Last week Jana and I met with my Australian oncologist, Dr. Weickhardt, for the bimonthly review of my latest imaging, a CT scan this time. As I understand it, there are three major foci of cancer in my right thoracic cavity. One is high in the sack that surrounds the heart, the pericardium. From August to October, this tumor shrank 66% from 27 X 51 mm to 15 X 31 mm. That sounds terrific, but it makes me wonder about the measurements, because these tumors are not supposed to shrink. Another area in the fissure between the upper and lower lobes of the lung, remained constant, 10 X 15 mm, while the third area, lower down, near the diaphragm, increased 61% from 18 X 59 mm to 26 X 66 mm.
I don’t’ know exactly what to make of these results. For one thing, the measurements are given in two dimensions. Are they so thin in depth that the depth can be ignored? It also seems strange that one would grow substantially and the other shrink by a similar amount. Of course, the growth of the lower disease area caught our attention because the increase does not seem to be “glacial” as was found two months ago.
I have found over the years that I better understand what I believe after I have written it down. Writing imposes a certain discipline because it requires me to ask myself, “Do you really believe that?” What follows is an attempt to clarify and document my thinking about what action to take. Most readers of this blog may want to stop here, but my thinking is here for any who might be interested.
Background
The initial plan in the summer of 2010 was to have my lung removed along with the lining of the thorax to be followed by radiation therapy in the hopes of obtaining a cure; however, finding mesothelioma in the pericardium blocked that plan, and all accessible tumor was removed. I subsequently received six rounds of chemotherapy. Since that time the tumors appeared to be stable, and frankly, my attitude towards the cancer changed. Before finishing chemo, I did not think I probably had too many more months to live, but the stability of my scans following chemo gave me hope that I might live meaningfully longer than I had expected. Now with the apparently significant growth in one area of disease, I have become more sober about my condition and must review where we go from here.
The findings initiated a discussion of where to go now. It would have been easy to say, “You’re the doctor, what do we do now?” However, I have sufficient knowledge of disease processes, biology, physiology, and the use of data to inform decision making that I want to understand the situation as well as possible in order to participate in the decisions. Consequently, we had a long discussion, and I am very grateful to Dr. Weickhardt for taking the time and having the patience to discuss the options thoroughly.
Four general treatment approaches are available—watch and wait, more chemotherapy, radiation therapy, and participation in a clinical trial. Each approach has its potential benefits and risks, and given the many unknowns in the situation, the decision-making process becomes an interesting intellectual challenge. How do you decide a course of action when the unknowns dominate the decision making? Because mesothelioma is such a rare cancer, the amount of research done is limited as is the understanding of the disease at the molecular level. For example, it is hard to get a critical mass of patients so clinical trials examining variations in treatment options can be tested.
Watching and Waiting
Since the end of my chemotherapy, I have been in a watch and wait phase, and the stability of my disease has been encouraging. I could continue to watch and wait to see what happens with the two major areas of the disease, and decide on a new course of action later; however, in the face of apparently more rapid growth, even if the situation is not completely clear, one feels an urge to take action. While my good quality of life argues for not doing anything until new symptoms develop, changes such as rapid growth in one or more of my lesions, developing other diseases or complications could occur that would preclude other lines of treatment. Do I risk sacrificing my good quality of life for the potential benefit that could come from a new treatment which would most certainly have risks and pain and suffering? If there is no potential for a cure or a significant extension of my life by undergoing a new treatment, is it worth it to do anything but watch and wait?
Chemotherapy
The second option would be more chemotherapy. Unfortunately, as far as I can tell, there is no second-line chemotherapy of proved efficacy. Dr. Weickhardt gave me an excellent review article entitled Current Chemotherapy and Emerging Systemic Strategies for Treatment of Unresectable Malignant Pleural Mesothelioma (Nowak, 2011) from which the following quotations were taken.
Patients almost invariably progress after initial therapy, and at this point many are fit for second-line treatment. . . [but] as yet there are no randomized studies showing survival benefit from subsequent treatment. (page 310)
Perhaps I could have another round of cisplatin and pemetrexed; however, there is no evidence that additional rounds would be beneficial, and I expect more cisplatin might have undesirable toxic effects. Would my lower quality of life be worth a life extension of only a few months? According to Nowak, “Treatment with a second pemetrexed regimen has been proposed, but only low level evidence is available for this approach. . . In the area of first-line pemetrexed, no second-line therapy is supported by enough evidence to consider it standard care.”
Nevertheless, I might be amenable to second-line treatment with pemetrexed if the side effects could be reasonably controlled.
Clinical Trials
Another option would be to take part in a clinical trial, especially a phase II or phase III trial where phase I results have shown that the treatment is relatively nontoxic and shows promise for improvement. Clinical trials are the sources of hope in the fight against cancer, and come in a variety of flavors.
Traditionally, cancer has been fought by the brute force methods of cutting it out, burning it out with radiation, and poisoning it with chemotherapy. The idea is to kill the cancer cells while sparing as much as possible the nonmalignant cells of the body. The cisplatin and pemetrexed I received and most other chemotherapeutic drugs have their affect by interrupting the functioning of rapidly dividing cells. Consequently, such systemic drugs affect healthy rapidly dividing cells as well which contributes to their side effects. Very little progress has been made in identifying new, effective drugs of this type in recent years; however, work continues on developing such drugs and drug combinations.
Another approach is to develop drugs that attack targets that are more specific to cancers than to other rapidly dividing cells. For example, drugs have been developed that attempt to stop angiogenesis, the growth and development of the blood vessels necessary to nourish cancer cells. Attempts have been made to induce the body’s immune system to attack cancer. Cells that have significant DNA damage normally self-destruct through a process called apoptosis, but cancer cells have lost that ability; consequently, attempts have been made to reinstate apoptosis in cancer cells. Again, work of this kind continues.
Another approach comes through using specific characteristics of a type of cancer to target those cells only. A major breakthrough came a few years ago with the development of the drug Gleevec (the drug Jana takes) because the drug targets a specific molecule that causes certain blood cells to reproduce unchecked. Subsequently, tens of drugs have been developed that target specific molecules, but unfortunately, my understanding is that most cancers do not have a single, unique mutation that can be targeted like CML, Jana’s cancer. Most cancers display multiple mutations, and it is unclear which one or number of those mutations are essential driver mutations for the cancer and which are only along for the ride.
If medicine is ever able to tame or eliminate cancer, therapies will be dependent on the understanding of the many genetic mutations that drive cancer cells to replicate relentlessly. As I understand it from Siddhartha Mukherjee’s The Emperor of all Maladies: A Biography of Cancer, scientists think that mutations in one or more of 13 major pathways may underlie all cancers which gives hope that cancer can be controlled much more effectively in the future. Success will depend on basic research into the biology, especially the genetics, of cancer before one or more specific targeted drugs can be developed and administered based on the mutations found in an individual’s tumor or tumors.
Given the small number of cases of mesothelioma and the fact that mesothelioma is characterized by the significant DNA loss, it seems unlikely that mesothelioma specific treatments will be developed any time soon. It seems that any upcoming advances in mesothelioma treatment may depend on the success of treatments that attack the characteristics seen in cancer cells in general. As Nowak wrote,
Mesothelioma is characterized by genomic loss, with loss of tumor suppressor genes rather than the constitutively activating mutations, which have been key to therapeutic advances in other diseases. Loss of regions encoding the tumor suppressor genes p16INK4a, p14ARF, NF2, and TP53 are common. Unfortunately, these losses do not readily translate to therapeutic strategies. However, mesothelioma also demonstrates abnormalities in growth factor receptor pathways, angiogenesis, and apoptosis, which may be amenable to intervention. (page 311)
Even though clinical trials are the source of hope for the defeat of cancer, I am not hopeful that a magic bullet will come along in time to provide me with any benefit; however, I look forward to participating in a clinical trial, even at the loss of some quality of life and with the low chance of a curative outcome, because a trial would provide both a modicum of hope and the chance to make a small contribution to understanding the disease.
Unfortunately, there are no clinical trials available to me now, but we will continue to look for them.
Radiation Therapy
The final option would be to undergo radiation therapy, if appropriate. To that end, I had a referral and thorough discussion of radiation therapy with Dr. Laurie Gaspar, a radiation oncologist at the University of Colorado Hospital. Dr. Gaspar explained that there are two common uses (if anything can be called common for a rare disease like mesothelioma) of radiation in mesothelioma. As initially planned for me, radiation can be given to the lining of the thorax following the removal of the lung and tumor burden with the intent to cure the disease. The other use is palliative treatment when the lung is still present in order to reduce pain and perhaps other symptoms as the tumor develops.
I do not fall into either group, so it is doubtful that radiation would be appropriate for me at this time. The problem is that there is no evidence that the radiation of my tumors would be curative; it would most likely only slow down the tumor growth and provide some months of life extension. It would not be curative because a full lethal dose of radiation might not be possible because of the effects of the radiation on nearby tissue, particularly in my case the other lung and the liver.
The radiation treatment is given by beaming the x-rays from several different angles so that the tumors receive a significant dose, but the other tissue does not. When I had prostate cancer, it was relatively easy to plan the treatment because the prostate is a small target in a relatively stable location away from important tissue that might be injured by the radiation. While she doesn’t seem very hopeful, the oncologist has agreed to order a special CT scan and a PET scan to enable her to develop a treatment plan. If the scan shows that it is possible to deliver a meaningful dose to my tumors with a reasonable risk of side effects, they will proceed.
One factor to consider with regards to radiation is what would happen if I got the therapy and then needed palliative treatment later. Could I have both rounds of radiation? I don’t see why not, if I am going to die anyway, but I don’t know the answer. Another factor is that having the radiation might foreclose participation in some clinical trials; however, from what I have read in the descriptions of clinical trials, it might only delay my participation by a month.
What to Do?
So how do I decide what to do. Here are the thoughts that seem most important to me:
- Mesothelioma is fatal, and it appears that my cancer has awakened and is growing again which causes me to want to take some action; however, I have some doubts about the scans because of the apparently significant decrease in one of the tumor sites. How reliable are the conclusions of different radiologists who examine the same images? How thoroughly do they compare scans from one date to another, and why don’t they look at progression across multiple scans rather than just comparing the two most recent?
- Watching and waiting preserves quality of life at the risk of developments that might prevent receiving another treatment later. If my cancer is growing again, what is the risk of waiting to take any action for another six weeks when my next imaging is scheduled?
- There does not seem to be any advantage to chemotherapy. I don’t believe that gaining a couple of months of life extension would be worth the loss in quality of life that chemotherapy would require.
- Clinical trials are currently unavailable, but I am positively disposed to participation if the rational for the treatment seems reasonable, even at the cost of a lower quality of life.
- Radiation is unlikely to be curative, and it would probably lower my quality of life as well as add some risk of damage to lung and/or liver.
The only avenue available for immediate action is to pursue the testing to see if a plan can be developed for me; however, given my lack of new symptoms, and the fact that I do not relish the idea of getting more radiation exposure from the CT and PET scans, I believe I will cancel those scans and wait until December before deciding whether or not to ask them to pursue radiation treatment. I’ve always believed that if there is no logical imperative to take one course or another, the best thing is to do what you want to do. At this time, that is to do nothing new but to wait and see if the growth of my cancer is confirmed by the December scans.
Mukherjee, S. The Emperor of all Maladies: A Biography of Cancer. New York: Scribner, 2010.
Nowak, A. K. Current Chemotherapy and Emerging Systemic Strategies for Treatment of Unresectable Malignant Pleural Mesothelioma, American Society of Clinical Oncology, 2011, http://www.asco.org/ASCOv2/Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2011/zds00111000309.PDF
