical outcomes and quality-of-life assessment for surgical patients through the development of the MSKCC Surgical Adverse Events program, including a comprehensive surgical complications database, which captures all patient care events rendered through the hospital s Clinical Information System. The currently available literature for robotic cancer surgery is characterized by conflicting reports that either expound the superiority of robotic surgery or fail to demonstrate any incremental benefits over conventional techniques. There are no well-controlled comparative studies powered to substantiate either claim. Information on improved outcomes is available mainly from singleinstitution reports of highly select patients, where poor or no control groups are used for comparison with the gold standard of open surgery.(3, 9) Morbidity data in favorable subgroups selected for initial robotic experience are compared to morbidity of overall, non-select open surgical series, Approved: Page 5 of 28

8 MEMORIAL SLOAN-KETTERING CANCER CENTER yielding a biased view of outcomes. Additionally, experience with open surgery is generally more limited among the robotic surgeons, who have published their findings; thus comparison to their open outcomes may not accurately represent the expected outcomes from more experienced surgeons performing open surgery in high-volume centers. This is particularly relevant given the documented association between surgeon volume/experience and morbidity/mortality outcomes for RC.(10) In an attempt to evaluate the feasibility and complication rates of the robotic RC, some possible advantages over the open surgery have been shown by recent studies, as shown in tables 1 and 2. Although no improvement in operative time, decrease in blood loss, complications, and hospital stay were encountered. (11, 12) Table 1 Prospective non-randomized trial comparing open versus robotic radical cystectomy Elhage et al., Abstract EAU 2008 (11) Table 2 Prospective randomized trial comparing open versus robotic radical cystectomy Nix et al., Abstract AUA 2009 (12) Pathologic Findings Several refinements in the technique and extent of surgery over the past few years have resulted in markedly better outcomes, and have demonstrated how the quality of cystectomy and lymph node dissection affects outcomes. A thorough PLND is an essential component of an RC. Twenty-five percent of patients with muscle-invasive disease will have metastatic lymph nodes at the time of cystectomy. Some patients with invasive bladder cancer, involving the regional lymph nodes, will be Approved: Page 6 of 28

9 MEMORIAL SLOAN-KETTERING CANCER CENTER rendered disease-free following a RC and thorough PLND. Given the important prognostic information provided by node status, accurate staging of the regional lymph nodes is of significant clinical importance. The surgical technique should not be a factor in determining the completeness of nodal dissection. A patient who undergoes a limited lymph node dissection may be under-staged due to limited sampling, while a more extensive lymph node dissection will provide a greater degree of confidence that appropriate nodal staging has been achieved. Herr et al evaluated measures of surgical quality using data from the recently reported Southwest Oncology Group, randomized, phase III, cooperative group trial (SWOG 8710, INT-0080). On multivariate analysis, the most important negative factors were whether the surgical margins were positive and whether fewer than 10 lymph nodes were removed.(13) Lymph node dissection and surgical margins have been addressed in several recent articles. The median number of nodes removed, ranged from 16 to 19, while studies evaluating open cases, varied from 11 to 43 nodes. Surgical margins had a wide variation between the two techniques, with open surgery showing 4.2% to 5.1% positive rate and 0 to 10.4% in the robotic series (Table 3) Table 3 Pathologic findings of open and robotic radical cystectomy Reference ORC/ LRC/ RRC No. Patients Positive Margins n (%) No. Nodes Retrieved median (range) Positive Nodes n (%) Dotan et al(14) ORC (4.2) 11 (1-66) 288 (24) Yossepowitch et al(15) ORC /214 (5.14) 97 (20.08) Madersbacher et al(16) ORC (24) Konety et al(17) ORC LND (40), 1-10 LND (37.8) Leissner et al(18) ORC (27.9) Stein et al(19) ORC (24) Dasgupta et al(3) RRC (6-28) 2 (10) Guru et al(20) RRC 58 6 (10.4) 18 (6-43) Murphy et al(9) RRC (+/-8) 2 (8.7) Pruthi et al(21)/pruthi and Wallen(22) RRC (8-37) 10 (20) Wang et al(4) RRC 33 2 (6.1) 17 (6 32) 6 (19) Oncologic Outcomes Approved: Page 7 of 28

10 MEMORIAL SLOAN-KETTERING CANCER CENTER Despite promising results when analyzing perioperative variables, concern with the oncologic outcome is still to be determined. Studies, with short-term follow-up of 1 to 2 years, have demonstrated comparable results to open surgery. Approved: Page 8 of 28

11 MEMORIAL SLOAN-KETTERING CANCER CENTER Table 4 Oncologic Outcomes of Open versus Robotic Techniques Reference ORC/ LRC/ RRC Months follow-up, mean (range) Upper Local Tract Recurrence Recurrence n (%) n (%) Distant Mets n (%) OS n (%) CSS n (%) RFS n (%) Dotan et al(14) ORC (3.6) 358 (22.5) 1049 (66) Yossepowitch et a(15) ORC 23 (4.7) 19 (3.9) 62 (12.8) 136 (84) Madersbacher et al(16) ORC 45 ( ) 40 (7.9) 3 (5.9) 179 (35.3) 304 (59) 364 (71.8) 314 (62) Konety et al(17) ORC 63 (0-131) 0 LND (32-66), >10 LND (39-100) Stein et al(19) ORC 120 (0-336) 77 (7) 234 (22) 695 (66) 717 (68) Hautmann et al(23) ORC 34 (0-242) 34 (3.13) a 30 (2.8) a Dasgupta et al(3) RRC 23 (7-44) 0 1 (5) 1 (5) 19 (95) 18 (90) Murphy et al(9) RRC 17 (4-40) (8.7) 22 (95.6) 22 (95.6) 21 (91.3) Pruthi et al(21)/pruthi and Wallen(22) RRC 13.2 (2-24) 0 2 (4) 7 (14) 45 (90) 47 (94) 43 (86) The unique and comprehensive nature of our study could have a major influence on how robotic technology is incorporated into the management of bladder cancer. From a healthcare systems and resources standpoint, this study may have a major impact given that: a) bladder cancer is the 4th most common tumor in men in the US; b) the reservoir of patients with bladder cancer is substantial, with an estimated 500,000 patients in the US and 800,000 patients in Europe; and c) bladder cancer is one of the most costly tumors to manage on a per-patient basis. Approximately 25% of the 67,000 new cases of bladder cancer each year, in the US, are invasive at presentation and optimally managed by RC.(24) An additional 15% of non-muscle invasive tumors will progress despite initial conservative therapy and require RC. This study will serve two major purposes. First, it will obtain comprehensive and accurate prospective documentation on the surgical complications, pathological findings, and recurrence rate associated with the management of bladder cancer, using both open and robotic techniques. This will allow a contemporary comparison to open surgery at a major cancer center that has extensive experience in the surgical management of bladder cancer. Second, the design of this study has the potential to serve as the model for which future controlled, prospective, comparative analyses, involving new technology in general and robotic surgery in particular will be based. Thus, the Approved: Page 9 of 28

12 Approved: MEMORIAL SLOAN-KETTERING CANCER CENTER communities affected by this study include, the population of patients with bladder cancer undergoing RC, as well as the substantially larger population of surgical patients with both cancerous and noncancerous disease, for which incorporation of new technology is under active consideration. 4.0 OVERVIEW OF STUDY DESIGN/INTERVENTION 4.1 Design This is a prospective, randomized study designed to compare two techniques of radical cystectomy with PLND (open and robotic) for bladder cancer. Surgical complications (intraoperative and the immediate 90-day postoperative period), pathology findings and recurrences will be assessed and compared between the two approaches. We expect to enroll 4 patients per month to each treatment arm, to achieve an accrual of at least 105 patients per arm and 210 patients total. 4.2 Intervention The following procedures described, constitute approved methods, which are routinely used in the surgical management of bladder cancer. In this context, clinical evaluation will include physical examination, routine blood analyses, abdominal/pelvic CT scans, chest x-ray, urine cytology, urine culture and examination under anesthesia with cystoscopy and transurethral resection/biopsy of the bladder tumor. The operation for all patients will be a cystectomy with bilateral PLND (open or robotic). For males, the surgical procedure will include wide local excision of all structures that potentially may be involved, including the bladder, prostate, seminal vesicles, and vas deferens. Care will be taken to excise all perivesical and perirectal fat. In women, the bladder, uterus, anterior vaginal wall, fallopian tubes, ovaries, and perivesical and perivaginal fat will be removed. A standard lymph node dissection will be performed, defined by the following boundaries: the proximal-distal aorta, lateralgenitofemoral nerve, distal-circumflex iliac vein, and the lymph node of Cloquet. At least four packets will be sent for pathology, including right and left distal pelvic and right and left common iliac lymph nodes. The urinary diversion will be performed by an open approach in both the open group and in the robotic group. We will utilize a uniform system, including gross description and histologic characterization, to stage and grade all pathologic specimens. All specimens will be examined under the supervision of Victor Reuter, MD, Attending Pathologist at MSKCC and recognized expert in genitourinary malignancies. 5.0 THERAPEUTIC/DIAGNOSTIC AGENTS The U.S. Food and Drug Administration (FDA) has approved the da Vinci Surgical System for adult and pediatric use in urologic surgical procedures, general laparoscopic surgical procedures, gynecologic laparoscopic surgical procedures, general non-cardiovascular thoracoscopic surgical Page 10 of 28

13 MEMORIAL SLOAN-KETTERING CANCER CENTER procedures and thoracoscopically assisted cardiotomy procedures. The da Vinci System may also be employed with adjunctive mediastinotomy to perform coronary anastomosis during cardiac revascularization, according to Intuitive Surgical. According to the manufacturer, today, over 1000 da Vinci Systems are installed in hospitals worldwide. As of December 31, 2007, Intuitive Surgical held exclusive field-of-use as well as nonexclusive licenses for over 200 U.S. patents and over 90 foreign patents, and owned outright over 140 US patents and over 60 foreign patents. Currently, MSKCC has three da Vinci robots, one Si model and two S models, which are used in the main OR rooms by the urology, gynecology, and thoracic services, Monday through Saturday. We are performing approximately 60 cases per month, split between 40% urology, 40% gynecology, and 10% thoracic. Twenty-two surgeons have robotic privileges. 6.0 CRITERIA FOR SUBJECT ELIGIBILITY 6.1 Subject Inclusion Criteria Age > 18 years. Scheduled for radical cystectomy at MSKCC 6.2 Subject Exclusion Criteria Prior pelvic or abdominal radiation therapy; Prior extensive open abdominal surgery, defined by the discretion of the attending surgeon Any clinical contraindication for Trendelenburg positioning 7.0 RECRUITMENT PLAN Urothelial carcinoma affects males more commonly than females (estimated incidence for 1998:39,500 men, 14,900 women). The disease occurs with equal frequency among racial and ethnic groups. Both genders and all racial and ethnic groups will be eligible to participate in this clinical trial, provided all other eligibility criteria are met. Approximately 210 patients will be enrolled in the study. Patients diagnosed with urothelial bladder carcinoma by transurethral resection of the bladder (TURB) who are appropriate candidates for radical cystectomy will be approached by the Urology Service. All newly diagnosed bladder cancer patients seeking treatment at MSKCC will undergo standard evaluation and consultation by one of the department's open urologic bladder cancer surgeons. (designated as the initial surgeon for each patient). Those patients eligible for the protocol will be offered participation. Once informed consent is obtained by the initial surgeon, randomization will occur and patients will be assigned to either 1) open or 2) robotic (plus open diversion) surgery. After randomization to the surgical technique, the surgical team will be assigned as follows (all options designed to maximize patient choice): Approved: Page 11 of 28

14 MEMORIAL SLOAN-KETTERING CANCER CENTER After randomized surgeon assignment will be as follows: If randomized to: - Open surgery, then no change is necessary since the patient will have already met with an open surgeon. This surgeon will perform both the cystectomy and urinary diversion. - Robotic surgery, the open surgeon will remain involved as part of the surgical team. He or she will perform the urinary diversion. He or she will also work with the patient to choose the robotic surgeon. The robotic surgeon will perform the cystectomy and lymph node dissection. The patient will get to choose from among all the robotic surgeons involved in the study. This choice is subject to scheduling availability. 8.0 PRETREATMENT EVALUATION Patients with non-metastatic bladder cancer defined as clinical stage TanyN0M0 tumors will be assessed by the following procedures at MSKCC or outside with review at MSKCC: Complete history and physical bimanual examination Cystoscopy and bladder biopsy (TUR) Abdominal and Pelvic CT scan Chest X-ray Routine blood analyses (CBC/Chemistry panel) Cytology Urine Culture Randomization to RARC or ORC 9.0 TREATMENT/INTERVENTION PLAN Patients will be randomized to open radical cystectomy, pelvic lymph node dissection and open urinary diversion, or robotic radical cystectomy, pelvic lymph node dissection and open urinary diversion. The urinary diversion technique to be utilized will be at the discretion of the surgeon and patient. The urinary diversion will be performed by open technique in the open group and in the robotic group. None of the techniques that will be utilized in this study are considered experimental., but open radical cystectomy is currently the standard procedure performed here at MSKCC for the treatment of bladder cancer. Robotic radical cystectomy is routinely performed by robotically trained and experienced minimally invasive surgeons. Approved: Page 12 of 28

15 MEMORIAL SLOAN-KETTERING CANCER CENTER The operating team will consist of 1 or more of 10 surgeons on faculty at the MSKCC Department of Surgery, Urology Service. Five surgeons will perform robotic-assisted RC and five surgeons will perform open RC. Any of the 5 open surgeons may also perform the reconstruction procedure (diversion) for either the robotic or open cystectomy group. The minimally invasive surgeons are: Vincent Laudone, Bertrand D. Guillonneau, Jonathan Coleman, Raul Parra, and Karim Touijer. The open surgeons are Jaspreet Sandhu, Bernard Bochner, Guido Dalbagni, S. Machele Donat, and Harry Herr. All of these surgeons have agreed to participate in the recruitment and randomization procedure specified in section 7. It is the expectation that those surgeons currently performing robotic surgery will perform the robotic radical cystectomies within the study population, and those surgeons currently performing open surgery, will perform the open radical cystectomies within the study population. It is conceivable that there may be cross over in these roles in the future, but such cross over would be allowed only at the discretion of the principle investigator. To minimize the impact of the learning curve on outcomes, surgeons in the open RC arm must have previously performed a minimum of one hundred open RC in order to participate in the protocol and surgeons in the robotic RC arm must be certified in robotic surgery and have previously performed a minimum of one hundred minimally invasive pelvic operations (laparoscopic, robotic or both) in order to participate in the protocol. We will utilize a uniform system, including gross description and histologic characterization, to stage and grade all pathologic specimens. All specimens will be examined under the supervision of Victor Reuter, MD, Attending Pathologist at MSKCC and recognized expert in genitourinary malignancies. Approved: Page 13 of 28

16 MEMORIAL SLOAN-KETTERING CANCER CENTER 10.0 EVALUATION DURING TREATMENT/INTERVENTION Pre operatively, all patients will have a history and physical examination, complete blood count and chemistry panel, urine cytology, chest x-ray and CT scan of the abdomen and pelvis. All patients will have undergone a diagnostic staging TURBT and the pathology reviewed at MSKCC. The ollowup for patients who undergo radical cystectomy on study will include: PROCEDURES: History and Physical examination 3 Months (+/-1 month) Clinic Visits and Tests Post Surgery 12 Months 18 Months (+/-1 month) (+/-1 month) 24 Months (+/-1 month) X X X X Abdominal and Pelvic CT Scan* X X X Chest X-ray* X X CBC (complete blood count), Chemistry panel X X X X Urine Sample/ cytology X X X X *Abdominal and Pelvic CT scan and Chest X-ray may be requested at any point if abdominal or pulmonary complication are suspected by the attending physician After 24 months, the follow-up will continue indefinitely, as part of the routine post-operative care for bladder cancer patients TOXICITIES/SIDE EFFECTS Careful and meticulous reporting of adverse events is critical to understanding the impact of surgery on the perioperative recovery experience of patients who require this operation. The complications database here at MSKCC captures both medical and surgical complications. All complications within 90 days of surgery are defined, categorized, and classified by an established 5-grade stratified modification of the Clavien system.(25) The definition of each complication grade is described in table 5 and specific complications expected to occur are listed in table 6. Approved: Page 14 of 28

17 MEMORIAL SLOAN-KETTERING CANCER CENTER Data is currently entered prospectively by all medical professionals involved in a patient s care through the electronic medical record. Disease and treatment specific records are captured with methods in place to continually cross-check and validate the collection of data, including dedicated research study assistants to help enter and/or manage data entry, monthly audits, and intermittent retrospective chart review for confirmation. Patients undergoing robotic-assisted RC at MSKCC are tracked in an identical manner as those who undergo conventional open RC procedures. Patients are also managed under identical, standardized care pathways, by a highly trained clinical team experienced in the unique care required by these cases. Day-to-day care and clinical parameters are prospectively entered into the Clinical Information System and can be used for supplemental data. Table 5 MSKCC Complication grades and definitions. Dindo et al.,(25) Shabsigh et al.(7) Approved: Page 15 of 28

18 MEMORIAL SLOAN-KETTERING CANCER CENTER Table 6 Most common complications and frequency related to open radical cystectomy. Shabsigh et al.(7) Approved: Page 16 of 28

19 MEMORIAL SLOAN-KETTERING CANCER CENTER 12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT Perioperative complications are defined as any complication graded in the MSKCC grading system occurring during the intraoperative and 90-day postoperative period. The intraoperative period is defined as the period from anesthesia induction to final skin closure. The postoperative period is defined as the period from final skin closure to 90 days following the date of radical cystectomy. For patients who experience more than 1 perioperative complication, the perioperative complication with the highest grade will be used for the purposes of the primary endpoint of grade 2-5 perioperative complications. Immediate perioperative morbidity is defined as any complication graded in the MSKCC grading system occurring during the initial hospital stay. Surgical time is defined as the length of time from anesthesia induction to final skin closure. Blood loss is defined as the estimate accounted from the suction device during the surgical procedure, as noted in the anesthesia record. Intraoperative complications are defined as any complications related to either surgical or clinical aspects during the procedure, as described by the surgeon. Bladder cancer recurrence is defined as any recurrence, local or distant, as diagnosed by imaging studies (CT or Chest X-ray) or biopsy. Local recurrence is defined as any pelvic recurrence diagnosed by imaging studies or biopsy. Upper tract recurrence is defined as: any evidence of tumor diagnosed in the urinary tract (renal pelvis or ureter) by imaging studies or biopsy. Distant disease is defined as: any evidence of tumor diagnosed by imaging studies or biopsy at any distant sites other than the above. Conversion is defined as interruption of the robotic procedure followed by continuation of the surgery through an open technique. It will be considered an intra-operative complication grade 3 ( operation required to treat an event ), since the MSKCC complications grading system is based on the treatment related to the adverse event and not on the complication itself CRITERIA FOR REMOVAL FROM STUDY Patients will have the right to withdraw consent at any time prior to surgery, even after randomization is performed. Patients who decline their randomization treatment assignment will receive standard open radical cystectomy and will be analyzed according to intention to treat. The Principal Investigator may also remove the subject from study, if the patient presents with disease progression to systemic disease prior to surgery, which would render the subject ineligible to radical cystectomy (eg. lung metastasis). Approved: Page 17 of 28

20 14.0 BIOSTATISTICS MEMORIAL SLOAN-KETTERING CANCER CENTER This is a prospective randomized trial of open radical cystectomy versus robotic radical cystectomy. Patients will be randomized 1:1 to either arm according to section 15.2, stratifying on age (<65 versus >=65) and ASA (1/2 versus 3/4). The analysis will be conducted according to intention to treat, with the following exception: patients who are randomized but who do not have radical cystectomy will not be analyzed. Patients will have routine clinical postoperative followup, which is standardized for both treatment arms. The primary efficacy analysis will be based on primary aim 1, with the outcome of perioperative grade 2 to 5 complications. It is possible that the type of urinary diversion would have an impact on complications. In order for urinary diversion to be a randomization stratification variable, the type of urinary diversion would need to be specified before the patient was randomized to open or robotic radical cystectomy. Since this is not practical from a clinical standpoint, urinary diversion will not be a randomization stratification variable. Instead, urinary diversion will be accounted for in the data analysis as specified in section Primary Aims 1) To test the hypothesis that the rate of grade 2-5 perioperative complications is lower for patients receiving robotic-assisted RC compared to patients receiving open RC. Based on historical data, the rate of grade 2-5 perioperative complications with open RC is approximately 50%. We expect the rate of grade 2-5 perioperative complications to decrease to 30% with robotic-assisted RC. In other words, we expect that the rate of grade 2-5 perioperative complications will be 20% lower in absolute terms for robotic-assisted RC compared to open RC. An absolute difference of 20% was chosen because this would be considered a clinically meaningful difference between groups. The rate of grade 2-5 perioperative complications will be estimated separately for each group. The absolute difference in the rate of grade 2-5 perioperative complications between groups will be estimated, along with a 95% confidence interval, with stratification by the randomization strata and urinary diversion Sample Size Justification The null hypothesis is that the grade 2-5 perioperative complication rate is equivalent for both groups (that is, the grade 2-5 perioperative complication rate in both groups is 50%). The alternative hypothesis is that the difference in grade 2-5 postoperative complication rates between groups is 20% (that is, the grade 2-5 perioperative complication rate is 50% in the open RC group and is 30% in the robotic-assisted RC group). For a study with 93 patients in each arm and a 5% two-sided type I error rate, the power to reject the null hypothesis is 80% if the alternative hypothesis is true. Due Approved: Page 18 of 28

21 Approved: MEMORIAL SLOAN-KETTERING CANCER CENTER to the interim analysis (stopping for futility), we will accrue a total of 105 patients in each arm so that the power of the study is 80% Secondary Aims The secondary aims are descriptive in nature, and the results will be used to generate hypotheses for future studies. 1. To test the hypothesis that intra-operative performance (surgical time, blood loss, intraoperative complications) is better for patients receiving robotic-assisted RC compared to patients receiving open RC. The mean surgical time and blood loss will be estimated separately for each group. The mean difference in these quantities between groups will be estimated using linear regression, with the randomization strata and urinary diversion as covariates. Intra-operative complications will be analyzed in a similar fashion as grade 2-5 perioperative complications. 2. The soft tissue surgical margin rate will be calculated for each treatment group, overall and separately by pathologic stage. 3. The number of lymph nodes removed will be described for each treatment group using medians and interquartile ranges. Defining an adequate lymph node dissection as removing at least 10 lymph nodes, we will calculate the proportion of patients with an adequate lymph node dissection for each treatment group. 4. Postoperative outcomes (bladder cancer recurrence, and local, upper tract, and distant disease) will be estimated using Kaplan-Meier survival estimates and Cox regression, with the randomization strata as covariates. The sites of distant disease will be summarized. Most recurrences occur within the first 2 years following radical cystectomy. To ensure adequate follow-up, this analysis will be conducted 1 year after the final patient is accrued. For all endpoints, exploratory analyses will be conducted to examine the effects of clustering within surgeon Interim Analysis We will conduct an interim analysis when 50 patients in each arm have been accrued and have a minimum of 90 days of followup. We anticipate that this will occur at approximately 15 months following the start of patient accrual. With the data from these 100 patients, we will calculate the upper bound of a one-sided 95% confidence interval for the difference in the rate of grade 2-5 complications between groups (rate in the open RC arm minus the rate in the robotic-assisted RC arm). If the upper bound is less than or equal to 20%, then the study will be stopped for futility. If the true difference between groups is 20%, then the probability of stopping early is approximately 5%; if the true difference between groups is 0%, indicating no difference in grade 2-5 complications between groups, then the probability of stopping early is approximately 60% Study Accrual Page 19 of 28

22 MEMORIAL SLOAN-KETTERING CANCER CENTER We expect to enroll 4 patients per month to each treatment arm. The expected time to complete study accrual is 30 months RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 15.1 Research Participant Registration Confirm in the electronic medical record that the patient has received the Notice of Privacy Practice. This must be obtained before the eligibility confirmation and obtaining of the research informed consent. Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. Obtain written informed consent, by following procedures defined in section entitled Informed Consent Procedures. All participants must be registered through the Protocol Participant Registration (PPR) Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 5:30pm at The PPR fax numbers are (646) and (646) Registrations can be phoned in or faxed. The completed signature page of the informed consent form, the completed signature page of the Research Authorization and a completed Eligibility Checklist must be faxed to PPR. During the registration process registering individuals will be required to answer specific eligibility questions and provide the following information: Registering Individual Notice of Privacy Status Research Authorization MSKCC IRB Protocol# Attending of Record (if applicable) Consenting Professional Informed Consent Date Participant s Full Name Participant MRN [Last, First Name] [Yes, No, N/A] [Date] [Last, First Name] [Last, First Name] [Last, First Name] 15.2 Randomization Randomization will be conducted by the Clinical Research Database (CRDB) at Memorial Sloan-Kettering Cancer, stratifying on age (<65 versus >=65) and ASA (1/2 versus 3/4) in randomly permuted blocks. This study will not be blinded DATA MANAGEMENT ISSUES A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA include project compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the activities of Approved: Page 20 of 28

23 MEMORIAL SLOAN-KETTERING CANCER CENTER the protocol study team. The RSA will enter the minimal data set into CRDB. The data collected for this study will be entered into a secure database. Source documentation will be available to support the computerized patient record Quality Assurance Weekly registration reports will be generated to monitor patient accruals and completeness of registration data. Routine data quality reports will be generated to assess missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be monitored periodically throughout the study period and potential problems will be brought to the attention of the study team for discussion and action Random-sample data quality and protocol compliance audits will be conducted by the study team, at a minimum of two times per year, more frequently if indicated Data and Safety Monitoring The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were approved by the National Cancer Institute in September The plans address the new policies set forth by the NCI in the document entitled Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical Trials which can be found at: The DSM Plans at MSKCC were established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: There are several different mechanisms by which clinical trials are monitored for data, safety and quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, compliance and data verification audits, therapeutic response, and staff education on clinical research QA) and departmental procedures for quality control, plus there are two institutional committees that are responsible for monitoring the activities of our clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center s Research Council and Institutional Review Board. During the protocol development and review process, each protocol will be assessed for it s level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the monitoring procedures will be established at the time of protocol activation 17.0 PROTECTION OF HUMAN SUBJECTS Approved: Page 21 of 28

24 MEMORIAL SLOAN-KETTERING CANCER CENTER This protocol/project does not include children because the number of children is limited and because the majority is already accessed by a nationwide pediatric cancer research network. This statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects. The subjects will be responsible for all charges associated with the items that are part of the routine clinical care. The subjects will not be compensated for their participation. If the patient is injured as a result of being in this study, emergency care, hospitalization, and outpatient care will be made available by the hospital and billed to the patient and his insurance company as part of his medical expenses. Every effort will be made to keep study records private. No identifiers will be used in any reports or publications resulting from this study, but the data will be used in the interests of the ongoing research. If the patient desires additional information about the consent process, research patients rights, or research-related injury, he or she may call the Patient Representatives Office at (212) Study Risks: Since the recent studies have shown beneficial findings with fewer complications and shorter recovery time with the robotic procedure, the main risks of being randomized to undergo robotic cystectomy is related to the lack of long term follow-up for oncologic outcome. (11, 12) Benefits: Patients who undergo robotic radical cystectomy may experience a 20% to 40% reduction in the complication rates, as well as shorter hospital stay and recovery time. (11, 12) Alternative treatment: Other treatment options for muscle-invasive bladder cancer are radiotherapy and chemotherapy. However, the results of these treatments are very poor, not being considered curative options at this point Privacy It is the responsibility of the Research Staff to ensure that protocol subjects received the Center s Notice of Privacy Practices. If the subject has not received one, MSK personnel must provide a Notice of Privacy Practices and obtain acknowledgment before the subject participates in the study. MSKCC s Privacy Office may allow the use and disclosure of protected health information pursuant to a completed and signed Research Authorization form. The use and disclosure of protected health information will be limited to the individuals described in the Research Authorization form. A Research Authorization form must be completed by the Principal Investigator and approved by the IRB and Privacy Board (IRB/PB) Serious Adverse Event (SAE) Reporting Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. The IRB/PB requires a Clinical Research Database (CRDB) AE report to be delivered Approved: Page 22 of 28

25 MEMORIAL SLOAN-KETTERING CANCER CENTER to the Institutional SAE Manager (307 East 63rd Street, 1st Floor) containing the following information: Fields populated from CRDB: Subject s name (generate the report with only initials if it will be sent outside of MSKCC) Medical record number Disease/histology (if applicable) Protocol number and title Data needing to be entered: The date the adverse event occurred The adverse event Relationship of the adverse event to the treatment (drug, device, or intervention) If the AE was expected The severity of the AE The intervention Detailed text that includes the following o A explanation of how the AE was handled o A description of the subject s condition o Indication if the subject remains on the study o If an amendment will need to be made to the protocol and/or consent form. The PI s signature and the date it was signed are required on the completed report INFORMED CONSENT PROCEDURES Participation in the study will be offered to all male and female patients who satisfy the enrollment criteria. Prior to study entry, the consenting professional will explain to each potential subject the research objectives, risks and benefits of study participation, alternative treatments available, and the subject s rights and responsibilities. Patients will be required to sign a statement of informed consent that meets the requirements of the code of Federal Regulations. Signing an informed consent and a HIPAA Authorization is a pre-requisite for participation in this study. Informed consent will be obtained by a member of the MSKCC staff designated to obtain the informed consent. The investigator will review the overall objectives, rationale and design of the study. He or she will explain the study protocol. At the same time, the confidentiality of data processing will be emphasized. The investigator will also discuss the alternatives available to the participant, including not participating in the study; the potential benefits and risks of this program and the probability of their occurrence; as well as the procedures to minimize these risks. The provisions available to ensure medical intervention should an adverse event occur will also be reviewed. Reasons why the risks are reasonable in relation to the anticipated benefits, incentives, costs that will or may be incurred as a result of participation in the study and efforts to maintain Approved: Page 23 of 28

26 MEMORIAL SLOAN-KETTERING CANCER CENTER confidentiality will also be discussed. If the patient is willing to participate, informed consent is obtained. The patient will sign three copies of the informed consent: one copy will be given to the patient to keep, one copy will become part of the patient s medical record, and one copy will be stored in the patient s research file. Approved: Page 24 of 28

27 MEMORIAL SLOAN-KETTERING CANCER CENTER 18.1 Research Authorization Procedures for obtaining Research Authorization: Before any protocol-specific procedures are carried out, investigators and/or designated staff will fully explain the details of the protocol, study procedures, and the aspects of patient privacy concerning research specific information. In addition to signing the IRB Informed Consent, all patients must sign the Research Authorization component of the informed consent form. The Research Authorization requires a separate set of signatures from the patient. The original signed documents will become part of the patient s medical record, and each patient will receive a copy of the signed documents. Approved: Page 25 of 28

28 MEMORIAL SLOAN-KETTERING CANCER CENTER 19.0 REFERENCES 1. Guru KA, Nyquist J, Perlmutter A and Peabody JO. A robotic future for bladder cancer? 2008 Lancet Oncol 9: Hemal AK. Role of robot-assisted surgery for bladder cancer Curr Opin Urol 19: Dasgupta P, Rimington P, Murphy D, Challacombe B, Hemal A, Elhage O and Khan MS. Robotic assisted radical cystectomy: short to medium-term oncologic and functional outcomes Int J Clin Pract 62: Wang GJ, Barocas DA, Raman JD and Scherr DS. Robotic vs open radical cystectomy: prospective comparison of perioperative outcomes and pathological measures of early oncological efficacy BJU Int 101: Dalbagni G, Genega E, Hashibe M, Zhang ZF, Russo P, Herr H and Reuter V. Cystectomy for bladder cancer: a contemporary series J Urol 165: Bochner BH, Kattan MW and Vora KC. Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer J Clin Oncol 24: Shabsigh A, Korets R, Vora KC, Brook CM, Cronin AM, Savage C, Raj G, Bochner BH, Dalbagni G, Herr HW and Donat SM. Defining Early Morbidity of Radical Cystectomy for Patients with Bladder Cancer Using a Standardized Reporting Methodology Eur Urol 8. Donat SM, Shabsigh A, Savage C, Cronin AM, Bochner BH, Dalbagni G, Herr HW and Milowsky MI. Potential Impact of Postoperative Early Complications on the Timing of Adjuvant Chemotherapy in Patients Undergoing Radical Cystectomy: A High-Volume Tertiary Cancer Center Experience Eur Urol 9. Murphy DG, Challacombe BJ, Elhage O, O'Brien TS, Rimington P, Khan MS and Dasgupta P. Robotic-assisted laparoscopic radical cystectomy with open urinary diversion: initial experience Eur Urol 54: Birkmeyer JD, Stukel TA, Siewers AE, Goodney PP, Wennberg DE and Lucas FL. Surgeon volume and operative mortality in the United States N Engl J Med 349: Elhage O, Keejan J, Challacombe B, Murphy D, Rimington P, Khan MS and Dasgupta P. A Comparative Analysis of Open, Laparoscopic and Robotic Radical Cystectomy for Bladder Cancer Eur Urol Suppl 7: Nix J, Coward M, Smith A, Kurpad R, Schultz H, Nielsen M, Wallen EM and Pruthi RS. Prospective Randomized Trial Of Open Versus Robotic-Assisted Laparoscopic Radical Cystectomy For Bladder Cancer: Interim Results J Urol 181: 377. Approved: Page 26 of 28

29 MEMORIAL SLOAN-KETTERING CANCER CENTER 13. Herr HW, Faulkner JR, Grossman HB, Natale RB, devere White R, Sarosdy MF and Crawford ED. Surgical factors influence bladder cancer outcomes: a cooperative group report J Clin Oncol 22: Dotan ZA, Kavanagh K, Yossepowitch O, Kaag M, Olgac S, Donat M and Herr HW. Positive surgical margins in soft tissue following radical cystectomy for bladder cancer and cancer specific survival J Urol 178: ; discussion Yossepowitch O, Dalbagni G, Golijanin D, Donat SM, Bochner BH, Herr HW, Fair WR and Russo P. Orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence J Urol 169: Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R and Studer UE. Radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy J Clin Oncol 21: Konety BR, Joslyn SA and O'Donnell MA. Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the Surveillance, Epidemiology and End Results Program data base J Urol 169: Leissner J, Ghoneim MA, Abol-Enein H, Thuroff JW, Franzaring L, Fisch M, Schulze H, Managadze G, Allhoff EP, el-baz MA, Kastendieck H, Buhtz P, Kropf S, Hohenfellner R and Wolf HK. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study J Urol 171: Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D and Skinner DG. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients J Clin Oncol 19: Guru KA, Sternberg K, Wilding GE, Tan W, Butt ZM, Mohler JL and Kim HL. The lymph node yield during robot-assisted radical cystectomy BJU Int 102: 231-4; discussion Pruthi RS, Stefaniak H, Hubbard JS and Wallen EM. Robotic anterior pelvic exenteration for bladder cancer in the female: outcomes and comparisons to their male counterparts J Laparoendosc Adv Surg Tech A 19: Pruthi RS and Wallen EM. Is robotic radical cystectomy an appropriate treatment for bladder cancer? Short-term oncologic and clinical follow-up in 50 consecutive patients Urology 72: ; discussion Hautmann RE, Volkmer BG, Schumacher MC, Gschwend JE and Studer UE. Long-term results of standard procedures in urology: the ileal neobladder World J Urol 24: Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ. Cancer statistics, CA Cancer J Clin 58: Approved: Page 27 of 28

30 MEMORIAL SLOAN-KETTERING CANCER CENTER 25. Dindo D, Demartines N and Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey Ann Surg 240: APPENDICES Not Applicable Approved: Page 28 of 28

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