CPT-11 For Brain Tumors
CPT -11 (CAMPTOSAR®, Irinotecan) REVIEW
Virginia V. Jory, Ph.D.
Last Updated 9/25/2008 - Note: Also see the Avastin article which mentions the combination of CPT-11 and Avastin!
Note: The supplement Curcumin can inactivate CPT-11. It is possible even the amounts in normal Indian food (it is also uses as a seasoning) may decrease the potency of CPT-11.
Note: The author of this paper is not an M.D. The contents of this paper are based on the listed references and are offered for educational and informational purposes only. Patients should refer to their health care providers for medical advice.
Generic Name: Irinotecan
USA Brand Name: CAMPTOSAR®
Distributed By: Pharmacia & Upjohn
Other Names : CPT-11
Campto (Rhone Puolenc Rorer SA)
In this paper the names CAMPTOSAR®, CPT-11, and irinotecan will be used interchangeably.
Active Ingredient: Irinotecan Hydrochloride 
FDA Approval: Irrinotecan received accelerated approval by FDA in June 1996 for treatment of metastatic colorectal carcinoma that has recurred or progressed after treatment with 5-FU , . Full FDA approval of CAMPTOSAR® was granted in October 1998 for metastatic colorectal cancer which has recurred or spread following treatment with standard chemotherapy .
Classification: Antineoplastic agent  of the topoisomerase I inhibitor class . (Antineoplastic = preventing the development, maturation, or spread of abnormal new growth. Topoisomerase = a type of enzyme converting one topological version of DNA into another.)
Delivery: Irinotecan hydrochloride injection for intravenous use only .
Description: CAMPTOSAR® is supplied as a sterile solution, available in two single-dose sizes: 2-mL vials containing 40 mg irinoteccan hydrochloride and 5-mL vials containing 100 mg irinotecan hydrochloride. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, which is an alkaloid extract from plants including Camptotheca acuminata .
Clinical Actions: CAMPTOSAR® inhibits topoisomerase I, an enzyme that relaxes supercoiled DNA during replication and transcription. Binding of CAMPTOSAR® to this enzyme stabilizes topoisomerase I and DNA. When advancing replication enzymes collide with the drug-topoisomerase-DNA complex, double-stranded DNA breaks occur that result in tumor cell death .
Pharmacokinetics: CAMPTOSAR® is metabolized primarily in the liver into its active metabolite, SN-38, which demonstrates potent inhibition of the enzyme topoisomerase I in laboratory tests .
Drug Interactions: "The adverse effects of CAMPTOSAR®, such as myelosuppression (myelo = bone marrow) and diarrhea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects. Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of CAMPTOSAR®. The concurrent administration of CAMPTOSAR® with irradiation has not been adequately studied and is not recommended. Lymphocytopenia (a reduction in the number of lymphocytes in the circulating blood) has been reported in patients receiving CAMPTOSAR®, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect ."
"Hyperglycemia (abnormally high concentration of glucose in the circulating blood) has been reported in patients receiving CAMPTOSAR®. Usually, this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of CAMPTOSAR®. It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients ."
"The incidence of akathisia (a syndrome characterized by an inability to remain in a sitting postion) in clinical trials was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as CAMPTOSAR® than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies ."
"It would be expected that laxative use during therapy with CAMPTOSAR® would worsen the incidence or severity of diarrhea, but this has not been studied ."
"In view of the potential risk of dehydration secondary to vomiting and/or diarrhea induced by CAMPTOSAR®, the physician may wish to withhold diuretics during dosing with CAMPTOSAR® and, certainly, during periods of active vomiting or diarrhea ."
There has been some anecdotal report of brain tumor patients experiencing seizure activity following CPT-11 treatment. There seems to be a decrease in the perceived effectiveness of dilantin, in particular, following CPT-11 infusion. At least one of the ongoing clinical trials discussed herein (PROTOCOL ID: JHOC-NABTT-9711 which appears in the table in Section 2 as Trial #00410) stratifies patients based on their use of anticonvulsant drugs. Arm I consists of patients who use anticonvulsant drugs that induce hepatic metabolic enzymes. Arm II consists of patients who use anticonvulsant drugs that cause modest to no induction of hepatic metabolic enzymes or no anticonvulsant drug.
Potential Side Effects and/or Toxicities: Diarrhea, alopecia (loss of hair), nausea, vomiting, cholinergic (relating to nerve cells or fibers that employ acetylcholine as their neurotransmitters) symptoms, neutropenia (presence of abnormally small numbers of neutrophils in the circulating blood; neutrophil = mature white blood cell in the granulocytic series) .
Warnings: 1. CAMPTOSAR® Injection should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents (see PDR(  for further information).
2. CAMPTOSAR® can induce both early and late forms of diarrhea (see PDR(  for further information).
3. Severe myelosuppression may occur (see PDR(  for further information).
Information for Patients: Patients and caregivers should be aware of the expected toxic effects of CAMPTOSAR®, particularly of its gastrointestinal manifestations, such as nausea, vomiting, and diarrhea. Each patient should be instructed to have antidiarrheal medication (loperamide) readily available and should begin treatment for late diarrhea at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than usual .
Cost: The list price to a wholesaler from Pharmacia & Upjohn is approximately $450 per 100mg vial, exclusive of wholesaler and pharmacy markup and exclusive of doctor or clinic costs .
Dosage: Dosage for brain tumor treatment is being determined in the clinical trials. Two different trial regimes include (1) 125 mg/m2 weekly for 4 weeks followed by 2 weeks respite and (2) 300 mg/m2 every 3 weeks , .
1. BRIEF HISTORY
CPT-11 (irinotecan) was tested, found successful, and approved as a second-line therapy for colorectal cancer which recurred or progressed following standard treatment with fluorouracil (5-FU). Irrinotecan received accelerated approval by FDA in June 1996 for treatment of metastatic colorectal carcinoma that has recurred or progressed after treatment with 5-FU , . Full FDA approval of CAMPTOSAR®, the US brand name for CPT-11, was granted in October 1998 for metastatic colorectal cancer which has recurred or spread following treatment with standard chemotherapy .
CPT-11 has also shown positive responses in small cell and non-small cell lung carcinoma, refractory lymphoma and leukemia, and gynecologic cancer . When preclinical laboratory tests of CPT-11 showed promise against human central nervous system (CNS) tumor xenographs (xenograft is a technique by which human tumors are transplanted into animal hosts, frequently mice)
including those from brain tumors, clinical trials were designed, approved, and initiated to test CPT-11 against adult and juvenile brain tumors. Some details are given in the following paragraphs. The progression gives a little of the flavor of how a treatment finds its way to clinical trials for brain tumor.
1.1 Chemotherapy for Colorectal Cancer
CPT-11 was extensively tested in Phase I, II, and III clinical trials as a second-line therapy for patients with colorectal cancer whose disease had recurred or progressed following initial therapy with fluorouracil, the standard treatment for rectal and colon cancers. In a Professional Announcement Letter, Pharmacia & Upjohn stated that CAMPTOSAR® Injection provides objective tumor response in 15% of the patients with metastatic colorectal cancer that has recurred or progressed despite therapy with 5-FU-based treatment .
In one phase III randomized study comparing the clinical benefits of CPT-11 with supportive care in patients with 5-FU-resistant metastatic colorectal cancer (Cunningham et al), it was shown that the overall survival was significantly better in the CPT-11 group with a one-year survival 2.6 times greater than that of the group receiving supportive care alone (36.2 percent versus 13.8 percent respectively). The overall survival benefit was 9.2 versus 6.5 months, p < 0.0001. There was also a quality of life benefit, especially for asthenia (weakness or debility) and pain in favor of the irinotecan arm of the trial. A similar conclusion was reached in a phase III randomized trial comparing CPT-11 to 5-FU by infusion in patients with advanced colorectal cancer after 5-FU failure (Van Cutsem et al). The one-year survival in the CPT-11 group was reported as 1.4 times greater than that of the 5-FU group (44.8 percent versus 32.4 percent, respectively). The median time of survival for the irinotecan treated patients was 10.8 months versus 8.5 months (p= 0.035) for the 5-FU group , .
1.2 Other Areas of Investigation
CPT-11 has also been shown to possess antitumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, and for patients with non-Hodgkin's lymphoma . CPT-11 alone and in combination with other chemotherapy agents has been tested against these carcinomas. Response rates of 20 to 22 percent (increased to 40 to 60 percent when irinotecan was associated to cisplatin (CDDP)) have been reported in non-small cell lung cancer and esophageal carcinomas . In the case of relapsed cervical carcinomas, response rates of 20 to 22 percent (increased to 65 percent in combination with CDDP) have been shown . A phase II study of twenty-five patients with platinum-refractory clear-cell or mucinous (containing mucin - a secretion) carcinoma of the ovary who were treated with a chemotherapy regimen including CPT-11 showed a median overall survival time for all 25 patients of 15.3 months. Mitomycin-C was part of the regimen .
In a combination phase I/II study of CPT-11 and carboplatin in relapsed or refractory non-Hodgkin's lymphoma, the response rate (25 percent 2/8) was not superior to that of CPT-11 alone in a previous phase II study (38 percent 26/69). Moreover, the maximal tolerated dose (MTD) of CPT-11 in combination with carboplatin was less than half the single-agent dose. Therefore, the researchers concluded that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients; instead, other suitable agents for such a combination should be sought . Another study concluded that etoposide is not recommended for combination with CPT-11 in non-Hodgkin's lymphoma patients because of unexpected frequent hepatotoxicities  (capacity to produce injury to the liver).
Rosen  observes that irinotecan has shown reproducible, if at times modest, activity in almost all of the diseases in which it has been studied and concludes that future research should be directed at conducting well-designed clinical trials of irinotecan alone and in combination with other agents.
1.3 Preclinical Laboratory Tests of CPT-11 for CNS Malignancies Including Brain Tumor
Studies to test the efficacy of CPT-11 against human tumor xenografts derived from adult and pediatric central nervous system malignancies have been conducted with promising results  through .
In one case, serial treatment of a childhood high-grade glioma xenograft (D-456MG) with busulfan resulted in a busulfan-resistant xenograft, D-456 MG(BR), but not resistance to cyclophosphamide or CPT-11 . In another study the anti-tumor activity of CPT-11 was evaluated in five advanced stage subcutaneous medulloblastoma xenografts in nude mice using different schedules of administration. With a 5-day schedule, the highest i.v. dose tested (40 mg kg-1 day-1) induced complete regressions in all xenografts but one. Delays in tumor growth always exceeded 30 days. The animals with two of the highly sensitive xenografts survived tumor-free beyond 120 days after treatment. Schedule dependency was observed in the xenograft-bearing mice with a protracted schedule resulting in 3 of 6 animals being tumor free on day 378. The conclusion of the study was that clinical development of irinotecan is warranted in pediatric malignancies . In a review paper, Vassal et al  point out that topoisomerase I inhibitors represent a very attractive new class of anticancer drugs to develop in pediatric oncology, since none of the anticancer drugs currently (1997) used in the treatment of cancer in children are targeted against topoisomerase I.
Coggins et al  investigated the combination of CPT-11 with three different alkylating (a drug or chemical that forms a derivatized tissue constituent permanently containing part of the drug or chemical compound; frequently carcinogenic and mutagenic) agents: 1,3-bis(2-chloroethyl)-1-nitrosourea, busulfan, and cyclophosphamide against a panel of human tumor xenografts derived from central nervous system malignancies including adult high-grade gliomas and a childhood ependymoma. The antitumor effects of the various combinations ranged from less than additive to statistically significant supraadditive effects. The authors concluded that the combination of the topoisomerase inhibitor CPT-11 and alkylating agents may increase the antitumor effect in some cases well above additive with no increase in host toxicity and should be considered for combination chemotherapy of central nervous system malignancies.
2. CLINICAL TRIALS OF CPT-11 FOR BRAIN TUMOR
Currently CPT-11 is in Phase I and II clinical trials for brain tumor. The Phase I trials are designed to test the safety and to develop the recommended dosage of the drug. The Phase II trials assess the efficacy of treatment. (See http://www.virtualtrials.com/What.cfm for a discussion of clinical trials.) These trials are listed on the Virtualtrials Web Site under Clinical Trials and on the Physicians' Data Query (PDQ) Clinical Trials Web Site. There is some overlap in the trials listed in the two sources, but each site also contains some listings that the other does not contain.
As of this writing the Virtualtrials Web Site http://www.virtualtrials.com lists seven clinical trials utilizing CPT-11 for brain tumor. Click here to view the trials!
3. REPORTED EXPERIENCES WITH CPT-11 FOR BRAIN TUMOR
Ivanhoe Broadcast News, Inc. has published an account of the first brain tumor patient treated with CPT-11 . According to the article, the patient's tumor had grown to the size of an orange when radiation and standard chemotherapy failed. After a year of treatment with CPT-11, the tumor had nearly disappeared. (The article contains a footnote with the report of the patient's death and a message of condolence and support for the family and friends.) The article states that of the 72 brain tumor patients CPT-11 had been tested on, up to 1998, the drug "worked" in about 50 percent of cases .
In an Ivanhoe Broadcast News Interview Transcript with Timothy Cloughesy, M.D., neurologist UCLA Jonsson Cancer Center, Los Angeles, Calif., Dr. Cloughsey is quoted as saying "To date it seems that, for the most part, about 50 percent of people will have no effect at all with CPT-11. An additional 30 percent will have stabilization for a period of time, and then another 20 percent will have some tumor shrinkage. What we're very interested in is not that it has stabilization or tumor shrinkage for a short period, but we're interested in a long period of time for these patients. That number gets to be a bit smaller as we go out ."
In response to the question "What are the long term implications...?" Dr. Cloughesy replied "We are dealing with 20 percent who get a real good response from CPT-11, but there's 80 percent who don't. So what I think we need to focus on more is trying to identify who that 20 percent is, and how we can predict who would have a good response so we can in turn get them the appropriate treatments ."
An abstract from the Proceedings of the American Society of Clinical Oncology, indicates that among patients with recurrent malignant glioma who were treated in six-week cycles with irinotecan (125 mg/m2 weekly for 4 weeks followed by a 2-week rest), partial responses were seen in 10 of 49 evaluable patients with glioblastoma multiforme (GBM) and 1 of 8 evaluable patients with anaplastic astrocytoma (AA). Minimal response was seen in 3 patients with GBM. Ten patients with GBM and 3 patients with AA demonstrated stable disease in the range of 18 to more than 36 weeks .
4. THIS PAPER AS A LIVING DOCUMENT
As results of the clinical trials for CPT-11 are published and as additional details are available from other sources, this paper will be revised to include them.
The author expresses appreciation to Pharmacia & Upjohn Drug Information Specialist David D. Short, R.Ph., MBA, for discussions on CAMPTOSAR® and the citation of two abstracts , .
It is noted herein that the use of irinotecan in cancers other than metastatic carcinoma of the colon or rectum which has recurred or progressed following 5-FU-based therapy is considered investigational and is not promoted by the Pharmacia & Upjohn Company. However, because of the observed activity against CNS xenografts, there is a rationale to conduct clinical trials of irinotecan in the case of glioma .
Inline definitions are derived largely from the PDR(r) Medical Dictionary .
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