M. Alma Rodriguez, M.D.
Vice President
Medical Affairs
Survivorship Program Executive Sponsor
The University of Texas MD Anderson Cancer Center
Good Afternoon, I am Alma Rodriguez. I am a Professor of Medicine at MD Anderson Cancer Center in the University of Texas System. And I'm here to discuss with you today the clinical problems that cancer survivors face after they have completed treatment.
Our objectives upon the completion of this lesson would be that: you would be able to identify trends in cancer survivorship; describe the phases of cancer survivorship and the unique problems associated with each of these phases; identify long-term survivor com --- effects of specific treatments; identify the components of long-term survivor care; and describe the Survivorship Passport.
Less than a century ago, the diagnosis of cancer carried with it a stigma and a poor prognosis for many patients. It was, therefore, something to be avoided and not discussed at all. Today, on the other hand, nearly 12 million Americans have survived cancer at least five years or longer. This is three times the number of patients who had survived this long after cancer diagnosis and treatment in 1970.
This graph illustrates how this --- the trend in the increase of survivors has continuously improved since the 1970s.
There are, however, an unfortunate series of consequences after cancer treatment and consequences of surviving cancer. This is not a new problem. In fact, nearly 25 years ago, Dr. Mullan, who himself was a cancer survivor, described his personal journey and his experience as a cancer survivor in an article in the New England Journal of Medicine published in 1985. In this article, he described how it was important that we not only focus on treating or arresting the cancer itself, but that one had to consider as well the effects that this treatment would have. And that one of the areas of focus or emphasis in the future of cancer care from that point should be to minimize the medical and social hazards of cancer treatment and survivorship.
So, let's digress a bit and then talk about who is a cancer survivor. This has been a debated topic. And in the lay literature usually the term cancer survivor refers to someone who has been alive a significant length of time after diagnosis and treatment. The official diagnosis, however, states that the a patient is a cancer--- an individual rather, is a cancer survivor from the time of their diagnosis until the end of their life. Furthermore, the definition also encompasses those that are affected by the cancer of the patient, that is, family members, friends, and caregivers. This is a very broad definition. And, therefore, it leads us to acknowledge that there are many stages along the course of the patient's life from diagnosis until death.
If we look at the experiences of the patient going through cancer treatment and thereafter as pointed out by Dr. Mullan in his article, there really are different identifiable periods or phases. Firstly, at the time of diagnosis, one would call this the acute phase. And it begins with a diagnosis of cancer. And it includes the period of testing and treatment for the cancer. Once treatment has been completed, the patient enters into what Dr. Mullan called an extended phase or, what also one could call an intermediate phase. And that is a period where maintenance treatments may be given, that is a much lower intensity therapeutic modality to maintain remission; consolidation, which could be a more intense treatment than the first induction treatment to reinforce the response; or simply observational monitoring with te --- appropriate tests to determine if there is a recurrence of the illness. When patients have been well and passed that period of potential recurrence, Dr. Mullan referred to this phase as the --- the permanent or long-term survivor. When Dr. Mullan wrote this article, it was expected that persons who were living with cancer would likely die of it. Today, 25 years later, we have transformed many malignant disorders into chronic illnesses by virtue of having alternatives of therapy that can be repeated several times and that can render the patient disease-free for intervals of time. These patients are also long-term survivors although they are living with disease.
Who survives cancer today? If we look at this population of 12 million survivors or so and we look at the characteristics of these patients, the majority are actually 65 years of age or older. This is approximately 60%. An additional 38%, that is bringing the total to nearly a 100%, are adults that one would consider in the working age or in the phase of life when productivity and work-related issues are important. It is projected, in fact, that between 2000 and 2050, persons who are aged 65 years of age or older who have survived cancer will double. And this is an important issue because the primary insurance source for persons older than 65 years of age is Medicare. And we know well that over time the policies and coverage and services that will be provided under Medicare will likely change.
If we look at the types of malignancies in --- among the population of survivors, the most common diagnosis is breast cancer. So the --- nearly a fourth of the cancer survivors are women who have survived breast cancer. This is followed by prostate cancer diagnosis, colorectal, gynecologic malignancies, and hematologic malignancies, in that order.
Going back to the phases of survivorship, it is important to distinguish them, not only from the patient's experience, but also because there will be different healthcare needs and different psychosocial support needs across these unique stages. Firstly, during the acute phase, the side effects of treatment are usually the most concerning issue as well as addressing any physical and psychosocial or psychological discomforts that the patient is experiencing. During the intermediate phase, patients often experience anxiety and fear regarding recurrence. It is during this period of time as well that patients need to begin to engage very actively in rehabilitation or recovery from the acute side effects of their primary treatment. During the long-term survivorship phase, patients then must deal with longer-term issues such as sustaining or maintaining employment. Many unfortunately suffer loss of insurance. They need to re-integrate back to normal living situations restoring relationships that may have been lost during their treatment, addressing issues regarding self image that may be a result of the treatment, and as well as facing acute or rather --- late effects that did not manifest during the acute treatment that --- but that may occur years later.
If we substratify or subcategorize the types of problems that cancer survivors face ---- I've clustered them here according to the following categories: on the physical side, we know that sometimes patients will face a physical change in their body, psychological as well as structural, related to, for example, surgical interventions. They may also have radiation-induced injuries and/or chemotherapy latent effects. Socioeconomic consequences that I've briefly touched on already, include loss of employment or radical changes in employment due to disability, insurance loss, and, still persistent to some degree, societal perceptions of cancer in cancer survivors.
Psychologically, many patients will suffer from persistent chronic depression and anxiety as well as, of course, as the disruption of their personal relationships, marriage, friendships, and other familial relationships.
To address then some of the specific medical concerns that patients may face, we'll start with complications that are related to surgical interventions. Surgery actually was the first therapeutic modality. Historically, it is the first therapeutic modality that was used to treat cancer. And, of course, the consequences of surgery are related to the organ system which has undergone surgical change. For patients with breast cancer, obviously, body image and disfigurement concerns are important as well as potential complications of that surgical intervention. For example, lymphedema in the extremity on the side of the breast that was resected, where lymph nodes are also sampled, as well as pain and long-term discomfort related to the primary surgical site. Patients with prostate cancer may have erectile dysfunction, urinary incontinence, and pain as results of prostate resection. Patients with bladder cancer may have difficulties, particularly if there was total removal of the bladder. They may have difficulties with chronic infections of their urethral stents. And they may also suffer from lymphedema of the lower extremities depending on the extent of lymphatic node dissection. Patients with colorectal malignancies may --- may suffer from rectal incontinence or may require a colostomy. There is obviously very significant physical alteration in that event. And there may also be, from a metabolic perspective, disruption of their nutritional status particularly if they lose absorption of certain essential vitamins and other nutrients. Patients with gynecologic or testicular malignancies, of course, face loss of fertility. This has very significant implications both from a body image perspective as well as the psychological sense of self and well-being with regards to sexual function.
Patients with brain and spine tumors who undergo significant neurologic surgery may have very major cognitive deficits after surgery. They may have motor or sensory function loss and may, unfortunately, also have latent and durable other negative effects such as seizures and neuropathies. Patients who have had thyroid resection for thyroid malignancy, obviously, will lose thyroid hormone function. And that in itself has, of course, also metabolic downstream consequences of unexpected weight gain, fatigue, hair loss, cognitive impairment, and other more subtle physical and physiologic changes. For patients who undergo resection in the head and neck area, not only do they have significant potential disfigurement of a --- a part of the body that is always visible, but they may also have significant anatomic and physiologic disruption of other functions that are also very important, such as swallowing capacity, loss of speech, loss of salivary production and --- and, therefore, poor nutritional status. Patients with sarcomas of the extremities, when rec --- when they undergo significant resection, will again of --- have physical disfigurement, but this may also result in loss of mobility and disability. There is also the problem of chronic phantom limb pain which can be very disabling. Lung cancer resections, on the other hand, although not visible to the eye, will result in very significant physiologic --- or can result in significant physiologic impairment with decreased lung capacity or decreased lung function. And this is limiting in terms of activity resulting in chronic fatigue as well as possible chronic pain.
There is hope, however, on the horizon in that surgical technologies are rapidly evolving in --- at the present time. The minimally invasive surgical techniques that were initially applied to other categories of surgery are now being applied in oncologic surgery. Robotic and endoscopic procedures are now much more applicable in many situations. At the same time, plastic and reconstructive technologies and tissue regeneration techniques are also rapidly changing, allowing us to reconstruct and render tissues almost to normal appearance and near normal function even after extensive resections. Limb-sparing procedures in orthopedic surgery as well as bone regeneration technology, similarly, is leading to limb-sparing surgery in many cases of patients with sarcoma particularly for young children and adolescents where normal growth is a very critical part of not only physical development, but also emotional development. It is also recognized now that early intervention with rehabilitation and psychological counseling is important in allowing patients a more rapid recovery to normalcy. Lastly, the addition or integration of multimodality therapies that lead to a reduction in the size of tumors prior to surgery, that is cytoreductive strategies, also can decrease the amount of tissue that is resected leading then to function --- better preservation of function in the patient.
The second modality that was applied for the treatment of cancer historically is radiation therapy. Radiation, unlike surgery, usually does not have obvious physical changes in the --- the patient's body. However, it does have lasting, more subtle, and durable physiologic effects. Each of the organ sites when affected by radiation will have a somewhat different response or somewhat different risk factors. The skin, for example, after radiation, will have increased sensitivity to sunlight as well as an increased incidence of secondary carcinomas, predominantly squamous and basal cell cancers, but melanomas of the skin also can arise within the within the --- within --- in the skin within radiated fields. The musculoskeletal system is somewhat more resilient to radiation; however, depending on the dose delivered, there can also be an increased incidence of sarcomas of bone as well as muscle. There is also an acceleration of bone loss at the site of the radiation port. And in some instances it may lead to osteonecrosis as well or total bone loss. There will be some fibrosis of muscles that can lead to reduced range of motion and this is particularly true if joints are included within the radiation port. If the eyes are exposed to radiation, the primary risk is from cataract development as well as dryness of the conjunctiva that can lead to long-term chronic eye infections and discomfort. Radiation to the oral cavity or the mucosa of the oral cavity can lead to decreased salivary production with an accelerated rate of tooth decay. Patients must be very careful to maintain good oral hygiene and to use fluoride dense solutions for rinse of their oral cavity for life.
Radiation to the lungs leads to fibrosis of the lung tissue which, like surgery, can lead to decreased lung capacity as well as the unfortunate risk of secondary lung cancers, particularly for patients who have been exposed to smoke injury either from tobacco or other toxic fumes. If the heart is within radiation fields, for example in mediastinal radiation ports, there is reported higher incidence of coronary artery sclerosis and thrombosis that can occur at an earlier age than would be anticipated. There can also be pericardial fibrosis with decreased myocardial mobility and myocardial fibrosis within the muscle of the heart leading to coronary ischemia or arrhythmias and heart block. Radiation to the thyroid leads to loss of thyroid function and secondary thyroid cancers. In the bowel fibrosis of the tissues surrounding the bowels or within the bowel, can lead to adhesions and blockage or partial obstruction of the bowel, decreased motility, which can lead to chronic constipation, and even a decreased absorption of some essential nutrients depending on the site of radiation.
The liver and kidneys, again, depending on the dose delivered, may suffer from fibrosis with gradual latent decline in organ function of these organs. The rectum, vagina, and uterine tissues, again, can suffer from fibrosis leading to fistulas in most --- in the most severe cases or possible stenosis, as in the rectal sphincter, for example. Gonadal organs, that is the testes and the ovaries, if exposed to radiation will become --- will lead to sterility. Radiation to the brain and spine may result, as well, in latent --- latent effects with spinal stenosis or fibrosis that can lead to neuropathies. Radiation to the brain, depending on dose, can to lead to a latent dementia syndrome and/or hypopituitary function.
As with surgery, radiation is also evolving and, at the present time, computer-assisted dosing as well as computer-assisted port planning with imaging improves the accuracy of treatment to the degree that it narrows very significantly the beam of radiation, decreases the scatter of the radiation beam, increases, of course then, the precision and the appropriateness of dose delivery to the tumor site. There are also evolving technologies with regards to the form of radiation --- of radiation energy. For example, proton technology is being increasingly used to treat sites of the body that are sensitive to radiation toxicity. And lastly, the --- the evolving field also of material barriers protects healthy tissue much more effectively against radiation exposure. And this in itself with the addition of better focusing of the energy can lead to less damage to surrounding tissues.
Chemotherapy, that is pharmaceutical therapies for cancer, are the new kid on the block. Cancer chemotherapy dates essentially to the 20th century. And its inception rests on observations after World War I from the unfortunate use of the nerve gas toxins. It was observed that patients who had been exposed to these toxins had decrease in their lymphatic tissue. And this led an astute pathologist to propose that perhaps this could be a modality used to treatment lymphatic malignancies. This was the first proposed application of chemicals to the use of cancer. The first curative model of pharmaceutical anticancer care was the treatment of Hodgkin's lymphoma in the 1960s with a regimen called MOPP, which was a combination of nitrogen mustard, vincristine, procarbazine, and prednisone. And the demonstration that this combination of chemicals could cure patients with advanced-stage Hodgkin's disease was the first proof that chemotherapy could have a very major role in the treatment of malignancies. Since then the field of chemotherapy has literally exploded with today dozens of chemicals available to all of us to use in the treatment of malignancies. The chemicals, of course, are not without harmful effects. There are some general toxicities related to chemotherapy drugs in general. For example, fatigue is a common side effect that patients who have been treated with chemotherapy will complain about. There are also other subtle syndromes. For example, patients complain of difficulty thinking or fuzzy thinking, which has been termed in the lay literature as chemobrain. I am going to discuss more specifically some of the syndromes or complex of toxicities that can be attributed to various classes of chemotherapies.
Specifically, cardiac toxicities are most commonly seen with a family of chemicals called the anthracenediones. And doxorubicin is the most common --- commonly used drug in this category of chemicals. It is used in breast cancer, lymphomas, and leukemia treatments very commonly. But there are other drugs besides doxorubicin that are also cardiotoxic. For example, Herceptin®, which is an antibody used in the treatment of her-2-neu positive breast cancer, is also toxic to the heart, as are another category of drug called taxanes. All of these drugs can decrease the strength of the heart muscle, which are called cardiomyopathy or it may result in alterations of heart rhythm. There are --- In a newer category of drugs called target specific therapies, there are emerging profiles that these drugs, which are usually driven or direct --- or designed to intervene or interfere with protein metabolisms ---various protein metabolisms --- metabolism mechanisms in the cell, that these drugs may also be cardiotoxic. Specifically they can prolong the QT interval. Therefore, the heart is one of the organs that we pay close attention to when new drugs are designed and developed.
Lung toxicity is most commonly seen with a drug called bleomycin, but it is also possible with a wide variety other drugs, notably a chemical called fludarabine, cytarabine as well as with high-dose chemotherapy regimens that we use in bone marrow stem cell transplantation. Toxicity to the kidneys, most typically is caused by heavy metals of which the most notorious is cisplatinum, but a number of other chemicals related to cisplatinum may also cause electrolyte disturbances. There can be profound loss of magnesium that can persist chronically after many years.
The liver, surprisingly, can --- usually deals well with chemotherapy. However, depending on the category of drugs and depending on the level of the drugs used, one could also observe hepatic toxicity. This is particularly true in patients who may have already an underlying injury to their liver from hepatitis, that is of a chronic infectious source or due to alcohol cirrhosis, for example. Neurologic side effects are common across a variety of drugs. Most notable again are the heavy metals such as cisplatinum and the alkaloids such as vincristine. Also toxic are the taxanes as well as proteosome inhibitors and other drugs, particularly for elderly patients and those with diabetes or peripheral vascular disease that predispose to distal peripheral neuropathy.
Hematologic toxicity is actually the most common toxicity that we see with all categories of chemotherapies. It is very notable, particularly with high doses of chemotherapy, as one would use in bone marrow stem cell transplantation, as well as with chronic doses of other categories of drugs such as alkylating agents. Alkylating agents in particular can cause myelodysplasia or a pre-leukemia syndrome that can lead to eventual transformation to leukemia even years after treatment. This is also true for several other classes of drug --- of medications particularly, again, etoposide can also induce secondary leukemias. More recently, we are seeing increasingly immunologic impairment due to chemotherapy that is persistent or long lasting. This is true for example of immune-directed medications or immune-directed approaches with antibodies that are targeted against lymphoid cells. This type of treatment, of course, is most commonly seen --- indicated for lymphomas and leukemias. There are some other chemicals, however, that can similarly cause suppression of the immune system, fludarabine being one of them. Again, this is a drug used for the treatment of lymphomas and leukemia. Graft-versus-host disease is a severe immune --- or can be a severe immune dysfunction that is related to allogeneic transplantation.
If we then look at the spectrum of care that long-term survivors would need, one then can cluster the healthcare need of survivors along these lines. Firstly, we must think of the consequences of the cancer itself and its treatment; that is, what medical and psychosocial late effects the patient might experience. Secondly, would be prevention of new cancers, and prevention as well of some potential late effects that could be prevented or ameliorated with earlier intervention. As an example of this, patients who might be unfortunately at risk of bone loss from radiation or certain hormonal treatments should be monitored closely for bone density and should be treated with supplementation of vitamin D and calcium, for example. A very critical component from the patient's perspective, obviously, is continued surveillance for a potential late relapse of their primary cancer, but equally important the emergence of a second primary cancer. And lastly a very critical component of care for survivors is coordination with their primary care physicians and other healthcare providers to ensure that the survivors' healthcare needs are addressed.
This slide summarizes in three categories some of the problems we already have discussed. The patients may have long-term symptoms such as fatigue, pain, sleep disturbances, cognitive dysfunction, sexual dysfunction, and infertility. They also may have medical problems and conditions that will need management with the help of other specialists, notably cardiovascular complications, psychiatric problems, endocrinological, gastrointestinal, infectious, neurologic, and other health issues. A third category that we must consider as very important is that of healthy living; advising patients to engage in activities that will strengthen and ensure their health, smoking cessation, for example, nutritional advice, and adjustment of lifestyle to lead to a healthier --- an overall healthier lifestyle, physical therapy, occupational therapy, as well as genetic evaluation and counseling for the patient and their families, if appropriate.
To look at cancer risk assessment and its components as noted, we advise patients to consider their environment as well as potential genetic conditions or --- genetic hereditary predisposition to certain malignancies. Genetic counseling, if available, should be encouraged for patients with familial history of malignancies.
Cancer risk reduction, as I have already touched on, principally tobacco cessation, nutrition counseling, physical activity, limiting alcohol and sun exposure are things that can --- that the patient has control of in their day-to-day life, but should be encouraged. Chemoprevention is a field that is disputed today. It's --- it is somewhat controversial, but there is some evidence that perhaps vitamin D, for example, may be helpful in preventing colorectal malignancies. Prophylactic surgeries may be indicated in some selected situations, for patients, for example, who have a history of ovarian malignancies as well as breast cancer malignancies. In many situations, potentially removing the ovaries and breast could save the patient from risk of these malignancies.
The patient should have a thorough physical examination by their oncologist or their primary care provider to focus on areas that we know are at risk for second cancers: the skin, which is the most obvious organ and most easily accessible for inspection to look for moles or other lesions that are suspicious; examination of the breasts and prostate exam; lymphatic exam; but also cardiac exam; and thyroid exam, since patients may --- particularly those that have received radiation in the thoracic area or head and neck area, are at risk for secondary malignancies of thyroid and possible earlier cardiac disease; a careful inspection of the oral cavity; as well as a careful inspection of the abdomen for any dis --- alteration in the spleen or liver, as well as for any abdominal masses. These would be considered very basic exam principles.
Certain laboratory examinations are also appropriate for certain disease categories. For example PSA in the case of prostate cancer, CEA in the case of patients with colorectal malignancy, and thyroid function tests if the patients have had radiation exposure. Chest x-rays are very important, particularly if the patients have had radiation to the lung or to the thoracic cavity area. Other radiographic studies may be indicated depending on the specific disease and according to guidelines, for example, mammography, and today, MRI in certain high-risk patients is recommended as well. Colonoscopy and/or stool examinations for blood would be appropriate for patients who have had a history of colorectal cancer, but actually are also recommended for all cancer survivors according to guidelines by the American Cancer Society and the National Cancer Institute.
As an oncologist, we then see our patient's journey through cancer to encompass several stages.
Duri --- During --- the acute care phase of the patient's treatment, we are mostly focused on the delivery of anticancer treatment in managing the acute complications that are occurring secondary to the treatment. At the same time, we want to start to think proactively about potentially preventing long-term side effects and educating the patient about what to anticipate once their treatment is completed.
In the transition phase, again educating the patient as well as their community healthcare providers of what the patient will need to follow-up on their overall healthcare.
Lastly, during the longer-term survivor phases, we must focus then on staying vigilant in diagnosing and treating late complications of the cancer therapy, monitoring for secondary malignancies, and assisting the patient in improving their quality of life and reintegrating into the community as well as maintaining health.
The community provider can be a very critical ally in the care of cancer patients. They can assist us in monitoring patients, managing comorbidities, as well as in assisting those patients who may unfortunately eventually succumb to either health problems or late recurrences of their malignancy to have a dignified end of life.
In reference to the community providers, a very critical tool is a timely and complete communication between the oncologist and the provider. One such tool, which we term the survivorship passport, is a summary document that outlines the patient's past cancer history as well as the treatment received, what types of the treatment the patient received including doses of radiation, surgical procedures and the types of chemotherapy drugs given, any current problems that the patient might be facing as well as what the oncologist recommends should continue to be monitored for the long term.
This may include routine cancer prevention screening, comorbidity assessment, and other screening studies related to late consequences of the cancer care.
To summarize the content of this presentation, we hope that you have learned that there is a rapidly growing population of long --- long-term cancer survivors in the United States; that cancer survivors unfortunately face a variety of treatment-related complications both at the time they receive the treatment as well as years later. Long-term cancer survivors will need prevention of new malignancies, surveillance for potential late recurrences of their cancer, but also surveillance for second and even third malignancies that can arise during the course of their life as well as management of health concerns and psychosocial effects related to the cancer treatment. The survivorship passport is an important communication tool that links the oncologist and the community provider in partnership in care delivery. We thank you for your attention. And we would like very much to hear from you, what you learned from this presentation and whether you found it to be beneficial. Thank you.
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