Every year, tens of thousands of the world's oncologists gather in Chicago for the annual meeting of the American Society of Clinical Oncology (ASCO). This huge meeting brings together cancer specialists as well as many others involved in this burgeoning field, including hundreds of journalists and, of course, representatives of the big pharmaceutical companies.
This year, there was concentration on the results in a few relatively rare kinds of cancer. Pediatric oncology was well represented, with plenary sessions on acute lymphocytic leukemia (ALL) and neuroblastoma. There was also a presentation on gastrointestinal stromal tumors (GIST). It was the clinical trial results in advanced–stage malignant melanoma that got the most attention. There were three randomized controlled trials positive for metastatic melanoma in terms of overall survival. Two of these worked by separate mechanisms; that is, immunological modulation and growth pathway inhibition. So this is some good news for melanoma patients, who have faced a dearth of positive research in recent years. The results were not as earth-shattering as you may have been led to believe, but it was a start. The new findings do create the possibility of combining these new agents to overcome the persistent problem of drug resistance.
The immunological approach was represented by ipilimumab combined with the drug DTIC ("Integration of Ipilimumab in the First-line Setting Improves Survival for Patients with Metastatic Melanoma"). "Ipi" is a monoclonal antibody that can be directed against a class of cytotoxic T-lymphocyte antigen 4 (CTLA-4). The drug, now named Yervoy, was approved by the Food and Drug Administration (FDA) in late March 2011 for the treatment of advanced melanoma. Approval was based on an increase in overall survival that had been observed with Ipi alone in patients with unresectable stage III/IV melanoma in whom previous treatment had failed.
To quote an ASCO press handout, ipilimumab combined with the standard drug dacarbazine "significantly prolonged overall survival … by 2.1 months compared with dacarbazine alone (11.2 vs. 9.1 months). … Ipilimumab/dacarbazine significantly prolonged progression-free survival compared with placebo/dacarbazine (2.8 vs. 2.6 months, respectively)."
Meanwhile, serious side effects were seen in more than half the patients: The combination of ipilimumab and dacarbazine resulted in a higher incidence of grade 3 or 4 adverse events compared with the control arm (56.3 vs. 27.5%). The ipilimumab-associated adverse events were consistent with previous studies and predominantly affected the liver, endocrine system, gastrointestinal tract, and skin.
A 2.1-month increase in survival (and 1-week increase in progression-free survival) may not seem like much to an outsider. But oncologists found it exciting because most other treatments for advanced melanoma do nothing at all.
Even greater excitement at ASCO greeted results with the drug vemurafinib. This drug attacks a specific genetic mutation that accelerates tumor growth. Adding vermurafinib adds between two and several months to the expected lifespan of people with advanced melanoma. But this clinical trial was ended early – before median survival data was available – because scientists thought it would be unethical to deny patients what seemed to be the superior option.
"This is an unprecedented time of celebration for our patients," Lynn M. Schuchter, MD, a melanoma specialist at the University of Pennsylvania, said at the ASCO meeting, as reported on the front page of the New York Times. A cure for melanoma would be an unprecedented time of celebration for patients. Two months' added survival falls a bit short. But oncologists are understandably excited at the emergence of a new treatment option, and it seems very possible that there will be improvement on these results in years to come.
CAM and ASCO
One reason that I go to the ASCO meeting is to assess the state of complementary and alternative medicine (CAM) within the larger picture of oncology. It seemed to me that the presentation of CAM at this meeting was more matter-of-fact than at previous meetings. That does not mean that CAM has been accepted, or integrated, but that its presence creates less of a stir than it did at previous meetings. In a sense, that it is a good thing.
There were a total of over 10,000 presentations and posters at this year's meeting. Of these, the following were on CAM topics:
- Vitamin D: 30 presentations
- Dendritic cell vaccine: 16
- Yoga: 6
- Antioxidants: 5
- Herbs: 5
- Acupuncture: 3
Not exactly a great harvest!
The most disturbing CAM study I saw was by H. Greenlee et al., "Antioxidant Supplement Use After Diagnosis and Breast Cancer Outcomes." This was a study of the so-called LACE cohort, which consisted of 2264 women who were identified primarily through the Kaiser Permanente Northern California Cancer Registry. They were diagnosed with early-stage primary breast cancer from 1997 to 2000. A mailed questionnaire collected data on frequency of antioxidant supplement use since diagnosis (multivitamins +/− minerals, combination multiple carotenoids, beta-carotene, lycopene, vitamin C, vitamin E, selenium, zinc, coenzyme Q10, soy), as well as other risk factors. Antioxidant supplement use after diagnosis was reported by 81% of women; 71% used multivitamins, 40% used vitamin C, 48% used vitamin E, and just 7% used combination multiple carotenoids.
First, the good news. Among antioxidant users, frequent use of vitamin C was associated with a 27% decreased risk of breast cancer recurrence, while frequent use of vitamin E was associated with a 23% decreased risk of recurrence. Vitamin E was associated with a 24% decreased risk of all-cause mortality. All of this seemed to validate the idea that antioxidants protect against cancer recurrence and death.
But, disturbingly, in a relatively small cohort of patients who reported that they took "combination multiple carotenoids," there was an increased risk of death from breast cancer (HR = 2.07) and all causes (HR = 1.75). Yet no such relationship was seen with either beta-carotene or lycopene alone.
The authors' conclusions were as follows:
Frequent use of vitamin C and vitamin E in the period following breast cancer diagnosis was associated with decreased likelihood of recurrence. Frequent use of combination multiple carotenoids during this same period was associated with decreased survival. Effects of antioxidant supplement use after diagnosis likely differ by type of antioxidant.
Perhaps some reader will have a cogent explanation of these puzzling results. How is it possible that beta-carotene and lycopene, the most commonly used carotenoids, taken alone had no negative effect on either recurrence or survival? Meanwhile, a combined carotenoid supplement had such negative effects? Is there possibly some hidden danger lurking in, for example, alpha-carotene, lutein, or zeaxanthin? I find this study hard to fathom, but disturbing nonetheless.
Some Oleander Results
Readers may have heard of a CAM cancer treatment called Anvirzel. This is an extract of the attractive shrub Nerium oleander L., which has been used for decades as an adjunctive cancer treatment. There is reason to believe that at least one ingredient in oleander, namely oleandrin (also dubbed PBI-05204), might have anticancer activity. It inhibits the a-3 subunit Na-K ATPase pump and expression of the a-3 subunit in tumor cells correlates with their proliferation.
In this first-in-human study, the authors, at the University of Texas M. D. Anderson Cancer Center, Houston, tried to determine the proper dose in advanced cancer patients as well as some preliminary treatment effects. PBI-05240 was given for 21 of 28 days of the trial. The most common adverse events were fatigue (56.1%), abdominal pain (41.5%), constipation (41.5%), nausea (41.5%), and diarrhea (39.0%). Oleandrin is a cardiac glycoside and thus cardiac disorders were reported in 10 pts (24.4%), all grade 1, except for 1 pt with grade 2 supraventricular tachycardia (SVT).
Of the 45 evaluable patients, 7 (15.6%) with bladder, colorectal, fallopian tube, breast, appendecal and pancreatic carcinoma (2X) achieved stable disease for more than 4 months. The authors concluded that PBI-05204 was well tolerated up to 10.2/mg/day with very few adverse events and little cardiotoxicity. But are such results (with no significant shrinkage of any tumors) sufficient to launch this treatment into phase III clinical trials? Given past experience, I rather doubt it.
Kidney Cancer and Alcohol?
In the past few years, there has been a significant increased incidence of kidney (renal cell) cancer. A number of factors have been identified that increase the risk of this disease. Cigarette smoking is one well-known risk factor (Mellemgaard 1994). In fact, about 30% of kidney cancer in men and 24% in women is ascribed directly to smoking (Yu 1986). Obesity is also associated with kidney cancer, particularly in women (Shapiro 1999). Certain industrial workers are at increased risk, including leather tanners, shoe workers, and those exposed to asbestos (Ross 1989). Being a long-term dialysis patient also increases one's risk.
But what about alcohol? According to Karin B. Michels and Walter C. Willett, writing in chapter 20 of the 2011 edition of the DeVita textbook, Cancer, "Besides body weight, the consumption of alcohol has been called the "best established dietary risk factor for cancer."
Alcohol is classified as a carcinogen by the International Agency for Research on Cancer (IARC). Consumption increases the risk of numerous cancers, including those of the liver, esophagus, pharynx, oral cavity, larynx, breast, colon, and rectum (World Cancer Research Fund, 2007). In the developed world, about 75% of cancers of the esophagus, pharynx, oral cavity, and larynx are attributable to the lethal combination of alcohol and tobacco. In the case of breast cancer, there is also a small but significant increased risk even with one drink per day. For most of these sites, ethanol itself seems to be the deciding factor.
Since all liquids are filtered through the kidneys, it might seem logical to assume that alcohol also increases the cancer risk in this pair of organs. This is stated by some sources. But according to the 2011 NIH-AARP Diet and Health Study, there is actually a decrease in the incidence of kidney cancer among those who drink a moderate amount of alcohol. Specifically, when compared with those who drink less than 5 grams of alcohol per day, the risk in those who drink between 15 and 30 grams of alcohol per day is reduced by 25% in men and 29% in women. In those who drink more than 30 grams of alcohol per day the risk is reduced by 33% in men and 57% in women … a stunning decrease.
The report concludes: "Alcohol consumption was inversely associated with RCC [renal cell carcinoma] in a dose-response manner." This is not reason enough to start drinking alcohol, because of its many other health issues. But if you already do drink alcoholic beverages, and are concerned about kidney cancer, you can probably put your mind at ease. If anything, a daily glass (or even two) of pinot noir isn't likely to increase your risk of kidney cancer, and may actually decrease the danger.
Ken Schueler's Passing
Kenneth (Ken) Schueler, a well-known figure in the world of complementary and alternative medicine, passed away in May 2011. The cause was pancreatic cancer. Ken was founder of HKS Patient Advocates in New York City and was himself a long-term survivor of lymphoma. His organization was dedicated to guiding patients through the complex world of modern medicine and managed health care. By serving as a personal case manager, Ken was able to provide many patients with prompt access to medical experts and services, research into the latest and best treatment options with ongoing updates, and advocacy to enhance communication between all members of the health care team. I saw Ken in March in Florida, at the annual conference of the Annie Appleseed Project, of which he was a board member. We had a pleasant chat and there was no indication at the time that he was ill. Such is the terrible nature of this disease that two months later he had passed away. He will always been remembered for his cheerful disposition and for the real help that he provided to innumerable patients.
Ralph Moss, PhD
Greenlee H, Kwan, Kushi, et al. Antioxidant supplement use after diagnosis and breast cancer outcomes. 2011 ASCO Annual Meeting. J Clin Oncol. 2011;29:suppl; abstr 1539.
Henary HA, Kurzrock R, Falchook GS, et al. Final results of a first-in-human phase I trial of PBI-05204, an inhibitor of AKT, FGF-2, NF-Kb, and p70S6K in advanced cancer patients. J Clin Oncol. 2001;29:abstr 3023.
Lew JQ, Chow W-H, Hollenbeck AR, Schatzkin A, Park Y. Alcohol consumption and risk of renal cell cancer: the NIH-AARP diet and health study. Br J Cancer. 2011;104:537–541.
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Pollack A. Drug shows promise slowing advanced melanoma. New York Times. June 5, 2011.
Ross RK, Paganini-Hill A, Landolph J, Gerkins V, Henderson BE. Analgesics, cigarette smoking, and other risk factors for cancer of the renal pelvis and ureter. Cancer Res. 1989;49:1045.
Shapiro JA, Williams MA, Weiss NS. Body mass index and risk of renal cell carcinoma. Epidemiology. 1999;10:188.
Yu MC, Mack TM, Hanisch R, Cicioni C, Henderson BE. Cigarette smoking, obesity, diuretic use, and coffee consumption as risk factors for renal cell carcinoma. J Natl Cancer Inst. 1986;77:351.
World Cancer Research Fund. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. American Institute for Cancer Research. Washington, D.C.: World Cancer Research Fund 2007.
Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.