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The Kenneth B. Schwartz Center at Massachusetts General Hospital, Hematology-Oncology Department, Boston, Massachusetts, USA
Correspondence: Richard T. Penson, M.D., Hematology-Oncology Department, Massachusetts General Hospital Cancer Center, Cox Building, 100 Blossom Street, Boston, Massachusetts 02114-2617, USA. Telephone: 617-726-5857; Fax: 617-726-6974; e-mail: rpenson{at}partners.org
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ABSTRACT |
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The September 1999 Schwartz Center Rounds addressed the growing attention around the phase I trial of EndostatinTM. Endostatin represents a new treatment paradigm. It is an antiangiogenic protein, an endogenous fragment of collagen XVIII. In an attempt to ensure a fair allocation of a very limited number of treatment slots in this classical phase I trial, a lottery was established. More than 1,400 patients enrolled within 2 days of the lottery, all vying for three places in the first cohort. Two contrasting cases are presented, each a potentially eligible patient. The discussion focuses on the dilemma presented by patients desperate for an unproven treatment and the responsibility of staff to explain and support without compounding the hype or suffocating the hope.
Key Words. Endostatin • Phase I • Hype • Hope • Caregivers • Psychosocial
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PRESENTATION OF CASES |
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| In an attempt to ensure a fair allocation of drug, a lottery has been established...fourteen hundred people have been put on the list within the first week.
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The second vignette is of a 72-year-old man who has really beaten the odds. He was diagnosed with metastatic pancreatic cancer two years ago and has responded twice to gemcitabine and continues to respond. I am not aware, in the literature yet published, of anyone who has responded for this long to gemcitabine. He is actually a wonderful man and his wife is a wonderful lady. But every time I see him in clinic, they ask for Endostatin. Their plan is that they want to stop gemcitabine and get Endostatin and I tell them "no, I can't do that." Ultimately it's his decision. He is an interesting man because he had Hodgkin's disease 25 years ago, and this is probably a radiation-induced cancer. So he has a different perspective on treatment and what he wants out of life. He thought he was going to die 25 years ago and he's still alive. He thought he would be dead 2 years ago because the median survival is 6 months for patients with metastatic pancreatic cancer. And he's still going and has watched everybody else die, because people with pancreatic cancer kind of know each other in clinic. They share the same nurses and doctors. So every visit with this couple, as well as with most other patients, I spend nearly all my time talking about Endostatin. If I'm honest, I don't want him to get Endostatin, although clearly I can't stop him if he wants to go ahead and do it. And I do really want "Mary," my 23-year-old patient, to get it.
The Lottery: In an attempt to ensure a fair allocation of drug, a lottery has been established. A call center handles direct phone calls from patients and referrals from doctors and nurses. People who can walk patients through the criteria and help to evaluate whether they are eligible candidates or not, staff the phones and register patients. Registration forms are available on our web page and can be faxed to the Call Center. At a certain point in time, three patients will randomly be selected for the first cohort. Once people are selected, they will be assessed to make sure they are eligible for the trial. More prospective candidates may have to be selected. Fourteen hundred people were put on the list within the first week of opening to accrual.
Eligibility and Treatment: The Endostatin study is open to patients with any solid tumor. They have to be 18 years or older. They have to have reasonable kidney and liver function and have exhausted all curable or accepted standards of therapy. Their tumor can't be responding to any treatment. They have to have a good performance score and a predicted life expectancy of at least 6 months. Treatment is a 20-minute i.v. infusion of recombinant human (rh) Endostatin (NSC-704805), continuously 7 days a week for 28 days of a 42-day cycle. The objectives of the phase I clinical trial of Endostatin are to assess the safety of rhEndostatin, to determine the serum pharmacokinetics, antigenicity, effect on angiogenic proteins, alterations in endothelial cell proliferation and to evaluate tumor response to treatment with Endostatin.
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DIALOGUE |
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Cancer Resource Room Worker: The Cancer Resource Room is primarily staffed by social workers, with the exception of a couple of our oncology chaplains, nurses and volunteers, and that's no mistake. When people come looking for information, they come in frequently just after being newly diagnosed or having had a recurrence. They're really emotionally fragile, and they're not always just coming in for information. After the press release about Endostatin coming to MGH and the trial starting here, the Resource Room was just completely chaotic. You know, we had to call for backups and the answering machines were left on because we couldn't answer the phones. The people coming in were just desperate. People were calling from their deathbeds. There was at least one patient who died before we called him back. They were frightened. There is this new hope and the media is just expert at pitching miracles, advertising miracles and that's what it has been touted as. The people run the gamut from the very savvy, well-researched people to those who are just coming in saying I think there's some drug, I heard about it in the news, it's the cure for cancer. So it's had a big impact. From my colleagues' perspectives, it's had a huge emotional impact. We all know the patients are on a roller coaster continually. They try a new drug and then it doesn't work and then they try another new drug and it doesn't work. And it reminded me of a news report about the power ball lottery after one of the big jackpots was won, and how mental health hotlines and depression hotlines get more calls after lotteries because people are depressed. They start thinking there's something better, and unrealistically, expect that this could change their life. It's like the lottery of life. Most of them with a relatively short life expectancy think about the possibility of a miracle. I think that it's a heavy cost in this round of science.
| Presenting a phase I study to a patient can feel like walking a tightrope between providing hope and a realistic portrait of expectations.
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Physician: I had a patient say to me the other day, "It's sort of like, you watch a war movie and they sign the peace agreement. You look at the soldiers still fighting each other and you're thinking, God, you don't want them to get shot after the peace agreement has been signed. Sort of that same kind of feeling that you don't want to miss out, to miss that chance."
Facilitator: This is a highly emotional field; and you need to feel you have some control over the emotional atmosphere. You must just feel assaulted by the media. I can't imagine how you say to them, "but your chances are very, very slim on this." How do you say that and balance it off with, "I want to give it to you and help you."
Phase I Trialist: I don't know. Everybody is different. In part it's the problem with phase I studies. When I meet phase I patients for the first time and they're under the care of another doctor, within the first 5 minutes, I'm trying to gauge how much they know and what their expectation is. We all know that for most patients on phase I studies, the prognosis can be very bad. Therefore, presenting a phase I study to a patient can feel like walking a tightrope between providing hope and a realistic portrait of expectations. When it comes to Endostatin, I would say, except for this particular patient, "Mary," I have downplayed it in an effort to cancel out my own bias. But I'm aware of this only in retrospect.
Facilitator: I think one of the things that your case scenarios point out is that we're not neutral stakeholders in this particular set of stakes.
Oncologist: I've also had patients ask me "how can I get Endostatin." I've also had patients who, without telling me, have gone to see a doctor at the Brigham & Women's Hospital and a doctor at Beth Israel hoping that they will get three chances. They've also gone to Wisconsin and down to Texas. Along those same lines, another patient called me up and said, "I don't think you understand who I am?" and I said, "No, I don't know you." He said, "I can give several million dollars to the MGH" and I said, "I'm sure you can, but there's a lottery system." That's one of the nice aspects of the lottery system. One of the members of the Scientific Review Committee (SRC) said "if we don't have a lottery system, the perception will be that we'll have an auction for Endostatin." And I think the amount of money people would be willing to pay would really be staggering. I said to him, "I think you probably could get the drug, if you bought EntreMed," and then he said "how much would that cost?" "At a market capitalization of about 490 million dollars, it would probably cost you twice as much." And I realized that even at 900 million dollars, there are several hundred people who could do that.
Nurse: It's very emotional when a patient comes to me and says "You know this might be my last chance" and I try to reinforce that there are other options, that this isn't her last hope. "Mary" actually was accepted into a program in Washington, D.C. for a ras vaccine. It's really emotional when patients breakdown, and they say this could be their last hope. You really have to reinforce that there are numerous other phase I studies we can try. But it's really been an emotionally draining time for everybody.
Facilitator: Maybe I'm taking a Pollyanna approach but if what they're asking is for you to join them in their effort to live, then you obviously want to say "I want you to live." Maybe it's too hard for you, because they're pushing you too hard but can you say "here are some other ways you can do it." How do you explain the options?
Phase I Trialist: I usually start off by saying that very few drugs were designed to do exactly what they do. Most really, really good drugs have been discovered by serendipity. And the fact of the matter is we're very good at explaining why drugs work after the fact. Before the fact, anything that makes it to phase I has looked good in preclinical testing. I mean part of the hype that has been so frustrating is that every drug that makes it into the phase I group, well almost every drug, kills cancer in mice. Yet, the reality is that very few people benefit from phase I drugs. Even the phase I trials of paclitaxel (TaxolTM) only demonstrated responses in a few patients, and it is the greatest drug to enter the clinic in the last 10 years. Am I doing a disservice to a patient if they don't understand that most people who enter into a phase I study have actively entered into the dying process? For patients who really are sick, I feel a certain obligation to make sure that they understand their situation on some level. And so, perhaps I start off on a cynical note and if I think they understand it, then I get a little bit more hopeful. Perhaps a more hopeful approach would be better. Ultimately, it's the patient's decision to proceed.
| The reality is that very few people benefit from phase I drugs; and even the phase I trials of Taxol only demonstrated responses in a few patients, and it is the greatest drug to enter the clinic in the last 10 years.
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Oncologist: If you just look at what Endostatin does in mice by itself it is actually no better, and probably inferior to most of the drugs which we are currently offering in other phase I studies that are open. So imagine if you were a mouse with cancer and you came in and you wanted an honest consult about Endostatin, taxotere, CPT-11, and oxaliplatin or NX-211 or SarCNU or any other drugs that we have open. The mouse says, I want to know which one of these, by itself, has the best chance of getting me free of cancer. Endostatin would actually be at the bottom of the list as a drug by itself. It does interesting things when mixed with other molecules but those other molecules are not part of this study. So yes, we don't have people kicking down the doors saying if I don't get SarCNU, I'm going to have a fit. As a matter of fact, nobody knows the names of any of the other drugs that are on the phase I list. It's easy and quick to blame the press: they hyped it, but we're part of that hype. This study is going to open up and my guess is there are going to be several thousand people on the list and that it will be covered in The Boston Globe. But isn't that partly the medical profession buying into the hype? The fact that there is at least a passive, OK, I'll register you, leads us directly or indirectly into the hype.
Oncologist: I also get concerned when other people start blaming the media. The media is us. The media isn't some conspiracy that's out there, that tries to run society. The media reflects what we want to read about. What we want to see. That's all they do. What concerns me is the flip side of this. Think of the households. Here we have 100 people in this room and we're talking about the stress we have about Endostatin. But think of the thousands of cancer patients who are either fighting cancer now or who are surviving cancer or who had cancer, think of them and their families as they wait and find out that the first several patients weren't cured with Endostatin. Think of how many people are holding out their hope that Endostatin is going to be the answer, that it's going to be the cure.
Oncologist: To a certain extent we have all been caught. We're all talking with our hearts more than our brains. You heard DR tell about this 23-year-old woman. He said "I want her to get Endostatin" and this is a guy who is as cynical as they get, and yet deep down in his soul he wants this 23-year-old woman to get Endostatin. I think that tells you everything.
Phase I Trialist: It's hard to explain why I want that part of it. I'm sure I'm caught up in the hype. But part of it is, it's a novel concept. This drug represents a new way to think about cancer to a certain extent. It's not just another cytotoxic. Do I think it's going to work deep down in my heart? No, but on the other hand, I want to do something good for my 23-year-old. I'm caught up in the hype to a certain extent. Hell, I bought a power ball ticket.
Facilitator: How'd you feel when you lost?
Phase I Trialist: Usually what happens is I just toss the ticket in the car and then I can't find it.
Facilitator: I work with patients and families around these end-of-life issues. Part of my fear is that it will become a scapegoat. There are different levels of comfort that physicians have in saying, "I'm done, I really don't think anything else is going to work." It's very easy to say, "I'll put you on the list and keep that hope running." It's painful to see that families aren't going to do the work they need to do or have quality time together. Time that they need to have because they're just going to keep on holding out and pursuing one more drug in the arsenal. Yet, it's hard to take away their hope.
| Endostatin therapy is extremely unlikely to be the sole cure for cancer, but hopefully it can be used in combination with other treatments to stabilize the disease and as an important adjunct to adjuvant treatment.
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Nurse: Another issue that the lottery stirs up is it maintains hope but it is such a limited resource. One of the things that I think American medicine struggles with is the notion that nobody should be denied anything. What the Endostatin study has set up is a sense that only three people out of all the people who want the drug will be allowed to have it. That pulls for anger in the process of coming to terms with the end of life. There are always a host of emotions, difficult emotions, at the end of life. To give people a concrete hope that in fact, there is one more thing out there they heard about, that somebody is going to get, and they're not that somebody, adds to the anger. Why are you keeping this from me? People are elbowing each other trying to get into the trial.
Oncologist: You need to remember that the other thing about the lottery is that it is designed, not only because of limited resources, but because we have no idea if this drug causes harm. Everyone has been talking about it as if it doesn't have side effects. How do we know that in humans it's not going to cause massive strokes? So part of the reason it has to be controlled in terms of the way it's used at first is because the fact is, we have no idea what the toxicity profile of these compounds will be like. There is an analogy to the development of drugs against AIDS. In the AIDS situation a lot of these new drugs were allocated by lottery and it seemed to work pretty well and allowed them to study them in a systematic way to find out which ones work and which ones don't.
Nurse: In the infusion unit they do all talk to each other and everybody knows what everybody's getting. How do we handle that?
Facilitator: I guess that's a situation where I personally would want to get together with my colleagues and brainstorm about it. There is something unique about it but it also isn't totally unique. You have to deal with this in all kinds of ways regarding what patients know about, what other patients are going through, the jealousy and who gets most help and so on. There's a whole social interaction aspect to it. There is this whole thing of "why me?" and who gets chosen with any fatal illness. Also, I would think it would be really important to talk with their other caregivers to find out what they're saying to them. It might be worthwhile having some kind of institutional support not only for the caregiving staff but also for the patients and the families. This is really something people have to pull together on. It's very easy for people to scapegoat each other and their frustration on this, or to see someone as being too cynical or denying people the chance to work on the truth of what they're facing by being too optimistic. So, the more you can talk with each other openly about it, the more you can get clear about how you feel and where you stand.
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DISCUSSION |
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| Currently, about 19 angiogenesis inhibitors are being tested in human trials.
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Endostatin: Flagship of a New Paradigm
Angiogenesis, the formation of new microvessels from existing vasculature, is fundamental to reproduction, development, and repair. Physiological angiogenesis occurs as brief bursts of tightly regulated capillary blood vessel growth in an otherwise quiescent endothelium. Tumor angiogenesis is essential to enable growth beyond a few millimeters in diameter. The switch from the resting state to the angiogenic state appears to occur as a result of a change in the net balance between angiogenic and antiangiogenic factors [4].
Inhibition of angiogenesis may result in cessation of tumor growth and metastasis as well as the regression of established tumors. The hunt for an antiangiogenic factor was based on the surgical observation that the removal of a primary sometimes leads to the "wild-fire" progression of metastatic disease, perhaps because of the loss of an endogenous inhibitor. Endostatin was eventually isolated from EOMA, a murine hemangioendothelioma. It is a 20-kD fragment derived from the carboxyl terminal of collagen type XVIII, a protein localized mainly in the perivascular basement membrane. In mice, using the Lewis Lung Cancer Model, treatment with Endostatin caused tumor regression and appeared to induce indefinite dormancy. Encouragingly, the tumors did not develop resistance to the drug and there were no apparent side effects [5].
Currently, about 19 angiogenesis inhibitors are being tested in human trials. Most are in phase I or II studies. Five drugs are under investigation in phase III trials: Marimastat—non-small cell lung, small cell lung and breast cancer; AG3340—non-small cell lung and hormone refractory prostate cancer; Neovastat—non-small cell lung cancer; Interferon-alpha and IM862 in AIDS-related Kaposi's sarcoma [6].
To prove the concept of therapeutic antiangiogenesis, evidence from phase III trials demonstrating improved survival required a huge investment. Some phase II studies may demonstrate proof of principle and provide a surrogate for survival data, using biopsy material and microvessel density examinations [7], molecular signatures or imaging with MRI or PET [8].
Hyping Hope
Within a year of the report of the discovery of Endostatin, it was on the cover of Nature and named "resistance-free cancer therapy" [9]. On May 3, 1998, Endostatin reached the front cover of the Sunday New York Times. In the article Dr. James Watson, father of DNA, was quoted saying, "Judah is going to cure cancer in two years" [10]. The next morning the stock price of Entremed, Inc., the biotechnology company developing Endostatin production, rose from about $10 to $85. However, by the end of the week, the price plummeted to $33 [11].
The initial excitement was soon followed with stinging criticism when on November 12, 1998, The Wall Street Journal reported that Dr. Folkman's results could not be reproduced by researchers at the National Cancer Institute. Subsequently, research has confirmed that Endostatin strongly inhibits tumor growth in mice [12].
Cancer research is not without its frustrations. On December 23, 1971, President Richard Nixon signed the National Cancer Act that was to provide, "a total commitment of Congress and the President to provide the funds for the conquest of cancer." Soon after the Act was signed, the first monoclonal antibodies were developed in 1975. Research has focused on using them in both cancer diagnosis and therapy. Yet it was not until 1986 that Muromonab-CD3 (OKT3) (Ortho Pharmaceuticals; Raritan, NJ), was approved for immunosuppression in patients with renal transplants followed in 1997 by the licensing of the first monoclonal antibody for the treatment of cancer, Rituximab (IDEC Pharmaceuticals; San Diego, CA).
Advances in cancer research are often not predictable. Cisplatin, a platinum salt, has emerged as a principal chemotherapeutic agent and is currently among the most widely used cytotoxic drugs in cancer chemotherapy. Cisplatin was discovered serendipitously as a result of the observation that bacterial cells stopped dividing in the presence of alternating current delivered through platinum electrodes [13]. The introduction of cisplatin into the treatment of testicular cancer dramatically improved survival [14].
Advances in cancer treatment can take a long time to fulfill their promise. Paclitaxel, the most potent cytotoxic to be introduced since cisplatin, was discovered in 1964, isolated from the bark of the Pacific yew tree. Its structure was described in 1971. It entered phase I trials in 1983, and was finally licensed by the FDA in 1992 for clinical use in refractory ovarian cancer and in 1994 for breast cancer [15].
| The biggest side effect of the phase I study may be disappointment. Not that the drug or the study is expected to fail, but that demand has grossly outstripped supply and that to adequately regulate a study, only a very limited number of patients can be treated.
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Interferon was the first human protein shown to be effective in cancer treatment, and often labeled a "silver bullet." Interferons have antitumor and antiviral actions. In some ways the development of the interferons may parallel that of Endostatin. Although interferons are currently approved for use in patients with hairy cell leukemia and melanoma and are commonly used in patients with renal cell carcinoma and chronic myelogenous leukemia, there has at times been an uncomfortable transition from hype to an established role [16]. Interestingly, the discovery in 1988 that interferon-
2a was antiangiogenic lead to the first successful antioangiogenic therapy in humans, with its use in life-threatening hemangiomata [17].
Hype and Expectations: The Harbingers of Disappointment
There is too much at risk to allow science to be just trial and error. If the studies of Endostatin prove disappointing, they have to be conducted such that most can be learned about this promising new agent and how antiangiogenic agents can be incorporated into the management of cancer in a way that may eventually control it as a chronic disease or effect a cure.
Although concerns about vascular integrity, wound healing, chondrogenesis, fertility, and teratogenicity are valid, the biggest side effect of the phase I study may be disappointment. Not that the drug or the study is expected to fail, but that demand has grossly outstripped supply and that to adequately regulate a study, only a very limited number of patients can be treated. When patients hear that Endostatin eradicated cancerous tumors in mice, their understandable question is "should I get it?" The oncologist has to explain to the patient what is currently known about Endostatin, describe the process of drug discovery and how new agents are introduced into clinical practice, and clearly address any misconceptions that patients may have. What happens to the patients who enter the lottery but do not receive Endostatin? The task of encouraging realistic optimism becomes more difficult and suggesting that alternative options for standard treatment may help becomes less viable. Increasingly such patients pursue other novel anti-cancer therapies. These include gene therapy, cancer vaccines, antisense therapy, and monoclonal antibody therapy [18].
With the hype over Endostatin, our expectations may have become unrealistic. Is the cure for cancer in our hands? The reasons that people go into this field are complex. The motives can be noble ones of academic curiosity and compassion. But, inevitably, staff are vulnerable to the frailties of humankind. It is helpful to be aware of dysfunctional defense mechanisms, which appear to offer some solace, but which prevent us from maintaining a degree of objectivity in our work. For physicians these are typically denial, chronic hypomania, intellectualization, and self-destructiveness [19]. To this should be added, "riding the tiger" of unrealistic hopefulness. Try to get off and you're eaten!
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CONCLUSION |
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ACKNOWLEDGMENT |
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FOOTNOTES |
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REFERENCES |
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