Changing the Paradigm of Chemotherapy

gdpawel

Thirty years of randomized clinical studies point to the need for changes in our approach to the chemotherapy of the most common forms of adult cancers. Despite reportably doubling of response rates, there has been no hint of improved overall patient survival.

Experience in metastatic breast cancer is very informative and indicates this lack of improved overall patient survival. Back in the early 70s, the median survival for metastatic breast cancer was just under two years. Today it is precisely the same, just under two years. In scores of prospective randomized trials involving tens of thousands of patients, response rates have gone up. Some patients unquestionably have their lives prolonged by years. Yet the overall survival rates have not improved.

The reason may be because it's all a zero sum game. You give more aggressive chemotherapy in diseases like metastatic breast cancer and you increase response rates, but you don't improve overall survival. The true situation is not that either chemotherapy works or it doesn't. The true situation is that ineffective, aggressive chemotherapy can diminish not just quality of life but also quantity of life, through organ toxicity, immunosuppression, or by inducing mutations in genetically unstable tumor cells to make them more aggressive. The result is no improvement in the treatment of the most common forms of metastatic cancer over the past 30 years

What you may want to do is to reserve the aggressive therapy for those patients who will derive more benefit than harm, while identifying the most promising treatment regimens for everyone. In patients with tumors very resistant to cytotoxic chemotherapy in general, the most promising treatments may include angiogenesis inhibitors, growth factor inhibitors, or more holistic therapy approaches.

It could be that a better approach for treating recurrent cancer is not to give more aggressive and toxic and mutagenic and immunosuppressive combinations, but to give targeted single agents, or to give the least toxic and mutagenic active combinations. Higher response rates don't necessarily lead to improved clinical outcomes.

The era of empiric, aggressive, multi-agent cytotoxic chemotherapy for recurrent/refractory adult solid tumors should come to an end. We should put much more emphasis on matching treatment to patient, through the use individualized testing, have more respect for minimal partial response or stable disease, when it can be achieved through the use of least toxic and mutagenic drug regimens, and reserve the use of higher dose therapy or agressive combination chemotherapy to those fortunate patients with tumor biologies most amenable to attack and be subjected to total or near-total destruction by these aggressive treatments.

The hallmark of cancer is heterogeneity. Not just many types of cancer (ovarian, breast, lung, colon, etc.), but many subtypes of cancer within a given type. Many types of ovarian cancer. Many types of breast cancer. Many types of lung cancer, etc. The biologies are very different and the response to given drugs is very different.

The hallmark of cancer treatment is heterogeneity. There are currently over 100 FDA approved cancer drugs, with hundreds more in the pipeline. All of these drugs tend to be partially effective, and even then, in only a minority of cases, and often for only a short duration of time.

The single most neglected area of cancer research has been the development of methods and technologies to be "matchmakers" between individual cancer with individual cancer treatment.

The single most neglected area of cancer treatment has been the unwillingness to utilize, or even study, the matchmaker technologies which have already been developed and which are already available. These technologies involve studies of cancer cell responses to drug exposure in cell culture systems, "outside" of the patient's body, before they are put "into" the patient's body.

One of the ways of matching the treatment to the patient is assay-testing. Not all patients will have the same response to the same chemotherapy. Special laboratories can test tumor samples from individual patients to see which chemotherapy drugs have the best likelihood of killing tumor cells and optimizing survival. The results provide medical and surgical oncologists with patient-specific tumor information that may provide additional insight when determing the appropriate course of treatment for a patient.

Assay-testing focuses on the unique characteristics of a particular cancer. The test results help the physician to determine which anti-cancer drugs are "likely" to be effective against a particular cancer. The assay test also helps the physician to determine which anti-cancer drugs are "unlikely" to affect a cancerous tumor, which can help to avoid toxic and possibly ineffective therapy.

The tests have a specifity (for drug resistance) of 0.92 and a sensitivity (for drug resistance) of 0.71, which means that a treatment regimen "not" resistant in the assays is 7-9 fold more likely to work than is a treatment regimen which "is" resistant in the assays. A preponderance of evidence would indicate that it would be worthwhile to consider the assay results in drug selection.

For more information about the technology of assay-testing:

http://www.positivehealth.com/test/articles.asp?i=1832

leo · Site Admin Joined: 23 Sep 2004 Posts: 1574

Dear gdpawel,

I understand the need for more effective therapy, but it is really untrue that in 30 years we haven't made a difference in survival. If you saw the patients I see you would understand; and it's not just here.

best regards,
Dr Leo
_________________
Leonardo F - Webmaster Cancer Forums
Disclaimer: this information is for informational purposes only. It is not medical advice.

gdpawel

Leo

Actually, I have seen the patients. My wife had chemotherapy in 1972 (before the drug concession), and then again in 1997 (after the drug concession). Before, she took it with ease. The postoperative drug she took, Chlorambucil (Leukeren) was among the slowest acting and least toxic of the alkylating agents (well tolerated oral drugs). Depression of the immune system was slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells. She went twenty-four years before experiencing any recurrent cancer.

She could not believe what happened in 1997. Infusion-therapy, given in big doses, with breaks of several weeks between doses to let the body try to recover (or else it can kill a patient). Spending five days before therapy (shooting up). Then spending five days after therapy (shooting down). The effectiveness of her combination regimen was limited because of the late stages of her recurrent cancer and most patients develop resistance. Most cancer patients have the drug bounce off their tumors, doing little if any good (in her case, and thousands of others, totally worthless). We met numerous other patients during her treatment that didn't make it (they died while being treated).

So yes, I've seen them. I look forward to the day that "infusion" therapy goes by the way of the Neanderthal.

leo · Site Admin Joined: 23 Sep 2004 Posts: 1574

What you do not realize is that infusion or oral drugs act in the same manner, t is just a different way of giving it. I would like to give pills to everyone, it is just chemically not possible to make some compounds absorbable. I've said before and will say again: there have been major advances in treatment, but people still continue to die of metastatic disease, unfortunately. It does not mean nothing has changed. They do live longer in most cases.

best regards,
Dr Leo
_________________
Leonardo F - Webmaster Cancer Forums
Disclaimer: this information is for informational purposes only. It is not medical advice.

gdpawel

Due to more people not smoking, detecting cancer eariler, the use of more mammograms, etc., more lung and breast cancer cases, and others, are being detected earlier and this results in statistical increases in survival when dated from the day of first detection.

brainman

I do not know what it is like to have best cancer. But I hear the plain in your posts gdpawel. It does seem like we are trying to swim up-stream but just keep falling further and further behind.

We [b][u]have[/u][/b] made great strides over the last 30 years. You said that most of the improvements are due to early detection, people not smoking as much, and improvements it technology. These play a part in the over all improvement in “cure” rates. We should continue to impress on people how some elements in their live-style could lead to a future encounter with cancer.

However, we have also made great improvements in the area of medical oncology (chemo) and radiation oncology. I have a primary brain cancer first diagnosed in 1992. Yet hear I am, 13+ years later due to chemotherapy! I am old enough to remember times when my diagnosis would mean probable death within 3-5 years. So, I gave up 13 months of my life to chemotherapy. But it gave me 13+ wonderful years of meaningful life.

I can remember times when breast cancer was almost always a death sentence. No, it is almost always curable. Not just put it into remission… curable! It is the only cancer that many of my oncology friends will actually describe as curable.

Nevertheless, by nature, chemotherapy is a poison! It has always been. I do not know much about drug toxicity, however, it would not surprise me to find out that over the last 30 years our chemotherapeutic drugs have become more toxic. And, gdpawel, I hate to point out the obvious, but… your wife is also 30 years older which makes it harder for her body to tolerate chemo. I wish that over the last 30 years we had found THE pill… I am willing to go for an injection… that would keep women from having breast cancer. But to say we have not made significant progress… No, I can’t say that.
_________________
Jim
Site Administrator and long-term cancer survivor
1992 Astrocytoma grade 2, left motor strip
2005 Recurrence this time said to be an Oligodendoglioma grade 3, same location.
My Story Part 1: http://cancerforums.net/viewtopic.php?p=7350
My Story Part 2: http://cancerforums.net/viewtopic.php?t=8029
Blog http://jimhawkinsport.blogspot.com/

gdpawel

Sometimes I go along with what the scientists conclude. In the March 15, 2004 issue of the Journal of Clinical Oncology, an editorial stated that a review of all the large, prospective, randomized trials published comparing the newer taxane-based regimens, none of these regimens have increased either complete response rates or overall survival, with median survivals remaining at two years or less. This is precisely the same results which were being obtained 30 years ago.

The January 10, 2002 issue of the New England Journal of Medicine noted that 20 years of clinical trials yielded survival improvement of only 2 months for patients with advanced lung cancer. It also pointed out that oncologists at a single institution may obtain a 40-50% response rate in a tightly controlled study, but when these same studies are administered in a real world setting, the response rates decline to only 17-27%.

In the September, 2002 issue of The American Journal of Oncology Review, there was a commentary by Lawrence N. Shulman, M.D., Vice Chair for Clinical Services/Adult Oncology, Dana-Farber Cancer institute (Harvard Medical School), Boston. His commentary described the complete lack of progress in the chemothereapeutic treatment of metastatic breast cancer since 1970.

The results of nearly 30 years of clinical investigation in the treatment of patients with metastatic breast cancer, neither standard or high-dose chemotherapy had done a great deal to improve the outcome of patients with this disease. For over the past 20 years, we relentlessly combined chemotherapy agents in various regimens with ever-increasing dose intensity and the survival for patients participating in these studies was exactly the same, less than two years. Not a hint of significantly improved survival.

Dr. Shulman noted that a retrospective comparison, well-characterized standard-dose database with a less well-characterized high-dose database suggested that there was increased early mortality for high-dose therapy. Highly selected patients whose tumors are responsive to chemotherapy can have long-term remissions from standard-dose chemotherapy. One large randomized trial showed no difference in survival for patients treated with standard-dose versus high-dose chemotherapy. The median survival for both groups was two years, and no subset of patients seemed to benefit from high-dose therapy.

Even if one were an optimist and concluded that the high-dose data suggested that a small subgroup of patients benefited from this approach, one must remember that the patients participating in these studies are already highly selected for age, performance status, response to induction therapy and other factors. At best, it must be helping only an incredibly small percentage of the patients with this disease.

According to clinical investigators, reference is made to "remission" or "clinical response" (tumor shrinkage), and not "cure." If a patient's condition changes even for a week or a month, the patient is listed as having "responded" to chemotherapy. The fact that the tumor comes back stronger soon after treatment is stopped, is not figured into the equation. Tumor shrinkage should not be the criteria for approving cancer drugs. The system needs major reform.

That being said, there are some advantages to chemotherapy. Even today, 90 percent of all drug cures occur in only 10 percent of cancer types that are intrinsically drug-sensitive, e.g., Burkitt's lymphoma, Choriocarcinoma, Acute Lymphocytic Leukemia, Hodgkin's Disease, Lymphosarcoma, Embryonal Testicular Cancer, Wilm's Tumor, Ewing's Sarcoma, Rhabdomyosarcoma, Retinoblastoma. While most of the other 90% can be treated as a "cronic" disease, if the patient has the correct regimen of drugs.

Clearly, more effective therapies are desperately needed for women with metastatic breast cancer, and other cancers, and after 30 years of investigation aimed at intensified multi-agent chemotherapy, we should look for other avenues of study. The fact that regressions of breast cancer had no influence on overall survival must reflect the inadequacy of present-day chemotherapy. How the use of chemotherapy which induces responses in some patients, cannot have affect in overall survival? Does chemotherapy shorten survival of some patients, while prolonging the survival of others?

It's a zero sum game.

It is likely that surgical skill is a more important determinant of prognosis than the aggressive nature of the cancer or its stage at diagnosis. In cancer treatment, surgery is generally used if it can "cure" the cancer. In addition to efforts to detect cancer in its early stage and treat it appropriately with surgery and proper chemotherapeutic drugs, newer methods of management must be investigated. These include intraperitoneal chemotherapy, use of biologic response modifiers, combinations of multi-agent chemotherapy with whole abdominal radiotherapy, photodynamic therapy, and chemotherapy based on newer methods of chemosensitivity testing.

	Cancer Forums Forum Index -> General Cancer topics	All times are GMT - 5 Hours
Page 1 of 1

A website for discussions about any type of cancer, including lung cancer, breast cancer, mesothelioma, prostate cancer, laryngeal cancer, leukemia, lymphoma, multiple myeloma and others