Monday, May 3, 2010

The National Cancer Institute's Broken Clinical Trials Program and The New York Times

There was an editorial in The New York Times last week on a report by the Institute of Medicine on the NCI's clinical trials program and its difficulties. The editorial made the point that the clinical trials effort is at the heart of transferring technology to cancer patients, and that it needs fixing.

The IOM report and the editorial missed the major problem, however. So did the letters to the editor on Sunday 2 May from Drs Doug Blayney and Alan Lichter, on behalf of the American Sociey of Clinical Oncology, and from Dr  Bruce Chabner, Clincal Director at Massachusetts General Hospital Cancer Center in Boston.

Blayney and Lichter extoll the virtues of the clinical cooperative groups and claim that the problem is money. They are underfunded, they say. True. Chabner points out that the  NCI's cooperative group program is no longer the main instrument for developing new treatments anyhow. Also true. (In fact they never were. But that's another story.)

But everybody missed the main source of the problem: over regulation.

Apparently this is too much of a lightning rod for people to discuss in public. Over regulation, in the name of patient safety, affects both cooperative group and industry studies. In the name of protecting patients from harm they stifle new developments and instead "protect" patients from access to new treatments.

I refer the reader to an editorial I wrote on this subject in 2009 for Nature Reviews Clinical Oncology and reprinted on this blog shortly thereafter. Pumping money into the archaic mechanisms of doing clinical trials in NCI's cooperative groups won't do an ounce of good if the structural problems aren't fixed first.

Friday, March 12, 2010

A Possible Breakthrough: Personalized Treatment for Hodgkin's Disease

My friend and colleague, Jose Costa, and I recently had an opportunity to write an editorial about  an exciting paper by Steidl et al.  published in The New England Journal of Medicine on March 11, 2010. I thought it would be worthwhile reprinting some of our commentary here because I think the data may be what we've been looking for when it comes to changing the direction of the treatment of Hodgkin's disease. 

The data provided by Steidl and his colleagues, in fact, offer the breakthrough we have been looking for to select patients with a particularly poor prognosis, regardless of stage, for more-aggressive treatment and bring more logic to the treatment of this very curable malignancy.

Steidl and his co-authors discovered a gene signature of tumor associated macrophages and monocytes in patients with Hodgkin’s disease that correlated with outcome. Remarkably, they were able to validate the correlation in an independent cohort of patients using CD 68—an immunohistochemical marker of normal macrophages. 
The correlation of CD 68 positive macrophages with outcome was striking. All patients with limited disease, minimally positive for CD 68, were alive and free of disease at the time of the report. The association of CD 68 positivity and disease specific mortality rates was strong in all subsets analyzed. In advanced disease the correlation between macrophage number and progression-free survival is significant.

This study provides a rationale for the use of molecular tools when effective treatments are available but we cannot prospectively separate those who will be cured from current treatment from those who will not respond. 

Hodgkin’s disease is a good example of this type of situation. For almost 40 years now, early stage disease has been curable by radiotherapy, and combination chemotherapy can cure both early and advanced-stage disease. Despite an overall cure rate of around 80%, treatment has stagnated in the past two decades because of the absence of precise markers that can predict response to therapy. As a result of this situation most patients, especially those in early stages of disease, are over treated— they receive radiotherapy and combination chemotherapy. As a consequence, long term toxicity from treatment is significant. 

In some studies where young women have received both chemotherapy and radiotherapy, the incidence of beast cancer reaches almost 30% at 15 years after treatment. Almost all patients with classic Hodgkin disease will go into remission with initial treatment but about 30% of patients with advanced disease and almost 15% of those with early stages of disease will also relapse. Early relapses in patients with both advanced and localized disease treated with chemotherapy defines a drug resistance subset of Hodgkin’s lymphoma. This group carries a very poor prognosis through all subsequent treatment approaches including high-dose treatment with stem cell support.

It is of considerable interest that early relapse from complete remission carries the same poor prognosis in all tumor types where remission is possible, suggesting a common mechanism of resistance across tumor types. If at the time of diagnosis we could identify the small subset of Hodgkin patients who are destined to fail to respond to chemotherapy, most patients could be spared the use of a combination of modalities as initial treatment, especially radiotherapy, that is associated with long-term toxicity.    

The Reed–Sternberg (R-S) cell is unique amongst lymphoma cells in that a number of important signaling pathways have been shown to be constitutively activated, including the JAK-STAT, receptor tyrosine kinases, NF-kappa B and other pathways. The R-S cell also secretes numerous cytokines, including granulocyte-macrophage colony-stimulating factor, which may be responsible for the assembly of inflammatory cells in involved lymph nodes. It has been termed the master regulator of the surrounding inflammatory response.

Almost all tumors types are invaded by macrophages and it was once thought that this invasion represented a host immunological response to the tumor. However, most evidence now links tumor-associated macrophages (TAM) with a poor prognosis, as demonstrated in the study by Steidl and his colleagues. Termed ‘tropic macrophages,’ TAMs bear a close resemblance in function to embryonic macrophages associated with cell migration during development.These macrophages have been shown to mediate blood vessel formation by regulating the angiogenic switch through secretion of VEGF and hypoxia inducing factor.

Migration of macrophages to areas of the tumor seems to be a late event in Hodgkin disease. It is difficult to explain the impact of trophic macrophages on response to treatment unless at some point in the evolution of the disease, a critical pathway to apoptosis is crippled in the R-S cell and this is associated with the secretion of a cytokine that leads to macrophage infiltration of the tumor. Such an event could inhibit cell death in response to cytotoxic treatments. 

Thursday, February 25, 2010

Rationing Health Care is Bad for Cancer Patients

       The current bill before  the house and Senate does a disservice  for cancer patients. It is not correct to say,  " it's true that some people are covered well, but many are not" as I have heard said by people who should know better. It's more correct to say that ,"most Americans  are covered well in the current system." This is especially true of cancer patients. So be careful what you do to change it.
      Cancer patients suffer most when they try to change jobs and are denied health care in a new job because of a preexisting  condition or when the amount they can spend on health care is capped. Like most Americans, they are also concerned about cost of insurance as well.
      In prior postings I exposed the numbers game used by those who support this bill for what it was, a bogus use of numbers to scare the American people into reform they don't need and don't want. There are not 47 million Americans uninsured. Even President Obama has begun to use a lower figure, 30 million,  a little embarrassed , I think , to be caught  using a number no one bothered to check ( this is still an overestimate). The American Cancer Society should feel some embarrassment for doing the same thing.
     But what is as clear as can be is that there is no way the current House and Senate proposal can stay within budget without rationing care. And people I know close to the administration say to me " get real, Vince, rationing is coming". They barely hide this although they don't trumpet it for fear of scaring more people away. They do admit to the need to cut billions from Medicare though.
     The preferred method to decide what to ration is to use "Comparative Effectiveness Research"(CER) to decide what should be approved. A billion dollars has been allocated in the bill for this. The best way to characterize CER is to say that it compares yesterday's therapy with that of the  day before yesterday. It is always behind the curve. The newest approaches need not apply. Cancer patients always get the short end of the stick when care is rationed.
      Look at the UK's National Institute of Clinical Excellence ,(acronym ,NICE -British doctors refer to it as "not so nice"). Their decision to deny coverage for the use of the drug Erbitux in patients with head and neck cancer was one example of  a feckless disregard for cancer patients. There are more. Studies have shown an enormous, statistically significant, difference in survival for those who are irradiated with Erbitux compared with those who don't receive it. Yet they denied coverage.  They actually don't even question the data, they just say it is not cost effective to use it. In other words if you have the misfortune of having head and neck cancer in the UK, you are not worth saving.
      This is the system the bill tries to emulate. It includes commissions to determine standard of care ( in the cancer field, " standard of care" is a moving target ) and authorities to the secretary of HHS that would allow her to limit the use of new technology even without  CER, as NICE did in the UK with Erbitux. The new drug from Plexicon, to which every patient with metastatic melanoma should have access, wouldn't even be considered for CER.
      They know they will need to ration care to pay for this version of health care reform. At the most exciting time in the history of cancer research, when new clinical advances are being made every day in the cancer field these provisions would  stop clinical innovation in its tracks.
      What is needed for the cancer patient is a stepwise approach that preserves the best of the current system and provides more security . Like most people I could write a bill in  ten pages to do this, not the  2,700 pages in the current bill.
      Prevent denial of coverage for a preexisting conditions, remove caps on the amount of coverage and allow insurance to be purchased across state lines. This would do it for cancer patients and save hundreds of millions of dollars as well.
       It's the many mandates included in some state's policies that drive up cost. Purchasing across state lines would allow more people to buy less expensive policies that suit their purposes. This might mean giving up some of our precious  mandates but  isn't it is better to cover more cancer patients well, than force policies on them with too many mandates that are too expensive to buy? 
      Frankly I don't see any organizations purported to be speaking for the interests of cancer patients telling the congress the specifics of what they need and, most especially ,what they don't want. We need the three things mentioned above and we do not want  a system that will require rationing of care .
     Oh , and by the way, the Congressional Budget Office estimates the new bill would still leave 10 to 19 million people uninsured , which is more than are truly uninsured now.