Around March, my friend Howard Ozer told me he was heading out on a safari. He did these things often, adding to his collection of trophies.
In the Hemingwayan universe Howard inhabited, men shot animals. Women did, too. If you were his friend, you accepted that.
I wished him bon voyage and suggested that we catch up at the meeting of the American Society of Clinical Oncology and have a drink or three, but at the meeting in early June I didn’t see Howard swagger through the McCormick Center. I figured he had something better to do. We didn’t connect in the summer, either.
Then, late in September, at the meeting of the Association of American Cancer Institutes, I ran into Regina Schwind, who was the cancer center administrator when Howard was the director of the University of Illinois Cancer Center.
“How is Howard?” I asked.
“Not well. He died in April,” said Regina, who is now a graduate student and program director at UIC.
And so I learned that Howard, the Eileen Lindsay Heidrick professor in oncology at UIC, had died in the jungle of Cameroon, near the Boumba River, on April 6. He was 71.
Oddly, most of our mutual friends had no idea that Howard was gone, so I decided that a late obituary is better than none at all, and I would catch up and publish it in the final issue of 2018.
“He loved life, and he died doing what he loved, and I am happy that he got to do that,” Trina Matta, Howard’s daughter, said to me.
On the first day of his last safari, Howard shot a bongo.
“Bongos are very secretive animals, and you have to track them,” said Guav Johnson, a safari operator who had taken Howard on four hunts over the past dozen years. “It rained that morning, so we huddled under a tree for an hour until the rain stopped, and we carried on, and about an hour later, we found fresh tracks of a bongo after the rain, and together with the Pygmies, we started tracking it with the dogs, and we were lucky, because the trail was very fresh and we managed to bay the bongo pretty quickly, which was not easy, because the jungle was so thick, but we got right up, and with one shot he got his bongo. He got his main animal on the first day of a 15-day safari. He was lucky.”
This was the morning of April 2. Four days later, “we got up early, had normal conversation around breakfast, then we stopped mid-morning, there was a big tree across the road, and then we started walking, and it happened quickly,” Johnson said. “We were walking in the forest, and he felt tired, and we stopped to rest a bit, and we went a little bit further, and he stopped to rest again, and he collapsed.
Over the past 25 years, Howard was one of the people I called to make sure I am seeing the world as it is. On the professional side, my question to him was always the same: “Am I hallucinating? Would you tell me if I am?”
I first became aware of Howard in 1993, while writing my first investigative piece in oncology, and in the course of our friendship, Howard guided me through a multitude of stories, including the biggest story of my career—the overuse of red blood cell growth factors.
My coverage of these drugs, also known as erythropoiesis-stimulating agents, didn’t win any journalism awards, but it helped change medical practice, likely saving lives. Peripherally, the story also led to a Supreme Court decision—Amgen Securities Litigation—on certification of class action suits. Also, The Cancer Letter ended up in court, successfully defending a First Amendment principle related to subpoenaing journalists (The Cancer Letter, Sept. 4, 2015).
Howard and the downfall of Rajko Medenica
Ozer showing off his ASCO badge after being named Fellow of ASCO.
And now, dear reader, pour yourself a libation of your choice in honor of Howard, and settle in for the really good story you were either too young to have heard in real time or old enough to have forgotten:
In 1993, a miracle doctor named Rajko Medenica was curing cancer and a number of other diseases in Hilton Head, SC.
Medenica’s patients tended to be rich.
Consider Muhammad Ali. The champ was widely presumed to have Parkinson’s disease, but Medenica diagnosed exposure to household pesticides and prescribed plasmapheresis.
Medenica also claimed to have been involved in treating the Yugoslavian president Josip Broz Tito, the Soviet president Leonid Brezhnev and the Shah of Iran. Other patients included former U.S. Ambassador to South Korea Richard Walker, and Sue West, the daughter-in-law of John West, former South Carolina governor and former U.S. ambassador to Saudi Arabia.
Ali called Medenica “the greatest doctor of all times,” and Walker called him “the Michelangelo of the cancer world.” His U.S. citizenship oath was administered by then Sen. Ernest Hollings (D-SC), and his honors included the Order of the Palmetto, South Carolina’s highest award, conferred in 1989 by then Gov. Carroll Campbell.
The medical staff of the Hilton Head Hospital saw a different side of Medenica and his practice of medicine. There was concern about his unconventional treatment choices and wild toxicities to which his patients were subjected (The Cancer Letter, April 30, 1993).
So, they called a star of academic medicine—Howard Ozer, then chief of the Division of Medical Oncology of the University of North Carolina Lineberger Comprehensive Cancer Center.
And Howard showed up, and Howard reviewed a bunch of patient files, and Howard flirted with the Medenica receptionist (whom he later married), and Howard zeroed in on several cases, the most hair-raising case of which was Medenica’s treatment of Gayle Taylor, a 34-year-old breast cancer patient.
Under South Carolina law, Ozer’s report was to remain confidential and not subject to discovery in civil litigation. However, a copy was sent anonymously to the patient’s attorney—Howard said to me that he didn’t do it, and I believe him—and was made public.
The world has changed, cancer treatments have changed, but the report Howard dictated then is still captivating, probably because in medicine, like in hunting, a well-aimed single shot is still a well-aimed single shot:
As best I can tell from the chart, Dr. Medenica was consulted as the medical oncologist during the recovery period. Dr. Medenica’s lab also received a specimen from Ms. Taylor’s tumor on which they performed both drug sensitivity testing and DNA analyses.
I could find no detailed information regarding the drug sensitivity testing, although a note by Dr. Medenica subsequently states that the tumor was sensitive to CMF (cyclophosphamide, methotrexate and 5 FU) as well as to mitomycin-C.
The ploidy analysis performed by flow cytometry was available in the chart and shows a major population of cells in GO/1 and a second population of cells in mitosis (G2/M). Dr. Medenica interprets this pattern as showing “multiple peaks” which it most certainly does not. The pattern does indicate both a resting cell and a dividing cell population.
These data are consistent with a poor prognosis finding of an S-phase fraction of the tumor cell population higher than 10-20%, however, aneuploidy is not present, suggesting that Dr. Medenica has difficulty interpreting his own laboratory’s data.
In summary, then, we have a 34-year-old woman with node negative breast cancer, a tumor measuring 2.5 centimeters, positive lumpectomy margins and definitive therapy with a modified radical mastectomy and several poor prognostic indicators, including family history, negative hormone receptor status, and a high S-fraction of cells. This particular complex of problems is unfortunately all too common in oncology practice, and has been carefully evaluated in multiple clinical trials over the last 15 years by numerous groups, most notably the NSABP.
The evolution of thinking with regard to node negative T-2 lesions such as this one has evolved over this period of time. Originally, it was believed that no therapy following modified radical mastectomy was required. This simple observation of patients with no further therapy results in long-term survival of as much as 65% (see attached table 38-17 from DeVita).
Subsequently, the NSABP performed a trial in which they gave adjuvant chemotherapy in the form of MF to node-negative patients (they believed at the time that the addition of an alkylating agent with the long term risk of acute leukemia represented too great a risk in this group of patients) and determined that the adjuvant therapy provided approximately a 5-10% improvement in the 5-year survival rates. In subsequent studies, they included the alkylator cyclophosphamide in their adjuvant regime, (CMF) and demonstrated that in premenopausal, node-negative, hormone receptor negative patients receiving adjuvant therapy, there was improvement in 10 year survival in as many as 20 or possibly even 30% of these patients.
To translate the meaning of this, as many as 1/5 to 1/3 of the patients receiving adjuvant CMF for high risk resected breast cancer should be expected to benefit with longer survival and probably cure. Thus, through these trials, CMF has become the gold standard utilized by most medical oncologists for adjuvant therapy of high risk node-negative breast cancer. Any other therapy of breast cancer should, at this point, be considered both controversial and investigational, and not all oncologists accept even CMF as appropriate therapy.
Although some physicians might argue that CAP (substituting adriamycin for methotrexate) would be advantageous in high risk patients, this is also under investigation and is certainly not an accepted standard of practice.
The addition of any other agents to CMF is well beyond the envelope of standard practice and should be undertaken in the research setting only with great care, careful explanation of risks and benefits and virtual certainty that the risks in individual patients of relapse from breast cancer (involvement of 6 or more positive nodes, for example) is sufficiently great.
This patient was also on Tamoxifen at some point; this is obviously done despite the negative hormone receptors and would be a reasonable alternative to chemotherapy, if the patient had requested no chemotherapy. It should not be done in conjunction with chemotherapy, however, because it probably has no effect and should be reserved for a subsequent recurrence.
Dr. Medenica also pursued what I find to be an incredible number of ancillary tests of literally no value. Probably 90+% of the lab test chart for this patient are worthless and represent hundreds of thousands of dollars of unnecessary testing. All of the immune tests, as well as assays for interferon inhibitor and lymphokine inhibitor (assays unique to Dr. Medenica that are of no demonstrated value in the literature or in any other laboratory) were performed and evidently repeated with each patient visit. Flow cytometry of peripheral lymphocyte marker testing is also useless in this setting. A brain MRI is no better as a screen than a CAT scan of less expense which would have done perfectly well. The laboratory testing was repeated every few weeks. I mentioned the excessive testing in great detail in my last letter. It is evident that Dr. Medenica continues to do this. In a patient with node-negative breast cancer on adjuvant therapy, it is my personal opinion that this type of testing is not simply excessive but actually borders on the bizarre.
In early September (9-1-91), Dr. Medenica describes a positive interferon inhibitor and lymphokine inhibitor and says that he and the patient “need to talk about it.” At no point does he display evidence of informed consent for his use of mitomycin-C in addition to CMF, nor does he describe permission or understanding by the patient of the additional testing that he is performing. The adjuvant chemotherapy and all of the unnecessary lab testing is performed every 2 weeks between September 1 and January 17.
The patient first becomes anemic on 10-29, not surprising in light of chemotherapy although the cyclophosphamide was increased to 600 mgs. Without explanation on 10-1. Several unusual vitamins are begun in early January, apparently as a result of progressive anemia. On February 7, the patient requires a 2 unit cell transfusion and immodium therapy for diarrhea.
She is treated on February 10 for what Dr. Frank Hart believes is an anxiety reaction with migraine and a sensory radiculopathy. On February 20, she presents with pancytopenia, an elevated BUN and a mildly elevated creatinine. It is apparent from the chart that both Dr. Hart and Dr. Medenica realize that Ms. Taylor has a serious complication and they pursue a very intensive work up for autoimmune diseases as well as abnormalities of bone marrow function. Dr. Medenica performs a bone marrow aspirate at this point and to my great bewilderment, actually does flow cytometry, immune panel assays, colony forming units, immunomodulation and pharmacosensitivity assays and even a karyotype on this sample. I find this level of testing on Ms. Taylor’s bone marrow at this point in her history to be beyond bizarre.
It is clear at this point that Dr. Medenica does not realize what he’s dealing with. Her white count is 18,600, hemoglobin 7.9 and platelets 44,000 with an LDH of 566, a creatinine that begins at 2.3 and escalates to 2.8, a BUN that goes from 39 to 89 on discharge and a urinalysis showing 300 mgs% protein. She is Coombs negative and received packed red cells, erythropoietin, GCSF (actually contraindicated with an elevated white count of 18,600) and is treated with steroids and intravenous immunoglobulin despite the absence of evidence for autoimmune hemolytic anemia. Dr. Medenica’s discharge summary appears to be attempting to defend the diagnosis of autoimmune hemolytic anemia, despite the fact that the clinical data clearly make the diagnosis of hemolytic uremic syndrome. There is some discussion of whether this is a Keflex-induced hemolytic anemia that needs to be treated with steroids and intravenous immunoglobulin. Dr. Hart eventually makes the diagnosis of HUS secondary to mitomycin-C and Dr. Medenica claims in the summary that this is prevented with vitamin B-6 (not true) with which he has already been treating the patient. The patient is then transferred to Duke University for definitive therapy, presumably with SPA immunopheresis.
My interpretation of this course of events is that Ms. Taylor clearly received excessive and useless laboratory testing costing hundreds of thousands of dollars. Secondly, for a woman with a T-2 lesion and node- negative breast cancer treated with modified radical mastectomy, the appropriate adjuvant therapy would have been CMF with a relatively modest risk of complication. The addition of mitomycin-C, although the agent can work in refractory breast cancer, in the adjuvant setting is totally inappropriate and carries between a 5-15% risk of causing HUS. This risk is based on cumulative dose and it is quite evident that was the case with Ms. Taylor. The long term effects of HUS include severe renal dysfunction and even chronic renal failure requiring dialysis and potentially renal transplant.
Thus, Dr. Medenica has taken an individual with a potential of at least 50% of being cured of her breast cancer with no adjuvant therapy, an improvement to perhaps 70% of being cured of her breast cancer with CMF and added a chemotherapy drug of no proven additional benefit which would provide her with as much as 15% risk of development of a severe complication which did occur in this case. I find this particular therapeutic decision to be virtually incredible.
I hope I am not the only reader to discern moral outrage in this piece pseudo-dispassionate medical noir.
I took off my hat to Howard as a writer, because here I am, working hard to get every line on paper, and here is this guy with a big day job, pouring great prose into a Dictaphone, leaving it to a secretary to transcribe, and possibly never looking at it again, because he got it right the first time.
It may not come as a surprise that the Taylor case resulted in a lawsuit and that a jury in Hampton County, S.C., awarded $14 million in damages to the plaintiffs (The Cancer Letter. Feb. 24, 1995). Alas, Gayle Taylor never fully regained vision and kidney function and succumbed to breast cancer and the consequences of her treatment toxicities at age 40.
Medenica didn’t do well after his encounter with Howard, me and the courts. He surrendered his medical license and ended up in a Swiss prison, serving a sentence stemming from fraudulent acts he had committed before becoming an American medical celebrity. He died soon after a year-and-a-half stint as a guest of the Swiss government (The Cancer Letter, Dec. 5, 1997).
Surprising data on ESAs
Ozer with professional hunter, Guav Johnson, and a bongo, in the jungle of Cameroon on April 2. On April 6, Ozer collapsed and died.
I met Howard at ASCO in 1993, a few weeks after my first Medenica story ran in The Cancer Letter.
After that, we talked every few months, which meant that I got to see a lot of pictures of animals Howard had added to his trophy collection. Memories of a snapshot of two hapless grizzly bears still make me sad, as does the photo of a white mountain goat—something arctic—that looked sort of alive, but, alas, wasn’t.
And then there is the bongo, striped, magnificent, flies on its carcass, its amber-tipped horns reaching toward the gods, Howard smiling victoriously above it, Guav, the guide, kneeling beside him, tactfully relinquishing the center stage for Howard to tower over his kill. It’s April 2. Four days from now, Howard will collapse, and Howard will die, yes, but, goddamn, who cares what any of us thinks of this scene, because Howard will drink in these four final days of ultimate, primal bliss.
Five years after I met Howard, in 1998, he agreed to be one of the three reviewers of a pile of data I received from the Houston alternative medicine practitioner Stanislaw Burzynski. This was Burzynski’s entire filing with FDA, and the story still constitutes the only real journalistic effort to learn what goes on in that clinic (The Cancer Letter, Sept. 25, 1998).
“It’s not FDA’s job to design the trials for Dr. Burzynski,” Howard wrote in his review. “Their job is to monitor safety, and make sure that the trials are ethical.
“Based on the data I have seen, I believe that compassionate use of this drug is inappropriate at this time. Compassionate use should be reserved for cases when you know that a treatment is likely to benefit the patient, but the patient doesn’t meet the protocol criteria.
“I would not allow Dr. Burzynski to continue enrollment of new patients in his study. He has enough patients to demonstrate anything that could conceivably be there.”
In the fall of 2003, I was looking into the erythropoiesis-stimulating agents and a war fought by two ESA sponsors, Johnson & Johnson and Amgen. This was an intricate controversy that had multiple moving parts that defied understanding. There was no way to understand any of it until you understood all of it.
I was trying to keep my involvement under control.
That was until Howard told me that he was perplexed by the results of several studies that started coming out in 2001. As a scientist, he believed that anemia contributed greatly to cancer deaths while survival advantages offered by chemotherapy drugs at the time tended to be small.
Hence, if you corrected anemia, it would be logical that survivals would improve; yes?
This is not what we are seeing clinically, Howard told me, pointing me to the TJ Littlewood publication in JCO in 2001, the Brian Leyland-Jones letter about the failed BEST study in The Lancet Oncology in August 2003, and the Michael Henke paper in The Lancet in October 2003.
The Henke paper attempted to test the hypothesis that increasing hemoglobin levels before irradiating patients would add to efficacy. Instead, EPO in Henke’s study added to treatment failure.
Now, that was something more significant than a brawl between two drug companies. This was harm to patients. This was worth following.
I made a bunch of calls, and produced a story that set me on a five-year quest (The Cancer Letter, Oct. 24, 2003). As I read it more than 15 years later, I am amazed how much I was able to understand from the outset, but I cannot take credit for the scientific erudition of the piece. That came from Howard.
To pursue a story like that, you need a panel of experts, people who follow the stuff and understand what you are turning up. Howard was one of the people I called every time I returned to ESAs, and more often than not Howard went on record.
On four occasions during his career, Howard rose to the job of cancer center director. He has served as director of cancer centers at Emory University, Hahnemann University, University of Oklahoma, and University of Illinois.
“I think he did enjoy every day,” said Schwind. “He was not a person who had a mundane routine. He was incredibly generous with his friendship, time and the talents that he had.”
Howard understood what it takes to earn an NCI designation.
“He worked tirelessly toward gaining NCI designations in multiple environments, and those academic centers are all better off as a result of his efforts,” Schwind said. “The work that we were able to accomplish [at UIC] was astounding. We had a very strong external advisory board that was with us for four years and did a great amount of work toward preparing us for a submission. We went out to NCI with the university leadership, including the dean of medicine, vice president for health affairs, vice president for research, and Howard and myself.
“We had a pretty solid draft of the application, but then there was a change of heart by the university administration in terms of the timeline and resources needed.”
After he was removed from his position as director of the UIC Cancer Center, Howard remained courteous toward his successor, Robert Winn.
“He was gracious to me when he could have been quite unpleasant,” Winn said. “Instead, he came up to me and said, ‘There is no secret to doing well in this job: you just keep your head down and work as hard as you can.’ Then Howard added, ‘I should have done more of that.’ He was a gentleman, he knew his stuff, and he was a great clinician.”
Clearly, Howard loved his work-life balance—and his hunting expeditions.
“He was a good person, old Howard,” said safari operator Johnson. “He was very softly spoken. He never got worked up or angry, a nice guy, probably too nice, you know. Never had anything bad to say about anything.”
The bongo never left Africa.
“I am going to keep the bongo in my home in memory of Howard,” Johnson said.
Howard is survived by daughter Trina and her husband Rajiv Matta, and his son Chris Ozer and his wife Erin. He had four grandsons, Arjun Matta, Leo Matta, Dean Ozer and Grey Ozer.