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Clinical Trials for the California Digestive Diseases Institute
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Principle Investigators
Dr. Ian G. Renner
Dr. Manouchehr Adeli-Sardo
Dr. Leland Foshag
Dr. Patricia Gordon
Dr. Leonid Kleynberg
Dr. Vera Kleynberg
Dr. Levon Qasabian
Dr. Mehrdad Vosoghi
Dr. Clifford Merlo
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Inquiries to:
Ian Renner, M. D.
5901 W. Olympic Blvd. Suite #300
Los Angeles, CA. 90036
310.556.7747
Fax: 310.556.7757
e-mail: CDDI@olympiamc.com
Clinical Trial
A clinical trial for pancreatic cancer using IMRT and a-Interferon-Based Adjuvant Chemoradiation in patients status-post whipple for resectable cancer of the pancreas and in patients with localized unresectable tumors of the head of the pancrease
California Digestive Diseases Institute of Olympia Medical Center
PRINCIPAL INVESTIGATOR: IAN G. RENNER, M. D.
PANCREATIC CANCER PROTOCOL
I. OBJECTIVES ^-top
We aim to analyze the effect of (a) adding a-interferon to our current chemotherapeutic regimen in patients with resected and unresected localized pancreatic cancer and (b) the efficacy of Intensity Modulated Radiation Therapy (IMRT) in reduction of morbidity as compared to EBRT will also be evaluated.
II. INTRODUCTION/BACKGROUND ^-top
The purpose of this prospective trial is to determine the benefit of a novel adjuvant chemo-radiation protocol, which includes alpha interferon and Intensity Modulated Radiation Therapy (IMRT) in patients with adenocarcinoma of the head of the pancreas. Two groups of patients with pancreatic cancer will be studied: a) patients status post Whipple resection and b) patients with unresectable but localized pancreatic cancer.
Since a randomized prospective trial with a non-treated control group is impossible because of patient refusal, it is therefore necessary and even desirable to use combined chemotherapy and external beam radiation therapy patient data as reference controls.
Radiation therapy alone affords poor local control, morbidity and poor long-term survival for locally unresectable, partially resectable or even resectable pancreatic carcinoma. After external radiation beam therapy with, or without surgery, the median survival time is less than eighteen months (1).
In the 1980’s patients with adenocarcinoma of the head of the pancreas had a less than 10%, five-year survival after pancreaticoduodenectomy (1,2,3). The failure of surgical resection to cure this disease has been attributed to residual tumor left at the time of resection. Circulatory tumor cells in the blood are present in about 25% of patients with pancreatic cancer and clearly increase with tumor stage (4). Not only is disease recurrence systemic, but also local recurrence almost always occurs.
Adjuvant chemoradiation therapy after resection has been associated with increased survival as compared with surgical resection alone (5-10).
In 1987 the Gastrointestinal Tumor Study Group (GITSG) reported improved survival in patients undergoing adjuvant chemo-radiation therapy after pancreatico-duodenectomy for cancer of the head of the pancreas over those receiving surgery alone (5). More recent studies have supported the beneficial effect of this adjuvant therapy with reported improved two-year survival rates of 40% (6-10).
However, results with radiation therapy techniques using external beam radiation therapy (EBRT) alone or in combination with chemotherapy are less than desirable. Major deterrents to EBRT are the limited dose tolerances of the liver, duodenum, small intestine, stomach, and spinal cord. These structures are all in close relationship to the pancreas, and inside the external beam field.
Patient tolerance to EBRT is a distinct limiting factor because of the almost universal presence of nausea, vomiting, diarrhea and fatigue. With IMRT the incidence of side effects such as nausea, vomiting, diarrhea, fatigue and the risk of radiation damage to adjacent organs shows is markedly reduced when compared to EBRT (11,12).
The use of Interferon-based adjuvant chemoradiation after pancreatico-duodenectomy for pancreatic adenocarcinoma was recently reported as giving an 84%, 2-year survival and an actuarial, five-year overall survival of 55% with a confidence interval (CI) between 46%-65% (13). These impressive results were tempered by the severe morbidity induced by EBRT in 42% of the patients in this study. In light of these inevitable and severe incidences of side effects from EBRT on dose limiting structures, we are seeking a better treatment option using IMRT.
Although this study did not involve treatment of patients with unresectable localized pancreatic cancer, there is some evidence to suggest that benefit may result, since residual tumor was present in 90% of the recent report of patients undergoing Whipple resection for pancreatic cancer (13).
In 2003 Picozzi et al (13) reported the results of an experimental protocol consisting of 5FU, cisplatin, and a-interferon (IFNa) in conjunction with EBRT. The two-and-a-half-year survival rate was 67%, while the actuarial survival rate for five years was 55% (CI = 46%-65%). While these results are very encouraging, 42% of the patients in this study were hospitalized during chemoradiation, virtually all due to gastrointestinal toxicity.
With the advent of IMRT, the ability to deliver focal radiation to the tumor site, with decreased radiation toxicity to the adjacent organs hopefully allows a new treatment modality to be used in cancer of the pancreas. Additionally, the role of a-interferon and IMRT in adjuvant chemoradiation therapy for unresectable cancer of the pancreas needs to be examined.
III. DESCRIPTION OF STUDY ^-top
A. General:
This is a prospective study for patients with localized pancreatic cancer involving the head of the pancreas, but without evidence of metastases. These patients will be divided into two groups, one group with localized resectable pancreatic cancer and the other group with localized unresectable cancer of the pancreas. Unresectable cancer is defined as tumor involving the head of the pancreas, adjacent lymph nodes, and/or celiac axis vessels.
Resectable cancer is defined as completion of a Whipple procedure regardless of whether adjacent lymph nodes removed at surgery are found to be positive for cancer. Both groups will receive identical chemo-radiation therapy.
The study will be conducted by the California Digestive Diseases Institute at Olympia Medical Center. The expected duration will be 5 years, with overall survival rates being determined at yearly intervals.
Patients with disease in the liver parenchyma or outside the local lymph nodes will be excluded from the study.
B. Study Design:
A total of 30 patients with unresectable but localized cancer of the pancreas will be entered into the study. Similarly a total of 30 patients with resectable pancreatic cancer will be entered into the study.
Prospective patients will be presented at the case conference meeting at the Olympia Medical Center Cancer Center. Once patient suitability is determined and the patient wishes to proceed, he/she will undergo enrollment, and the protocol will be carefully explained to him/her.
All patients will have a spiral CAT scan of the abdomen within 2 weeks prior to commencement of the study to obtain diagnostic staging. A positive tissue diagnosis, obtained by either endoscopy or CT-guided biopsy, will be performed before patient inclusion into either arm of the study. A biopsy report showing histological verification of the tumor must be available. Operability will be determined by CT scan assessment of the presence or absence of localized tumor involvement of the celiac axis. The goals of this study are to try and extend patient longevity, and to hopefully improve the quality of life in this dismal disease.
Interferon-based adjuvant chemoradiation will begin shortly after histological diagnosis in patients with unresectable localized cancer of the head of the pancreas.
Interferon-based adjuvant chemo-radiation will begin 6-8 weeks after Whipple procedure for patients status post resection of cancer of the head of the pancreas.
In both groups the same treatment protocol will be used, consisting of IMRT in doses of 4,500-5,400 cGy (25 fractions over 5 weeks) and 3 drug chemotherapy: continuous infusion of 5-Fu (200 mg/m2 daily, days 1-35), weekly intravenous bolus cisplatin (30 mg/m2 daily, days 1, 8, 15, 22, 29) and subcutaneous alpha, interferon (3 x 106 units, days 1-35). This chemoradiation is followed by continuous infusion of 5-Fu (200 mg/m2 daily, weeks 9-14 and 17-22). In the pancreatic resection group chemoradiation will be initiated 6-8 weeks after surgery.
Once chemoradiation therapy has been completed the patients will be monitored at weekly intervals by CBC and CMP values for 22 weeks. A spiral CT scan of the abdomen will be carried out every 12 weeks for 2 years and every 6 months thereafter. CA 19-9, magnesium, phosphorous, and zinc levels will be monitored every 4 weeks. In the seminal study using the above chemotherapy profile (13), EBRT was the form of radiotherapy used. This type of radiation is associated with considerable GI toxicity, and was the dominant factor in hospitalization of 42% of patients during the Picozzi et al study (13).
The use of IMRT to deliver focal radiation to a circumscribed area of the pancreas should markedly decrease the toxicity, compared to EBRT.
Assessment of response to the treatment will be monitored by observation of changes in tumor size or spread on repetitive CT scans, a documented decrease in blood tumor markers in the non-operated group of patients, and presence or absence of metastatic spread. CT-PET scans will be used at 6-month intervals to help determine if tumor spread has occurred.
IV. PATIENT SELECTION ^-top
A. Study population
Patients with localized pancreatic cancer involving the head of the pancreas, with no evidence of systemic metastases.
B. Inclusion criteria
1) Histologically documented cancer of the head of the pancreas.
2) Pancreatic cancer localized to the head of the pancreas and local lymph nodes in the resectable group.
3) Pancreatic cancer localized to the head of the pancreas, local lymph nodes, and/or celiac axis involvement in the unresectable group.
4) Karnovsky performance of 80 or greater.
5) No prior chemo-radiation.
6) CCR, EKG, and lab tests, all within acceptable limits.
7) Signed consent and Human Subject Rights form.
C. Exclusion Criteria
1) Tumor metastatic to liver parenchyma or beyond the local regional lymph nodes.
2) Prior radiation to pancreatic region.
3) Karnovsky Performance status of less than 80.
4) Significant abnormality of CXR, EKG, or lab results that place the patient at undue risk, rather than benefit.
5) Pregnancy or lactation.
6) Male patients unwilling to use a barrier method of conception.
7) Illness that would prevent patient from adhering to treatment program, or inability to give or understand informed consent.
8) An expected life expectancy of less than three months.
9) Other co-existing malignancy.
V. STUDY PROCEDURES ^-top
B. Pre-Study
1) Complete medical history.
2) Evaluation by radiation oncologist, oncologist, gastroenterologist oncologic surgeon, and any other specialty indicated by the patient’s condition.
3) Complete physical examination.
4) Spiral CT scan of abdomen and pelvis.
5) Clinical laboratory tests to include the following: CBC, CMP, PT, PTT, UA, CA 19/9, CEA.
6) CXR and EKG.
7) Pregnancy test where applicable.
8) Signed consent form and Human Subjects Bill of Rights.
C. Study Procedures
1) Commencement of IMRT five days per week for five weeks.
2) Commencement of chemoradiation regimen in both study groups.
3) Weekly lab tests, CBC, and CMP for 22 weeks, followed by repeat tests at 4 weekly intervals.
4) Spiral CT of abdomen and pelvis at 12-week intervals.
5) CA 19-9, magnesium, phosphorous, and zinc will be monitored every 4 weeks.
Patient response will be determined by reduction or no progression of tumor size on CT scan and/or the appearance of metastases in the patient with unresectable cancer of the pancreas.
Patient response in the patients S/P resection of the cancer of the pancreas will be determined by the absence of regional tumor growth and/or appearance of metastases.
D. Patient Response
The aim of this study is to evaluate the effectiveness of Interferon-based adjuvant chemoradiation in the patient with inoperable localized cancer of the pancreas and also in the patient S/P Whipple resection for localized cancer of the head of the pancreas.
In addition we aim to evaluate the incidence of radiation toxicity from IMRT as compared to EBRT.
Quality of life will be monitored by Karnofsky index (see below), which should give valuable information with respect to the effectiveness of IMRT as compared to EBRT (13).
Survival will be measured by mortality statistics and median survival time.
Kanofsky Performance Status Scale:
100% No symptoms
90% Able to carry on normal activity; minor signs or symptoms of disease
80% Able to carry on normal activity with effort; some signs or symptoms of disease
70% Cares for self, unable to carry on normal activity or do active work
60% Requires occasional assistance but is able to care for most of own needs
50% Requires considerable assistance and frequent medical care
40% Disabled; requires special care and assistance
30% Severely disabled; hospitalization indicated, although death not imminent
20% Very ill; hospitalization necessary; active supportive treatment required
10% Moribund, fatal processes progressing rapidly
0 Patient expired
VI. EARLY TERMINATION/WITHDRAWAL FROM STUDY ^-top
A patient will be removed from the study for any of the following reasons and the reason for removal will be clearly specified on the patient’s case record form.
1) Patient request.
2) Physician’s medical judgment that continuation of treatment would be detrimental to him/her..
VII. POSSIBLE RISKS/COMPLICATIONS TO SUBJECTS ^-top
The risks involved in the treatment of these patients are those attendant with chemo-radiation, namely nausea, vomiting, GI toxicity, hair-loss, anemia, infections, pulmonary reactions to cisplatin and thrombocytopenia.
VIII. POSSIBLE BENEFITS TO SUBJECTS ^-top
The possible benefits of the treatment protocol over current treatment models are: a) the ability of IMRT to deliver high-density radiation to a specific target, thus reducing acute and late-occurring, radiation-induced toxicity and b) an increase in longevity using a-interferon-based, adjuvant chemoradiation therapy.
I X. MANAGEMENT OF INTERCURRENT EVENTS/ADVERSE EVENTS ^-top
A. Departure from Protocol
Only when an emergency occurs that requires a departure from the protocol for an individual patient will there be such a departure and that will be only for that patient.
B. Adverse Experiences
In the event of a serious adverse experience, the experience will be described on the patient’s case record form and source document. Such toxicity will be reported to the IRB. All adverse experiences will be followed to satisfactory resolution.
C. Dropouts
If a patient is discontinued the reason for discontinuation will be documented on the case record form and all termination procedures will be carried out.
X. CASE RECORDING/DOCUMENTATION ^-top
A case record form will be provided and maintained for all study participants. All forms will be completed in black ink. An investigator will sign or initial and date each individual form upon completion. The last page of the case record form must be signed. Correction(s) of data on the case record form must be signed. Corrections of data on the case record form can only be made by crossing out the incorrect data (in a manner that leaves the previous entry identifiable) and correct data will be entered by the individual making the correction/alteration with the individual’s initials and date.
If any changes are made to a case record form after the investigation has signed and dated (e.g. additional data, corrections, classifications) the entry must be initialed and dated by the individual making the entry. If that individual is not the investigator, the investigator must initial and date the bottom of that page to indicate his awareness and agreement with the change.
XI. STATISTICAL ANALYSES/PROCEDURES ^-top
All statistical analyses will be performed by an independent contractor on a yearly basis. Investigators and the clinical nurse coordinator will not be responsible for performing any statistical calculations or estimations. Historical controls will be utilized as a reference. Since the individual patient data for the historical control is not available and the treatment modalities are not identical, the historical control data cannot be used for direct statistical comparison with the study data. Seminal observation against historical controls will be the yearly percentage survival post chemoradiation therapy of both groups.
XII. CONFIDENTIALITY ^-top
The results of the patient’s assessment will be made available to the patient, their primary physician, or to any of the professional whom the patient designates. If the results of this study are published, the patient will be in no way identified. Otherwise all results will be kept confidential and will not be divulged (except as required by law), without the patient’s further permission. During the cause of the study, pictures may be made for release of publications; however, the patient will not be identified.
XIII. COMPLETION OF STUDY ^-top
The investigator will complete and report (submission of case record forms) the study in satisfactory compliance with the protocol within 12 months after completing the last patient.
References:
1. van Heerden JA, ReMine WH, Weiland LH, et al. Total pancreatectomy for ductal adenocarcinoma of the pancreas. Am J Surg 1981;142:308-11.
2. Warren KW, Christophi C, Armendariz R, et al. Current trends in the diagnosis and treatment of carcinoma of the pancreas. Am J Surg 1983;145:813-8.
3. Jones BA, Langer B, Taylor BR. Periampullary tumors: which ones should be resected? Am J Surg 1985;149:46-52.
4. Z’graggen K, Centeno BA, Fernandez-del-Castillo C, et al. Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients. Surgery 2001;129:537-46.
5. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006-10.
6. Foo ML, Gunderson LL, Nagorney DM, et al. Patterns of failure in grossly resected pancreatic ductal adenocarcinoma treated with adjuvant irradiation ± 5 fluorouracil. Int J Radiat Oncol Biol Phys 1993;26:483-9.
7. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997;15:928-37.
8. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. Ann Surg 1997;225:621-36.
9. Whittington R, Bryer MP, Haller DG, et al. Adjuvant therapy of resected adenocarcinoma of the pancreas. Int J Rad Oncol Biol Phys 1991;21:1137-43.
10. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567-79.
11. Hatano K, Narita Y, Araki H Sakai M, et al. 3D-CRT and intensity modulated radiation therapy (IMRT). Gan To Kagaku Ryoho 2003;30(13);2050-5.
12. Penberthy DR, Rich TA, Adams RB, et al. Postoperative adjuvant therapy for pancreatic cancer. Semin Surg Oncol 2003;32(4):256-60.
13. Picozzi VJ, Kozarek RA, Traverso LW, et al. Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. The American Journal of Surgery 2003;185:476-480.
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