CACS meeting of 3/20/04:  Meeting summary

Topic:  Planning a clinical trial for carcinoid

Speaker:  Dr. James Ahlgren, Professor, Division of Hematology-Oncology, Department of Medicine, George Washington University Medical Center, Washington, D.C. ; field of interest:  gastrointestinal malignancies

James D. Ahlgren, MD
     Medicine - Hematology/Oncology

Topics to be covered.  Dr. Ahlgren said that he would talk first about carcinoid cancer in general and then about a specific clinical trial that he hopes to start within a few months. 

Introduction to carcinoid tumors.  Carcinoid tumors are uncommon.  Usually they originate in the gastrointestinal tract.  Most carcinoid tumors are asymptomatic.  They may be found during autopsies even though there was no sign of them when the individual was alive.  Some are hormonally active, and others are not.  Hormonally active carcinoid tumors lead to carcinoid syndrome after they metastasize. 

Carcinoid syndrome.  Carcinoid tumors in individuals with carcinoid syndrome secrete serotonin and/or other hormones.  Serotonin is a hormone that is produced normally in the gastrointestinal organs and elsewhere, but the tumors can overproduce it.  If the tumors are in the gut, then the liver gets a chance to degrade the hormones before they get into body circulation.  However, if the tumors have metastasized to the liver, their hormone products can then get into general circulation. 

Carcinoid syndrome can include a variety of symptoms---such as flushing, diarrhea, and wheezing. 

Treatment options.  The 2 basic approaches to treating carcinoid tumors are to (1) block the symptoms and (2) attack the tumors.  The latter is more difficult. 

Antisecretory therapy (blocking symptoms).  The natural body hormone somatostatin can block the release of other hormones, such as many of the hormones that the carcinoid tumors are making.  However, somatostatin does not last very long after its production: half of it is gone in fewer than 3 minutes (i.e., its half-life is 3 minutes).  Consequently, it would not be practical to inject extra somatostatin as it would disappear too fast. 

Medical researchers have made an analog of somatostatin called Sandostatin (commercial name) or octreotide (generic name) that lasts longer.  Sandostatin’s half-life is 113 minutes, and it also is about 100 times more potent than somatostatin.  Depending on the activity of the patient’s tumors, he or she may need 3 or 4 injections of Sandostatin per day.  A typical dose would be 200 to 600 micrograms per day.  These are usually subcutaneous injections.  The usual results include a decrease in certain plasma peptides (small chains of amino acids) and a decrease in diarrhea. 

A longer-acting form of Sandostatin is also available.  In Sandostatin LAR, thesandostatin is microencapsulated in a biodegradable polymer.  The LAR is delivered as a deep muscle injection.  It takes about 4 weeks for the body to hydrolyze all of the polymer, gradually releasing the sandostatin. 

One complicating side effect of Sandostatin is that it can slow motility, which may result in gallstones in the gallbladder or bile duct problems. 

How does carcinoid kill?  As mentioned above, Sandostatin controls symptoms, but the carcinoid tumors may continue to grow.  Some of the tumors grow quite a lot---that is, they are aggressive---while most carcinoid tumors are slow growing and indolent.   The tumors as they get larger could compress vital organs---especially the liver. 

A typical set of stages for an indolent and untreated carcinoid cancer over a period of 20 years might be (1) finding the primary tumor, usually when it is already several years old, (2) finding metastases at the same time or years later, (3) increased symptoms of flushing and diarrhea over several more years, and (4) death many years after the first tumor growth. 

Old data on survival rates gave only a 50:50 chance of a 5-year survival before the development of Sandostatin and other treatments.   

Antiproliferative therapy.  (1) The best option to prevent further tumor growth is surgery to remove as much of the tumor(s) as possible.  (2) Heat---that is, thermal ablation---can be used to kill certain sizes of tumors; when this is done using radiowaves, it is called radiofrequency ablation.  (3) Cryosurgery to freeze the tumors used to be done and was almost as effective as thermal ablation.  (4) Chemoembolization delivers chemotherapy via an artery to the liver with tiny balls of a substance then used to block small blood vessels and keep the chemotherapy in the vicinity of the carcinoid tumors in the liver for a longer period of time.  (5) Systemic chemotherapy can be used but is usually not as effective for carcinoid patients as for some other types of cancer.  (6) Interferon can be delivered systemically; when given along with octreotide/Sandostatin, the two appear to act synergistically to be more effective in causing tumor regression. 

5-year survival.  The dramatic increase in 5-year survival after the introduction of the somatostatin analogs suggests that they may be doing more than just controlling symptoms. 

Frequently, symptoms can be controlled at a very low dose---such as 300 micrograms per day, which is equivalent to LAR at 10mg per month.  Even at these low doses, a few patients have shown shrinkage of tumors, and others show tumor shrinkage with higher doses.  Some journal reports have been made about anecdotal incidents in which the tumors of individual patients disappear on scans and cannot be found during later surgery [e.g., Leong WL, Pasieka JL., Regression of metastatic carcinoid tumors with octreotide therapy: two case reports and a review of the literature. J Surg Oncol. 2002 Mar;79(3):180-7. Review.  PMID: 11870669 [PubMed - indexed for MEDLINE]. 

Receptors.  While antiproliferative activity of Sandostatin has been observed, its mechanism is not completely understood.  There are 5 known types of receptors that cells can have for somatostatin, called SSTR1-5.  When somatostatin binds to SSTR3, this induces the factor p53 and causes apoptosis (cell death).  When somatostatin binds to some of the other receptors, this induces Rb (another gene), which blocks cell progression through the G1 period; the block is prior to the cell synthesizing DNA in preparation for dividing.  The level of octreotide needed to interact with SSTR3 may be higher than that needed for some of the other receptors. 

Sandostatin has not shown excessive toxicity at high doses although data are limited.  Dr. Ahlgren is interested in exploring whether such high doses---perhaps as much as 8 milligrams per day---can stop tumor growth and cause tumor regression. 

Proposed trial.  Dr. Ahlgren is working on plans for a clinical trial at George Washington University Medical Center for neuroendocrine tumors, including carcinoids.  This would be a dose-response study.  The pharmaceutical firm that makes sandostatin has expressed interest in providing funding for this study. 

Participating patients would start at a the standard dose of LAR (30 mg every 4 weeks).  Chromogranin A would be checked every 4 weeks; this is a blood test that reflects the total amount of neuroendocrine tumors present in the body.  In addition, CT scans would be done every 8 weeks to keep track of tumor size.  [Note:  Many carcinoid patients (at least 50%) do not secrete hormones, and a lot do not secrete serotonin, but these individuals can still be tracked with CgA.]  [Note2:  Individuals on chemotherapy or currently taking interferon would not be eligible for this study.] 

If the chromogranin A level remains stable, the study participant would stay on the same dose of LAR.  If the chromogranin A level rises by more than 10%, the study participant would go to the next dosing level.  The 4 dose levels proposed to be tried are (1) 30 mg/4 weeks (= about 1 mg/day), (2) 30 mg per 2 weeks (= 2 mg/day), (3) 60 mg/2 weeks (= 4 mg/day), and (4) 60 mg/week (= 8 mg/day). 

The endpoints of the study include (1) an objective response rate at any dose (e.g., tumor shrinkage); this could be a change on the CT scan using specific criteria or a specific drop in the CgA level; (2) evidence of a dose-response effect based on the number of responses at each dose increment; (3) side effects; (4) quality of life. 

Where tissue is available, some correlative studies could be done:  (1) determining protein expression (including the SSTRs) in responders vs. nonresponders; (2) gene-chip analysis to determine gene expression in responders vs. nonresponders; and (3) growing carcinoid cells in primary culture to determine proliferative rates and apoptic potential and to correlate these with responses. 

The study is intended as a phase 2 clinical trial in which about 40 patients would participate.  It might take 2 years to enroll this number.  Three additional centers have expressed interest in cooperating:  University of North Carolina, University of Pennsylvania, and St. Vincent’s Cancer Center in NYC. 

During discussion, support group members wondered about the willingness of patients to participate in a study that might lead to even getting as many as 2 LAR shots per week because of the resulting buttock soreness.  Dr. Ahlgren indicated that an alternative way to give higher doses of octreotide is with an intravenous pump, but this would require an IV (intravenous) access device and carrying the pump at all times.  He thought most patients would prefer the injections.