Cancer Medicine's Dark Corners
In 1972, my wife had been diagnosed with ovarian cancer, when she presented with a left DVT (deep vein thrombosis) and pulmonary embolism at a hospital in San Diego, CA (blood clots "can" signal cancer). Workup which was triggered by this presentation revealed that she did have an ovarian carcinoma for which she underwent total abdominal hysterectomy and received Chlorambucil (Leukeren) treatment.
This postoperative chemotherapy drug was among the slowest acting and least toxic of the alkylating agents (well tolerated oral drugs). By giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors. Depression of the immune system is slow and reversible, allowing it to regenerate and contribute to healing.
A malfunctioning immune system can fail to stop the growth of cancer cells. She went twenty-four years before experiencing any recurrent ovarian cancer.
During the early 90's in Reading, Pa., she underwent a laparotomy (a surgical procedure which involves opening the abdominal cavity for examination) as a followup and this did not reveal any evidence of recurrent carcinoma. This is supposed to be the most certain way of diagnosing ovarian cancer and assessing the extent of cancer spread (metastasis).
However, negative second-look patients have a 50% chance of disease recurrence anyway. For the most part, her group of oncologists relied almost entirely on the CA 125 tumor marker (a blood test done to assess the amount of an antibody that recognizes an antigen in ovarian tumor cells).
The rate of "false positives" makes it inadequate for use "by itself" for screening of high-risk patients. It should be supplemented with transvaginal sonography and a rectovaginal pelvic exam all done at the same time.
It was our family doctor that found her first metastatic recurrence to her diaphragm in 1996 (not the medical oncologists at our local home town hospital). She was having dry coughing spells at first but then she began having a mucus discharge, which eventually was bloody.
A chest xray and Cat Scan had shown a lesion inside her diaphragm. That recurrent ovarian cancer was surgically excised at Fox Chase Cancer Center. It was a metastatic transdiaphragmatic tumor from the original ovarian cancer (1972), with attachment to the lung and other midline structures of the chest. Parts of those structures were surgically resected (the diaphragm is a common site for ovarian metastatic recurrence).
The thoracic surgical oncologist left us with the knowledge that a second place an ovarian metastasis possibly could occur maybe the Central Nervous System (CNS) like the brain and/or the spine. It is very rare for ovarian cancer cells to metastisize to the CNS.
In fact, up until 1994 there have been only 67 well documented cases in medical literature. A multi-institutional study of 4027 ovarian cancer patients over 30 years identified only 32 cases while an autopsy study of ovarian cancer reported an incidence of 0.9%.
My wife received postoperative chemotherapy by medical oncologists at our local home town hospital(seven months after having that metastatic tumor surgically excised).
She did not have any cancer tumor markers indicate any cancer within her system. Some tumors send out microscopic outposts while most do not. However, medical oncologists cannot tell which ones do, so they want to give chemotherapy in nearly every case.
The type of chemotherapy she received was the hit fast, hit hard type combination chemotherapy of Taxol and Carboplatin. It is usually 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).
Patients who develop recurrent ovarian cancer more than 6 months after first-line chemotherapy (in my wife's case, 24 years), can experience another remission following treatment with the identical first-line chemotherapy that was previously used (in her case, Chlorambucil).
It has not been shown that platinum-based combination therapy is superior to single agent alkylator therapy. The late stage of "recurrent ovarian cancer" makes the combination chemotherapy of Taxol & Carboplatin drug resistent to cancer cells and suppresses the immune system, making it possible new tumors to grow because the patient has been rendered unable to resist them.
In recent years the incidence of central nervous system (CNS) metastasis has increased. Unfortunately, some chemotherapeutic agents can weaken the blood-brain barrier (BBB) transiently and allow CNS seeding.
Taxol & Carboplatin are two of the drugs that violate the blood-brain barrier (dose dependent). In essence, it breaks down, damages the blood-brain barrier (BBB) to invite cancer cells into the CNS. A NCI observational study in 1995 reported experience in their clinic where recurrent systemic disease occurred in all patients for which they received dose intense paclitaxel (Taxol) therapy.
Brain metastasis was the only site of disease recurrence, presenting with headache, dizziness, unsteady gait, nausea and vomiting.
It was our family doctor that found her second metastatic recurrence to her cerebellum in 1998 (not the medical oncologists at our local home town hospital). She was presenting with headache, dizziness, unsteady gait, nausea and vomiting.
A large (3.5cm) solitary cerebellar brain tumor was found via enchanced Cat Scan (later confirmed by an enhanced MRI). The tumor was excised from her brain by a Neurosurgeon at Hershey Medical Center. Histologic features were consistent with metastatic papillary adenocarcinoma with extensive necrosis from the ovary.
The Neurosurgeon stated that he was 99% successful and felt that she should go back to our local home town hospital and receive focal radiation to the local tumor bed (which is 2cm beyond the periphery of the excised tumor site).
The treatment protocol recommended for brain metastases of large solitary tumors exceeding 2cm in diameter is surgical resection followed by 5 fractions of local radiation to the tumor bed. At the same time, she should receive an MRI of the spine because of suspicions of either another tumor, on her spine or a herniated disc, causing her leg problems.
However, the ideas of our local home town Radiation Oncologist were different from the Neurosurgeon who excised the tumor from her brain.
The Radiation Oncologist took it upon himself to give my wife 5 fractions of focal radiation to the local tumor bed, plus 20 fractions of Whole Brain Radiation over a 35 day period. The risk of neurotoxicity from Whole Brain Radiation is not insignificant and this approach is not indicated in all patients with a solitary brain metastases, particularly when platinum drugs lower the tolerance of the CNS to radiation.
Literature of the early and mid-80's on morbidity of Whole Brain Radiation, is flooded with papers reporting long-term side effects, such as dementia, memory loss, radiation induced necrosis, leukoencephalopathy, in up to 50% of two year survivors.
Whole Brain Radiation Therapy has been recognized to cause considerable permanent side effects in patients over 60 years of age. The side effects from WBR Therapy affect up to 90% of patients in this age group.
During radiation treatment, my wife received an Unenhanced MRI to the spine that showed a 1cm lesion. Instead of performing an Enhanced MRI to the spine to further evaluate, our local home town hospital performed a Bone Scan that showed normal bone imaging. Enhanced (contrast) agents increase the sensitivity, conspicuity and accuracy of an exam. The agent most commonly used is Gadolinium.
The proper medical protocol for all Brain and Spinal MRI's for metastatic diseases is Enhanced (contrast). An Enhanced MRI was not performed and the Radiation Oncologist told us the lesion was nothing and not to worry about it. He also ignored my complaints about her having seizures during radiation therapy.
Nine months later, my wife was admitted to our local home town hospital during the Memorial Day Weekend of 1999, for a week of testing and evaluation for unexplained falls and light-headiness. After two weeks of failing to find out what was wrong with her, I took her by ambulance to Hershey Medical Center.
At Hershey Medical Center, we found out by a medical onocologist and a neurologist that she had Leptomeningeal Carcinomatous (remember the undiagnose tumor of nine months prior, not further evaluated?). An Enhanced MRI showed now three (3) metastatic tumors on her spine. Spinal metastases can grow into adjacent structures, such as into the meninges from the spine. The largest of these tumors grew into the meninges on the spine into the spinal fluid, hence Leptomeningeal Carcinomatous. This was confirmed by a spinal tap.
With the damage already done to her by our local home town hospital, the doctors at Hershey Medical (in order to save her life or at least give her some time) had to administer Intrathecal Methotrexate along with systemic radiation to the spine (Admitted June 19,1999). When both therapies are performed at the same time it doubles the theraputic dosages of each therapy (increasing the neuro-toxic effects on the brain).
However, the cancer cells were eradicated completely from her central nervous system by this protocol. Ever since the second spinal tap at Hershey (when methotrexate was already being administered), all of her spinal taps were negative for 10 consecutive times up until January 14, 2000. A Whole Body Bone Scan (November 3, 1999) indicated that the skeletal system demonstrated normal uptake and an Enhanced Brain MRI (November 3, 1999) showed no new areas of abnormal enhancement.
My first experience with the side effects of combination chemotherapy and whole brain radiation was when she was at Hershey Medical Center in 1999. The doctors showed me the Enhanced Brain MRI from her previous year's cerebellum excision and the one done in 1999.
The scans showed the progressive deteriation of her white matter (white matter disease). Late delayed effects, occuring several months to many years later, are classified into diffuse white-matter injury, radiation-induced arteriopathy & stroke, and late delayed Radiation Necrosis. These reactions are due to changes in the white matter and death of brain tissue caused by radiation-damaged blood vessels.
This clinical syndrome generally occurs 6 months to 2 years after radiation therapy. Symptoms include decreased intellect, memory impairment, confusion, personality changes and alteration of the normal function of the area irradiated (all symptoms my wife had over the past year). Radiation Necrosis can be fatal! It causes pathological changes that impair vascular integrity. It causes cerebral infarctions (strokes). She suffered a stroke to the left basal ganlia area around the New Year 2000.
My wife had developed necrotizing leukoencephalopathy (a form of diffuse white matter injury that can follow combination chemotherapy), confirmed by an enhanced MRI in July of 1998 at Hershey. The white matter is the covering of the nerves within the brain. Its function is to speed up the passage of impulses along the nerves.
Necrosis is simply a cell dying, all of its coordinated activities going wrong and things shut down. If a cell gets too much hear or is poisoned by a toxic substance or exposed to chemicals that damage its proteins and membraines or radiation that breaks its DNA molecules, that cell can just stop functioning.
Because of the previous chemo-radiation treatments, a recurrence of the cerebral metastasis was very likely to happen in the future. Some long-term effects can include development of secondary maligancies (the risk is 16 times greater).
Resistance to standard chemotherapy regimens of Carboplatin with Taxol ultimately develops in nearly all adenocarcinoma cancer patients (mainly because of the late stages of the cancer). Recurrent ovarian cancer being such a late stage cancer, can be resistant to the combination chemotherapy of Taxol/Carboplatin. It can actually spread the cancerous cells rather than the cancer itself spreading. Since both radiation and chemotherapy suppress the immune system, it is possible that new tumors are allowed to grow because the patient has been rendered unable to resist them.
A person who is cured of cancer by these drastic means may find himself struggling with a new, drug-induced tumor a few years later. A malfunctioning immune system can fail to stop the growth of cancer cells.
Recurrence of the cerebral metastasis was observed via an Enhanced MRI of May 2000 at Hershey Medical Center and a Pet Scan of August 2000 at the University of Pennsylvania. Four, mm-sized metastatic tumors were found in and around the previously resected cerebeller tumor and because of my wife's weakened condition, Gamma-Knife would be the only best medical protocol.
She received Gamma-Knife treatment at University of Maryland Medical Center on September 12, 2000. During the whole time of her admission at the hospital, the doctors kept referring to her continued diffuse white-matter injury (brain necrosis), as if she may too far advanced in that injury to survive much longer. She died at home on Thursday, September 21, 2000 at the age of 68 from Cardio-Pulmonary Failure.
Minutes before she expired, her temperature was normal, her blood pressure was normal but her pulse was 150 (tachycardia). Her heart was racing to keep up with the lack of brain function and finally quit.
The white matter disease that my wife experienced and caused her death was primarily a result of Whole Brain Radiation and secondary a result of Combination Chemotherapy of Taxol & Carboplatin (Methotrexate was icing on the cake).
The Combination Chemotherapy of Taxol & Carboplatin caused microscopic ovarian cancer cells to seed inside the CNS to form a tumor on the cerebellum and tumors on the spinal cord, with concomitant necrotizing leukoencephalopathy. Carboplatin lowered the tolerance of her Central Nervous System to any radiation treatment.
The Whole Brain Radiation resulted in the death of tumor cells and associated reaction in surrounding normal brain. Such reactions tend to occur more frequently in larger metastatic lesions. Late delayed Radiation Necrosis (also known as Radiation Encephalopathy) is often irreversible and progressive, leading to severe disability or death (all symptoms my wife experienced).
My wife's life was greatly shortened and neurologically deteriorated by the chemo and radiation treatment received at our local home town hospital. Patients who develop recurrent ovarian cancer more than 6 months after first-line chemotherapy can experience another remission following treatment with the identical first-line chemotherapy that was previously used.
Aggressive treatment, like surgical excision of tumor and focal radiation to the local tumor bed, in patients with limited or no systemic disease can yield long-term survival. In such patients, delayed deleterious side effects of whole brain radiation therapy are particularly tragic and there is no survival benefit or prolonged independence. The patient cannot experience the benefical improvement in quality of life.
Hence the saying, "cancer medicine has been driven by external forces into dark corners, such as what amounts to generating more of an advertisement sent directly to a patient, than patient information and more disturbingly on TV and other media". There's this multi-billion dollar cottage industry called chemo-radiation therapy just waiting for an excuse to fullfil your cancer treatment needs.
Until Ann Pawelski met the infamous cancer doctors at our local home town hospital, she was a twenty-four year survivor before her first ovarian recurrence. Some patients can live 10 years with recurrent ovarian cancer. Ann had enough of a fight with a chronic disease without having to be subjected to inept local oncologists.
Cancer chemotherapy and radiation therapy almost without exception, will damage some normal tissue and diminish the immune system. Radiation has been known for a long time to both enhance cancer growth and to halt cancer growth. Damaging the immune system in turn is known to foster the growth of some kinds of other cancer. We do not yet have really outstanding treatments for most cancers.
Modern medicine in general and cancer treatment in particular, is very imperfect. In the hopes of curing disease or helping patients, the medical profession uses rather drastic treatments for devastating diseases they know will kill someone in a short time. Many physicians donít make the families aware enough that these treatments are drastic and can have serious side effects.
Patients should know what the demonstrated benefits are AND the risks, because the treatments can be debilitating and even life-threatening. It takes time for doctors to sit down with patients and truly explain the benefits AND the risks of treatment. They cannot tell which cancers are dangerous and which are not.
In an ideal world, patients would consider the benefits AND the risks of each treatment and make an informed decision with the guidance of a wise doctor. But, hurried doctors seldom spend much time discussing the benefits AND the risks and few patients ever question whether treatment may do more harm than good.
Gregory D. Pawelski
Online Journal of Health Ethics,
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