WEDNESDAY June 11, 2003

"ASCO 2003: What's New In Cancer Research?"

The American Society of Clinical Oncology meeting is the largest cancer meeting of the year. The biggest news in cancer research in general is the use of novel therapies. Various studies were presented:

• A randomized clinical trial looked at the effects of Avastin, or anti-VEGF (vascular endothelial growth factor), an antibody that blocks the growth of blood vessels to the tumor. Although the response rate in patients who received the antibody plus chemotherapy was greater than for those that received chemotherapy alone, the time to progression and survival were no different. This may be because patients had resistant cancers. Avastin may best be used on patients who have very early stage disease, destined to relapse.
•  Receptor signaling, although quite complicated, is really the future of cancer research. In order for receptors to be targeted, it is necessary to identify the ligand that inserts into the receptor and tells it to grow. The VEGF2 receptor has had its ligand identified, and Genentech has created an antibody to it. This antibody binds all the available VEGF so that none can attach to the ligand and enter the cell. Prior to this research we only had Herceptin for treatment of solid tumors. Herceptin is an antibody to a receptor rather than to the ligand. We also have developed antibodies to the phosphorus within the cell.
• A subset of patients has been found to respond to Iressa as treatment for lung cancer who have failed all other frontline chemotherapy.
• Velcade is a new drug which has been approved for resistant multiple myeloma. It blocks proteozomes.

Hormonal treatments for breast cancer, in combination with novel drugs, might block the resistance to hormone therapy that develops over time from Arimidex, Femara, and Aromasin. The receptors may block the ability of these drugs to affect the estrogen receptor. Combinations might restore sensitivity. Trials are just beginning.

• Erbitux is an antibody to the EGFR receptor. Iressa and Tarceva are two drugs that block the EGFR phosphorelation. EGFR is over expressed in 35 to 40% of cancers, so there is a lot of interest in these drugs.
• There is interest—and new trials—in blocking HER1-4. A new drug CI1033 blocks HER1, 2, and 4, another blocks HER1and 2. 

The biggest area for new cancer chemotherapy drugs is the creation of novel taxanes. The side effects of taxanes are neuropathy, low blood counts, and fluid retention. Because they don’t cross the blood/brain barrier, and we are tending to see many more patients with brain metastases, we need to develop more treatments that get into the spinal fluid early to prevent recurrence.  Novel taxanes that have been shown to work in patients resistant to normal taxanes include a class of drugs called epothilones and nanoparticles.  

Many of the studies presented at the advanced breast cancer session this year were too small to respond to. Unless the drugs have been proven to work longer, it is not worth the toxicity. There are still lots of questions and not many answers.

• With Herceptin and anthracycline, cardio toxicity seems to be relatively minor.
• A French study compared epirubicin-based chemotherapies FEC50 (standard) to FEC100. The results showed that FEC100 was a better regimen. The 10-year follow up showed that the benefit was preserved, particularly in patients with 4 or more positive nodes. There were a small number of leukemia cases, but no additional cardio toxicity.
• Researchers at UCLA looked at 18 women, 5 to 7 years out from their adjuvant chemotherapy. They did cognitive function testing while these patients were getting a PET scan, which allowed metabolic changes in the brain to be seen. They were able to show decreased metabolism in patients who received chemotherapy versus a control group. This was hard to correlate with cognitive testing, because stress, fatigue and aging make cognitive dysfunction more pronounced, subtle differences are not picked up. Most people undergoing stressful things like chemotherapy will notice cognitive effects. For most people these effects go away after chemotherapy. A small subset of people may have a genetic predilection for more toxicity and may still feel disabled many years afterward. PET scans may help us to understand these subtle differences and to determine who is at risk.
• A large intergroup study asked whether tamoxifen on top of ovarian suppression added any benefit to chemotherapy. The results indicated that tamoxifen made a big difference and that ovarian suppression was relatively safe. 50% of women who received CAF chemotherapy went into menopause, with the risk higher (80%) in women over the age of 40.
• Another study looked at Lupron, a GnRh agonist that suppresses the ovaries. It was given to women under 35 who wanted to preserve their menses in order to become pregnant. The women recovered their menses, but couldn’t become pregnant. Obviously, there are long-term effects of trying to preserve ovarian function, and the role of suppression is not yet clear. The quality of life issue strongly favors tamoxifen. Additionally, it is very important to study the effects on menopause, as most of these studies to date have included mainly premenopausal women.
•  The major plenary session was on using gene arrays to better understand cancer. In one study of colon cancer, genetic analysis of a particular gene predicted toxicity to a particular drug. A related study found that women who evidenced particular genes groupings had a 75% chance of pathologic remission (no cancer left after treatment) of their cancer with Adriamycin and a taxane, whereas other patients had only a 20% chance of remission. Hopefully, this will lead to being able to choose the right treatment for individual patients, and to choose it early.
• The results of NSABP B-28, a large randomized trial that used a taxane in addition to AC chemotherapy, gave AC+taxol or AC alone. Patients received tamoxifen if they were over 50 or hormone receptor positive and less than 50. It has taken a long time to get the results of the study because it has been necessary to wait for a certain number of relapses to occur in the study group. As women are living longer, it takes longer to get the data. The 3060 patients have been followed for approximately 65 months. They had tumors that were relatively small and 1 to 3 positive nodes. Almost 70% of patients were hormone receptor positive. 84% received tamoxifen. Most of the patients completed their chemotherapy with minor toxicity. The results showed improvement in relapse in patients receiving taxane. The 5-year disease free survival was 76% for those patients receiving taxane, and 72% for those who did not. Overall survival after 5 years was identical (85%). It will probably turn out that taxanes are important, but 5 years is too short an interval to see a survival benefit, as ER+ patients tend to relapse later and live longer.

What about vaccine or immunotherapy? It is a very exciting time in vaccine therapy with clear value for some cancers like renal cell and melanoma. The data in breast cancer is the best ever, with data on HER2-directed vaccines that have shown excellent immune response, and some suggestion of response to disease. The process requires filtering the cells and then stimulating them with growth factor. Research with Theratope, a vaccine, is looking at stimulating immune responses in women on hormone therapy.

Is there any research on bacteria being used to attack cancer cells? There is a lot of interest in using viruses to kill cancer cells, but it is very hard to deliver the toxic part of the virus to the cancer cell. Light is being looked at to activate cancer drugs, or to locate particular cancer cells in the operating room. The appeal is less side effects and less surgery.

What is the problem with quality of life after ovarian suppression? The symptoms are the same as menopausal symptoms, hot flashes, vaginal dryness, slower metabolism, and seems to be more in premenopausal patients.

Are there any studies using tamoxifen and an aromatase inhibitor concurrently? The ATAC trial had a combination arm. The results indicated that the combination was no better than tamoxifen alone, so that arm has been closed. More side effects occur with tamoxifen over time (endometrial cancer) and after 5 years patients may develop a resistance to the drug. Optimal treatment may be 5 years of tamoxifen followed by 5 years of an aromatase inhibitor.

Do cancers that develop premenopausally respond differently than those that develop after menopause?  We don’t seem to see differential responses to treatment based on when women develop their cancers. One exception might be in very young women, which is not yet well understood.

Would using an aromatase inhibitor reduce the risk of brain or spinal fluid metastasis? The enzyme aromastase is found in cells, so it affects the tissue estrogen more than the circulating estrogen. Having less circulating estrogen could slow the growth of brain mets, but you could not control where the AI went.

What is the response to whole brain radiation?  Generally radiation is done in small fractions over a 4-week period to keep the cognitive effects to a minimum.