How Do I Treat…?
Practical perspectives on cancer treatment by thought leaders, explaining how they would approach the treatment of a patient in their area of expertise.
Sunday, March 09, 2014
BY KENNETH R. HANDE, MD
Professor of Medicine (Hematology/Oncology)
Professor of Pharmacology
Vanderbilt-Ingram Cancer Center
On the surface, it may seem relatively easy to make appropriate chemotherapy dose modifications for patients with renal insufficiency. We generally have pharmacokinetic studies measuring renal clearance. We can estimate a patient’s renal function using a serum creatinine or glomerular filtration rate (GFR). If we have a patient who has half normal renal function and a chemotherapeutic drug where renal clearance accounts for 50 percent of overall clearance, we should make a dose reduction of 25 percent. If the drug is not cleared by the kidney, no dose reduction should be made.
Unfortunately, things are not a simple as one might think. Several variables make dose adjustments for renal insufficiency more complicated. How do we accurately measure renal function? What is normal renal function? Are drug metabolites formed? Are metabolites active? Are there multiple mechanisms for drug clearance? Can renal failure impact non-renal drug clearance?
I believe that most oncologists initially use a serum creatinine as a measure of renal function. However, a normal serum creatinine may not indicate “normal” renal function. Creatinine comes from skeletal muscle. If muscle mass remains steady and dietary creatinine intake remains steady (conditions that are not always met in cancer patients), the serum creatinine concentration is inversely proportional to creatinine clearance.
However 10 to 40 percent of urinary creatinine is secreted by the renal tubule. In early renal insufficiency, tubular secretion of creatinine will increase as GFR falls. Once a serum creatinine exceeds 1.5-1.8 mg/dl, the creatinine secretory process is saturated. In early renal failure, a small change in serum creatinine can mean a large drop in GFR. An increase in serum creatinine from 0.9 to 1.2 mg/dl corresponds to a decrease in creatinine clearance from 120 to 70 ml/min. Half of patients with a GFR < 60 ml/min have a “normal” creatinine so that oncologists should not assume that all patients with a serum creatinine under 1.5 mg/dl will have a GFR above 60 ml/min.
Measurement of Creatinine Clearance
Measurement of creatinine clearance (GFR) is a better indicator of renal function. GFR can be calculated by collecting a 24-hour urine sample and comparing the urine creatinine concentration with a serum creatinine (GFR = UCr x Volume/SCr). However, measuring creatinine clearance in the clinic is not practical due to time constraints and patients frequently not collecting all urine over 24 hours.
Estimates of creatinine clearance have been devised using serum creatinine and clinical variables. The Cockcroft-Gault and the MDMR (Modification of Diet in Renal Disease) estimates have been validated; they correlate well with each other and with some exception, make a reasonable estimate of GFR. Both can be used for dose modification in patients with renal failure.
However, the Cockcroft-Gault and MDRD estimates are less accurate in patients with unusual body mass (obesity, amputees) and in certain ethnic groups (specifically Asians). Patients with unusual diets or extremes of body weight may need to have a measured creatinine clearance.
It is also important to remember that the MDMR is normalized to a 1.73 m2 body surface area (BSA). An MDMR-estimated GFR needs to be multiplied by a patient’s BSA to obtain a GFR in ml/min. A “normal” GFR varies considerably among normal individuals and depends on body size, sex, and age.
An average person’s GFR declines by 0.75 ml/min per year. A normal GFR for someone under 40 is roughly 100-120 ml/min, but by age 70, the GFR may average 60-70 ml/min. Although not scientifically sound, in practical terms most individuals seen in an oncology clinic with a GFR over 60 ml/min are considered to have “normal” renal function. Even with this loose definition of “normal,” approximately 12 to 20 percent of cancer patients presenting for chemotherapy will have an abnormal GFR
If we have an accurate measure of a patient’s renal function, can we simply measure the percentage of renal drug clearance for that drug and adjust the dose for our patients based on these measurements? This would make sense if the parent drug were the only active moiety and if non-renal clearance of drug was not affected by renal failure. However, active metabolites are often present, and non-renal clearance may be changed in patients with renal insufficiency.
For example, cytosine arabinoside is primarily metabolized to uracil arabinoside, which has been felt to be a non-toxic metabolite. However, ara-U is cleared by the kidney and studies have suggested that high plasma concentrations of ara-U in renal failure patients receiving high dose ara-C may increase toxicity.
Irinotecan and imatinib are primarily cleared by hepatic metabolism. There is a suggestion that uremic toxins may decrease hepatic transport or metabolism of imatinib and irinotecan leading to increased toxicity. Thus, renal failure can impact clearance even if the parent drug does not undergo renal excretion. Conversely, drug toxicity may not increase in patients with renal insufficiency even if the drug has significant renal excretion.
Over 50 percent of oxaliplatin undergoes renal excretion. However, studies evaluating toxicity in patients with renal failure have found no measureable increase in toxicity down to a creatinine clearance of less than 20 ml/min. Thus, drug pharmacokinetics with estimates of renal clearance may not provide enough information to make appropriate dose adjustments in patients with renal insufficiency.
Studies measuring drug toxicity and efficacy in a significant number of cancer patients with renal insufficiency, in addition to pharmacokinetics measurements, would provide better information to make informed dosing decisions. Unfortunately, such studies are rare. For some drugs, no toxicity or efficacy data is available. Toxicity evaluations in patients with renal insufficiency are sometimes available but often in very small series. Information that dose modifications for renal impairment result in similar antitumor responses (response rates, PFS, and overall survival) is almost never available.
Given the lack of perfect information to make recommendations for dose adjustments for renal failure patients, what do I recommend when presented with a patient needing chemotherapy that has a creatinine clearance below 60 ml/min?
I would first review the package insert and/or ask my pharmacist if there is any information regarding studies of this drug in patients with renal insufficiency. Pharmaceutical companies may be a good source of information. I generally recommend using a drug where we have fairly good information (carboplatin is an example) or using a drug with minimally renal excretion (less than 20% of total clearance).
It is important to know what the goals of treatment are. For palliation, minimizing risk by avoiding a drug with potential for increased toxicity may be a better plan. If the goal is potential cure, then using a drug with the potential for high risk of toxicity may be justified. Chemotherapy is sometimes appropriate for patients on dialysis. In addition to dose adjustments for lack of any renal function, it is important to remember that drugs may be cleared by dialysis. Chemotherapeutic agents should generally be administered just following a dialysis session.
There are many review articles and book chapters providing suggestions as to dose modifications for renal insufficiency. These suggestions are at times based only on “expert opinion.” I categorize the information regarding the need for dose adjustments of chemotherapy drugs into three groups:
· Grade 1 evidence is that a drug (or active metabolite) is renally excreted, that there is evidence of increased toxicity using standard doses in patients with renal failure and that there is some data as to dose adjustments for renal failure. Chemotherapy drugs falling into that category include: capecitibine, carboplatin, cisplatin, lenalidomide, methotrexate, and oxaliplatin. For carboplatin, oxaliplatin, and lenalidomide, good data for dose adjustment exist, and I would be comfortable using these agents. Equations for adjusting carboplatin doses based on GFR are well-known. Oxaliplatin can safely be used down to a GFR of 20 ml/min. Dosing guidelines for lenalidomide are available. In myeloma patients with renal insufficiency, lenalidomide therapy may improve renal function. I tend to avoid cisplatin and methotrexate in patients with renal insufficiency as the risks are just too great without good information for dose adjustments. The risk of standard-dose cisplatin is worsening renal insufficiency to the point of dialysis. If there is no concern about worsening renal function, then cisplatin is a reasonable choice.
· My Grade 2 evidence includes drugs that are excreted via the kidney and for which there are case reports or small series suggesting increased drug toxicity in renal failure. Suggested dose modifications are only guesses without much data or where toxicity studies are conflicting. Category 2 drugs include: arsenic trioxide, bleomycin, high-dose cytarabine, etoposide, fludarabine, imatinib, melphalan, pentostatin, sorafanib, sunitinib, topotecan, and vandetinib.
· Category 3 drugs either have significant renal excretion or a case report noting increased toxicity in a patient with renal toxicity but minimal or conflicting information. Category 3 drugs include chorambucil, cyclophosphamide, daunorubicin, epirubicin, erbulin, ifosfamide, irinotecan, lomustine, nitrosoureas, and pemetrexed.
Thursday, March 06, 2014
BY ARNOLD B. ETAME, MD, PHD
Attending Neurosurgeon and Scientist
Director, Awake-Brain Surgery and Image-Guided Surgery Program
Co-director, Stereotactic Radiosurgery Program for Brain and Spine Metastatic Tumors
Department of Neuro-Oncology
Moffitt Cancer Center, Tampa, Fla.
It is estimated that more than 70,000 primary brain tumors will be diagnosed in the United States in 2013 based on the Central Brain Tumor Registry of the United States (CBTRUS) data. Metastatic brain tumors are more common than primary brain tumors and have a much higher incidence. In addition, metastases can often present as multiple lesions in contrast to primary brain tumors.
Management strategies for brain tumors often entail some combination of surgery, chemotherapy and radiotherapy. Benign symptomatic primary brain tumors might require only surgery, whereas malignant primary brain tumors often require surgery, chemotherapy, and radiotherapy. In addition, surgery followed by radiotherapy is sometimes desired for large symptomatic metastatic lesions. Furthermore, given the volume constraints of the intracranial compartment, an expanding tumor mass with associated edema will invariably result to neurological symptoms. These include headache, nausea, vertigo, motor, sensory, visual, gait, cognitive and most commonly seizure-related symptoms. In such instances, surgical resection has the added advantage of quickly ameliorating tumor-related mass-effect and hence improves quality of life. Surgery therefore remains a cornerstone in the management of brain tumors.
Defining the goals of surgery is a critical component in the surgery decision-making process, because such goals ultimately have to be balanced with any potential neurological morbidity. Tumor location is another important factor to consider because language and motor areas could provide significant limitations towards the goal of safe maximum resection. In such instances functional preservation is paramount, which implies that a subtotal resection would be acceptable.
In other instances, surgery is intended strictly for the purpose of tissue diagnosis as opposed to resection. Such patients would be subjected to either a stereotactic needle biopsy or an open craniotomy biopsy depending on tumor location and risk, as well as the pretest probability of a successful diagnostic yield based on radiographic characteristics of the tumor.
Open biopsies are ideal for superficial tumors and provide the advantage of larger sample size coupled with the ability to easily sample various regions of the tumor. For deeper lesions, stereotactic needle biopsy is preferred.
At our comprehensive cancer center, we encounter brain tumors at a higher frequency. I am mostly involved with the surgical, as well as the stereotactic radiosurgery, management of brain tumors. Patients are discussed at our weekly interdisciplinary tumor board, whereby surgical candidates are identified on a consensus basis. In recommending brain surgery, the overall functional status and disease burden of the patient are taken into account, especially for patients with systemic metastatic disease.
A major priority of my surgical approach with brain tumors is to enhance neurological outcomes for brain tumor patients. In order to accomplish this objective, I have incorporated MRI-guided imaging approaches that permit intraoperative interrogation of both tumor and critical white matter fiber tracts in patients undergoing brain surgery. I employ diffusion tractography imaging (DTI), which uses diffusion of water molecules within white matter fibers in the brain as a surrogate for the orientation and localization of those fibers. Hence DTI permits delineation of critical white matter fiber tracts that are closely associated with the tumor.
The ability to localize and spare critical fibers during tumor resection undoubtedly enhances neurological outcomes. In addition, I employ awake-brain tumor surgeries strategies for functional interrogation during tumor resection. All of these are accomplished through stereotactic techniques that permit navigation during tumor resection.
I take brain eloquence into consideration when deciding stereotactic craniotomy options for brain tumors. Tumors in areas that are eloquent for speech, motor, and visual pathways (temporal/occipital) are surgically treated distinctly from tumors in non-eloquent regions. The risk of neurological deficits is quite profound in eloquent regions, and the deficits themselves can be very disabling for patients. Tumors in non-eloquent brain regions are treated with using a standard stereotactic craniotomy. The stereotactic component permits a safe and reliable approach to the tumor for resection using trajectories that minimize cortical damage.
When patients harbor tumors in eloquent regions of the brain, DTI is often incorporated into the stereotactic craniotomy technique, thereby permitting simultaneous interrogation of tumor and closely associated critical white matter fibers. For tumors close to the visual pathways within the temporal and occipital lobes, I often delineate Meyer’s visual fibers (temporal) and optic radiations (occipital), and stereotactically ascertain their positional relationship to the tumor.
A surgical trajectory to the tumor that spares the visual fibers is then planned. This is particularly important for occipital lobe lesions whereby compromise of visual fibers could result to dense visual field defects. Similarly, for tumors that are close to the motor cortex but do not actually involve motor fibers, I would often incorporate DTI for corticospinal motor fibers into the stereotactic craniotomy technique, thereby permitting simultaneous interrogation of the relation of tumor with motor fibers. In addition, a motor functional MRI (fMRI) is also incorporated to delineate the motor cortex.
When patients present with tumors that involve the motor cortex or speech areas of the dominant frontal and temporal lobes, intra-operative correlation with function is critical. I would always therefore perform an awake-craniotomy that stereotactically incorporates DTI tractography and fMRI.
The awake-surgery permits intraoperative mapping or direct correlation of function to brain anatomy, thereby delineating what can be safely resected. In addition, potential neurological deficits can be identified early since the patient is awake, thereby minimizing the chances of irreversible damage.
The synergy of image-guided co-localization and interrogation of tumor and critical white matter fibers, coupled with the functional advantage of the awake-patient during surgery, significantly improves the outcomes of surgeries in eloquent areas, as has been realized in our brain tumor program.
In summary, surgery has a central role in the management of brain tumors. The goals of surgery should always prioritize neurological functional preservation. Tumor location is critical, and can correlate with surgical morbidity. Stereotactic techniques that permit co-localization of critical eloquent fibers in relation to tumor can minimize neurological deficits. Awake-brain surgery permits safe resection of tumors in brain areas that are eloquent to motor and speech functions.
Algorithmic Representation of Craniotomy Options for Patients with Tumors in Eloquent Brain Regions for Speech, Motor, and Vision
Copyright © 2011-2014 H. Lee Moffitt Cancer Center and Research Institute; reprinted with permission.
Friday, February 21, 2014
BY ALAN P. VENOOK, MD
The Madden Family Distinguished Professor of Medical Oncology and Translational Research
Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco
The incidence of colorectal cancer is decreasing thanks to some success with screening, yet there will still be more than 140,000 patients diagnosed with the disease this year. And although more patients with colon cancer are cured than are not, about 50,000 people a year will be diagnosed with metastatic disease. As opposed to the majority of stage IV solid tumor patients who are being treated for palliation, however, patients with limited metastatic colorectal cancer may be treated with curative intent. That makes every decision an important one.
Sometimes, the first decision has been made before the oncologist is involved.
As many as one-third of patients will present with metastatic disease and the primary cancer in place, often reflecting the ability of PET scan and CT imaging to detect low-volume metastases. Depending on who sees the patient first, therefore, the patient with metastatic disease may be recovering from surgery, which may necessitate a delay before treatment can be initiated. If the patient has not yet undergone surgery, then that is where the debate begins.
The pendulum swings back and forth as to whether the primary should or should not be left in place. The balance between immediate chemotherapy or surgery is a nuanced one and is even more complicated if the tumor is in the rectum (the distal 12 cm of the large bowel), where radiation to maximize local control also needs consideration.
In general, patients with markedly symptomatic primaries should be strongly considered for definitive upfront management (either surgery or chemotherapy and radiation) unless the difference of six or eight weeks in delaying systemic treatment while the patient recovers from surgery is a concern in the patient with bulky metastases.
Regardless of the events leading up to the visit to the oncologist, there is always a push to start chemotherapy as soon as possible. However, it is important for oncologists to make sure they know enough details of the tumor biology to proceed. Someday that may include routine multi-gene platform assays, but as of today, that would mean assessment of KRAS status; and if the patient is KRAS wild-type, a check for BRAF mutations.
With that in mind, it is important to check with the pathologist to be sure there is adequate material for these assays. (The expectation, though, is that KRAS testing will soon give way to “expanded” RAS testing, which may require more tissue and more time.)
Which Combination of Chemotherapy?
With that information either in hand or pending, the complex decision of which combination of chemotherapy to begin with can be addressed. Actually, based on market information, this is not really a complex decision for most practitioners: the majority of patients with metastatic colorectal cancer start treatment with FOLFOX and bevacizumab. This is certainly a reasonable choice, albeit not based on any comparative data. And because the first-line treatment will impact subsequent lines of therapy by process of elimination, if not by complications or toxicities, the initial steps may be determinant of whether the patient can be cured or not and/or will be saddled with a toxicity or complication that will persist throughout the remainder of their life.
FOLFOX and FOLFIRI are for all intents and purposes equivalent in outcome but carry different risks and toxicities. FOLFIRI causes alopecia and can be poorly tolerated, particularly in patients with Gilbert’s syndrome. FOLFOX is rarely problematic for patients – until six or seven doses have been given, when nearly every patient develops peripheral neuropathy and when patient and clinician must decide whether the neuropathy is enough to warrant a change in approach. Even then it may be too late, since common wisdom aside, neuropathy may get worse rather than better even when the oxaliplatin has been discontinued.
For that reason (and not only to be contrarians), we typically start with FOLFIRI as the first-line backbone (after a check of prior serum bilirubin levels makes the likelihood of Gilbert’s nil – about 10% of the population actually has a UGT1A1 polymorphism that makes irinotecan a bad idea.)
We continue FOLFIRI as long as it is well tolerated and in the absence of progression, with a check at two months if the plan is to go to curative metastectomy lest the patient develop hepatic complications from chemotherapy. Capecitabine can be substituted for the 48-hour infusional component, but we do not mix it with irinotecan regimens.
The chemotherapy actually may work remarkably well by itself so bevacizumab or an EGF-R antibody (cetuximab or panitumumab) are not mandatory at first or even later on. The antibodies – with the recently approved ziv-aflibercept -- add to overall survival on average when used in multiple lines, but there are occasional severe complications and the sequence of their use, the possibility that discontinuing bevacizumab may lead to a sort of rebound effect, and the acneform rash of the EGF-R antibodies are all factors to be considered.
A biomarker for bevacizumab or ziv-aflibercept would be a great advance just as the identification of KRAS and other RAS mutations enabled us to target patients likeliest to benefit from EGF-R blockade.
The decision to change treatments is obvious when there is overt progression. We follow patients with good old-fashioned contrast CT scans to inform the less obvious cases and look for clear-cut progression before doing so. We do not let changes in PET imaging dictate therapeutic decisions, by and large, because these are often misleading. In fact, I believe that chemotherapy decision-making in colorectal cancer should be a PET-free zone.
However the decisions are made, when the above combinations have been spent, we turn either to regorafenib or to an experimental therapy we deem promising, with an emphasis on combinations with the capacity to reverse KRAS mutation and resistance. Many patients will have had their tumors analyzed for a plethora of mutations by this time, but most of the “findings” do not beget a treatment. The exception is the BRAF mutation: we determine that status at the beginning, and such patients are targeted early for experimental approaches, either at our center or nationally.
The algorithm described above is just one person’s opinion. We await the results of CALGB 80405 to determine if there is one best approach for all patients or one best approach for an individual patient.
Friday, February 21, 2014
BY SARA HURVITZ, MD, is Assistant Clinical Professor of Hematology/Oncology at UCLA Medical Center and a researcher at Jonsson Comprehensive Cancer Center.
It is well recognized that the treatment of HER2-positive metastatic breast cancer has been revolutionized in the last 15 years -- first by the introduction of trastuzumab; followed nine years later by lapatinib; and in the last two years, by the approval of two additional HER2-targeted therapies, pertuzumab and trastuzumab emtansine (T-DM1). The availability of these treatments has literally altered the natural history of HER2-driven disease, allowing many patients to live years, and in some cases beyond a decade, after diagnosis with metastases.
In my own practice, I now routinely utilize trastuzumab, pertuzumab, and a taxane in the first-line HER2+ metastatic setting based on the improved overall survival and progression-free survival as well as relatively similar tolerability of this regimen compared with standard trastuzumab plus docetaxel in the phase III CLEOPATRA study.
I discuss with the patient the differences between docetaxel and paclitaxel in terms of side effects profile and dosing frequency (q3 weekly vs. q weekly respectively), and based on this discussion will select which taxane to use. In keeping with the design of CLEOPATRA, my goal is to have the patient complete at least six cycles of chemotherapy, and at that time, if the disease is responding, we may discontinue the chemotherapy and continue pertuzumab and trastuzumab until the time of disease progression.
If a patient’s tumor co-expresses estrogen and/or progesterone receptors, I will often add an anti-hormonal therapy upon discontinuation of the chemotherapy. While the CLEOPATRA study design did not include hormonal blockade in its design, my opinion is that using endocrine therapy in combination with dual HER2-blockade after the initial chemotherapy cycles may be beneficial to patients with ER+/HER2+ disease.
At the time of progression on trastuzumab and pertuzumab, I will consider resuming the taxane (and continuing the dual HER2-targeted therapy). Again, whether this practice is as effective as immediately switching therapy to another drug such as T-DM1 is an unanswered question at this time. My theory is, if the patient’s disease responded well to the taxane previously and the patient has no significant neuropathy, then reintroducing the taxane and continuing the pertuzumab/trastuzumab may regain control of the disease. Patient preference regarding taxane-related side effects including hair loss certainly plays a role in this decision process, however.
In the second-line setting (or in the case of a patient whose disease relapsed quickly -- i.e., within six months of adjuvant trastuzumab), I recommend initiating T-DM1 based on the results of the EMILIA study. Patients with HER2-positive metastatic breast cancer resistant to trastuzumab and taxane had a better progression free survival-treated with T-DM1 compared with capecitabine and lapatinib. Patients tend to tolerate this therapy extremely well, although it is important to monitor platelets and liver transaminases as dose delay or reductions are occasionally warranted.
While the CLEOPATRA and EMILIA studies have nicely defined optimal treatment in the first- and second/third-line settings respectively, the most effective sequencing and therapeutic combinations beyond the first two or three lines of therapy have not been defined. In addition, management of brain metastases remains a significant challenge in clinical practice. These questions will hopefully be addressed in the coming years with ongoing studies.
In the absence of this data, however, clinicians are faced with making treatment decisions based on a combination of factors including hormone receptor status of the tumor, response (or resistance) to prior therapies received, disease burden, and the patient’s performance status, comorbidities, and residual toxicities as well as her goals of treatment.
It is not uncommon for patients with HER2+ metastatic breast cancer to have more than five lines of therapy. In my own practice, I will continue to treat a patient with subsequent lines of therapy as long as she has a good performance status (ECOG 0-2) and she desires to continue therapy. Data is mounting that strongly supports continued use of HER2-blockade even in the face of disease progression while on HER2-targeted therapy.
Thus, in subsequent lines of therapy I will always continue either trastuzumab or lapatinib. I find the combination of trastuzumab with vinorelbine to be especially well tolerated and active. Other trastuzumab and/or lapatinib-based regimens include combinations with capecitabine, gemcitabine, or eribulin, and in the case of hormone receptor-positive disease, fulvestrant or an aromatase inhibitor.
I will also use T-DM1 if a patient has received multiple lines of therapy but has not yet received T-DM1. The phase III TH3RESA study reported in late 2013 suggests that T-DM1 is better tolerated and is associated with an improved progression-free survival rate compared with treatment of physician’s choice in patients who are beyond the third-line treatment setting.
I have also found lapatinib plus trastuzumab to be generally well tolerated and active; however, patients must be prepared for the possibility of diarrhea and should be monitored closely in the first few cycles. Needless to say, patients are strongly encouraged to participate in clinical trials of newer therapeutic combinations and novel targeted therapies especially in the later-line disease setting.
One problem that remains vexing in clinical practice is the most appropriate management of central nervous system metastases. Local regional therapy with stereotactic radiosurgery, surgical resection, and/or whole-brain radiation are used as an initial approach in the absence of a suitable clinical trial. I will often utilize lapatinib in these situations, given its potential for better penetration of the blood-brain barrier compared with trastuzumab.
It will be interesting to see the results of ongoing studies evaluating drugs that are able to penetrate the blood-brain barrier, including the mTOR inhibitor everolimus. Hopefully in the next several years we will see an improvement in our ability to treat, and ultimately prevent, CNS disease.
While there are multiple treatment options available for patients with HER2+ metastatic breast cancer, treatment resistance remains the rule. An increasing number of treatment options will no doubt continue to emerge as clinical trials evaluate new biologically targeted therapies aimed to prevent or circumvent treatment resistance.
The use of tumor genetic profiling will in the future, it is hoped, improve our ability to select therapeutic choices and sequencing in an era where so many options for therapy exist.
Tuesday, October 29, 2013
HYMAN B. MUSS, MD, is Professor of Medicine and Director of the Geriatric Oncology Program at the University of North Carolina Lineberger Comprehensive Cancer Center.
Breast cancer, like most solid tumors, is a disease of aging, with an incidence that dramatically rises with increasing age. As the population ages, more and more older women with breast cancer will require oncology services that will pose challenges for surgical, medical, and radiation oncologists. What’s different about older women with breast cancer is that they frequently have major comorbidity, and breast cancer is not always their most important medical problem.
The first thing I do when seeing an older breast cancer patient is take a detailed social history so I get a feel of what the patient’s life is like, her social support system, and what’s important to her. After that I usually take a few moments and calculate her life expectancy -- exclusive of her breast cancer. I use www.eprognosis.org for this. It has several scales that give reasonable estimates of survival for community-dwelling elders. You should select a scale to use in your practice because some of the questions in the various scales relate to geriatric issues that most of us don’t incorporate (or ask about) in the usual history and physical examination (like how far can you walk?). Once you know your patient’s life expectancy, the next order of business is to define the goals of therapy. For older women with metastatic disease, the goals of treatment are ameliorating cancer-related symptoms while maintaining the highest quality of life. The best approach for almost all these older women with metastases is to use endocrine therapy for those with hormone-receptor positive tumors until it is clear that the tumor is refractory to endocrine treatment, and then consider sequential single-agent chemotherapy.
For those with earlier-stage disease, the goal of therapy -- as in younger patients -- is increasing the chances for cure. Unless older women have a very short estimated survival, definitive surgery with either lumpectomy or mastectomy should be considered. Older women with hormone-receptor positive tumors can be managed with primary endocrine therapy, but unless they have very short estimated survival, the majority will have tumor progression by five years, and initial surgery is a better option for most. In addition, older women with hormone-receptor positive tumors less than or equal to 2 cm treated with lumpectomy, and who are willing to take endocrine therapy, can be spared breast irradiation without any adverse influence on survival. Women who elect this path of treatment will have a higher rate of in-breast recurrence at 10 years -- about 10 percent compared with two to three percent for patients who receive breast irradiation – but if they relapse they can be treated again with surgery and then if needed, radiation.
For older women with hormone-receptor positive tumors, endocrine therapy is the mainstay of systemic treatment, and the decision as to whether to also suggest chemotherapy should be based on its potential added value to endocrine therapy. For most node-negative patients, and many with one to three positive nodes, genomic assays (Oncotype DX and others) can be helpful in estimating the potential benefits of chemotherapy. In addition, it always pays to remember that the bulk of relapses in women with hormone-receptor positive tumors treated with an adjuvant endocrine therapy occur after five years. This is why it’s so important to calculate the non-breast cancer related estimated survival as even older hormone-receptor positive patients with extensive nodal involvement will rarely benefit from chemotherapy if their estimated survivals are less than five to 10 years.
For those with early-stage hormone-receptor negative and HER-2 negative (“triple-negative”) tumors and estimated survivals exceeding five years, chemotherapy is the treatment of choice and should be considered for most patients. Those with small tumors less than 1 cm should be considered for chemotherapy on an individual basis. Online programs such as www.adjuvantonline.com and www.predict.nhs.uk/predict.shtml can help greatly in the selection of treatment. Unless there is a major benefit from more intensive anthracycline- and taxane-based therapy in these patients -- I like to see at least a 3% improvement in overall survival for the more aggressive, toxic, treatment -- I favor non-anthracycline regimens such as docetaxel and cyclophosphamide (TC). Cyclophosphamide, methotrexate, and fluorouracil can also be considered in this setting, although it is not as effective and takes longer to complete treatment than TC does. I use white blood cell growth factors in all older patients I treat with TC as in community settings the risk of neutropenic fever can exceed 20 percent.
What about older patients with HER2-positive breast cancer? For those with early-stage potentially curable cancers and reasonable life expectancy, I recommend chemotherapy and anti-HER2 directed treatment. It’s important to factor into your treatment decision that women with hormone-receptor positive, HER2-positive tumors (HR+/HER2+) have less aggressive clinical courses than those who present with hormone-receptor negative and HER2-positive phenotypes. I use www.predict.nhs.uk/predict.shtml to calculate the added value of chemotherapy and anti-HER2 based therapy in HER2-positive patients as HER2 status can be incorporated into the model. For those for whom I recommend chemotherapy and anti-HER2 directed treatment, I tend to use non-anthracycline combinations such at docetaxel, carboplatin, and trastuzumab. Trials of anti-HER2 based adjuvant therapy without chemotherapy are in progress. In addition, new agents such as ado-trastuzumab emtansine may prove to be ideal treatments in this setting. For those with metastatic HER2-positive breast cancer there are numerous choices, and such treatment decisions should be individualized and based on the tempo of the disease, the extent of the metastases, anticipated toxicity, and symptom burden.
A comprehensive geriatric assessment can play a major role in optimizing the management of older patients with cancer, regardless of type. Screening instruments and short versions of such assessments are gaining popularity and likely to be helpful in suggesting interventions that improve function and quality of life prior to and during treatment. In addition models that use a combination of clinical and geriatric assessment variables may prove to be extremely helpful in predicting chemotherapy toxicity. Consider also the frail elderly; here the overriding goals of care are maintenance of function and quality of life and any treatment that does not support these goals should be discouraged.
My hope is that this discussion will be helpful to you for treating the older woman with breast cancer. Expected survival, which is dependent on so much more than age, and the goals of treatment, are the prime considerations when approaching the older breast cancer patient. In addition, and most important, is asking the patient and family what their expectations of treatment are, and tailoring treatment options to their wishes. Providing the best options and making the right treatment decision for an older patient frequently is a major challenge but is always worth your time and effort.