Technological advances are changing the field of medical oncology at a rapid rate. The successful incorporation of immune checkpoint inhibitors and other immunologic strategies to facilitate activation of the patient's own immune system as part of the standard treatment of many malignancies has been a major advance. Other changes include expanded routine use of molecular profiling in several tumor types and the resultant application of precision therapeutics, which are selected on the basis of specific mutations within a person's tumor. “Precision medicine,” or “precision therapeutics,” is a term often used interchangeably with “personalized medicine,” but rather than denoting therapeutic approaches tailored to individual patients, precision medicine focuses on identifying effective approaches for patients based on genetic, environmental, and lifestyle factors. However, many aspects of oncology, including the use of traditional histologic diagnosis and clinical staging, as well as extensive use of cytotoxic chemotherapy, radiation therapy, and surgery, remain central to current oncologic practice.
Despite the many technological advances, careful clinical evaluation and staging, understanding and communicating realistic goals of care, and recognizing and promoting patient preferences remain central to the practice of oncology. Meaningful progress has been made in many cancers. However, most cancers, once metastasized, are treatable but still incurable. Oncology has also become the focus of concerns regarding unsustainable costs in care, specifically in terms of the costs of new drugs, and the impact of financial toxicity has become an important consideration in oncologic care.
In order to plan a proper treatment strategy, a clinician must first determine the stage, or extent, of the cancer. Early-stage cancers often can be cured by local therapy, such as surgery or radiation, whereas more advanced-stage cancers require a more systemic approach. With the use of the TNM cancer staging system, most solid tumors are staged on a scale of 1 to 4. In the TNM system, T (T1-T4) refers to the size or extent of local invasion of the primary tumor, N (N0-N3) indicates locoregional lymph node involvement, and M indicates the absence (M0) or presence (M1) of distant metastases. If the main tumor, cancer in nearby lymph nodes, or metastasis cannot be measured, this is denoted with X (for example, TXNXMX). Some hematologic tumors have unique tumor-specific staging systems.
The required studies and imaging techniques will be dependent on the expected behavior pattern of each cancer type and will differ from one tumor to the next. Therefore, a proper cancer evaluation requires knowledge of the specific disease entity so that the necessary tests can be done. Tests with a very low yield should not be ordered in the absence of specific directing symptoms. For example, bone and brain imaging is appropriate in the staging of patients with lung cancer because bone and brain metastases are common in the early course of this disease. However, patients with presumed locoregional colorectal cancer rarely present with bone or brain metastases; consequently, routine imaging of these sites as part of staging in the absence of specific symptoms is not necessary. Thoughtfully performed staging is generally the most accurate prognostic indicator and largely dictates the therapeutic strategy for patients with cancer.
Performance status is a means of quantifying how medically fit a patient is overall. A good performance status predicts favorable tolerance and response to treatment. Patients with a poor performance status are much more likely to experience serious or life-threatening toxicity and much less likely to benefit from treatment.
It is important to differentiate patients with a poor performance status who are debilitated due to chronic comorbidities from patients who would otherwise be medically fit but are acutely debilitated by their disease. The latter situation may warrant an attempt at aggressive treatment, because reversing the cancer process is the only thing that will improve the patient's overall condition, whereas the former may need to be treated with less aggressive treatment or possibly no specific anticancer treatment. Cancer drug approvals are based on clinical trials, virtually all of which limit participants to patients with good performance status, so the degree to which the results of these trials are relevant to patients with poor performance status is questionable.
In addition, age alone should not be regarded as a reason to avoid aggressive treatment. Elderly patients who are otherwise medically fit and healthy and hence have a good performance status may tolerate aggressive therapy well, whereas younger patients with several medical comorbidities resulting in a poor performance status may be unable to tolerate aggressive treatment.
The two most commonly used performance status scales are the Karnofsky score and the Eastern Cooperative Oncology Group/World Health Organization system (also called the Zubrod score). These are outlined and contrasted in Table 36.
Clear and candid communication between clinician and patient is essential for good oncologic care. When communicating treatment options and recommendations, clinicians must work to establish realistic treatment goals. When cure is not realistically possible, goals such as lengthening survival, shrinking a tumor, controlling disease growth, palliation or prevention of disease-related symptoms, and maintaining quality of life at a level acceptable to the patient should be considered. The potential benefits of treatment have to be weighed and discussed along with their risks and toxicities. Patients with incurable cancer face choices of more aggressive therapy associated with more unpleasant and potentially dangerous side effects that are designed to prolong their life. The gravity of those side effects is weighed against the duration of prolonged survival, but all patients have a unique perspective on how they interpret this equation. Similarly, more aggressive initial therapy may result in prolonged remission or disease-free survival but no change in overall survival. Some patients would gladly accept the increased toxicity of such therapy for a prolonged period without cancer, whereas others would not.
More recently, as costs of anticancer treatments have increased astronomically, the concept of financial toxicity—the impact that the cancer diagnosis will have on the patient's financial stability and overall well-being—has received greater attention. A diagnosis of cancer has been shown to be a leading cause of personal bankruptcy, and studies show financial worries contribute to the anxiety of many patients with cancer. Inability to meet copays or coinsurance requirements, especially for expensive oral anticancer medications, is a leading cause of failure to properly receive therapy. A clear understanding of the goals of care and the toxicities, including financial toxicity, is necessary for patients and physicians to make informed choices in treatment options. This concept of financial toxicity goes beyond individual patients in affecting the overall health care economy. Quantifying the overall benefit of extending a patient's life by relatively short periods (less than 2 months' median benefit) and contrasting that benefit by the financial cost of care require complex ethical, economic, and public health decisions.
Early-stage cancers often have a high chance of cure. With increasing cancer stage, however, the possibility of cure diminishes. Most metastatic cancers are treatable but not curable. This is especially true for patients with poor performance status due to chronic medical comorbidities or those who have not been able to tolerate initial treatment attempts. For such patients or for those who have exhausted standard treatment options, supportive, comfort-oriented care may be most appropriate. Use of adequate analgesia, as well as support from palliative medicine specialists, is important throughout the continuum of care but particularly so in patients with pain or with symptoms from either disease or therapy. Recent studies suggest that such palliative care, when instituted as part of early aggressive therapy, helps patients better tolerate their cancer care and should not be delayed to the point at which no more active cancer therapy is considered.
The field of oncology has its own language and terminology that is often misunderstood. A clear understanding of this terminology is necessary to facilitate informed discussions and develop realistic treatment goals.
The one pure and simple term is cure. Cure means, as one would expect, that the cancer is gone, no further treatment is required, and the patient will live out his or her life without seeing that type of cancer again. This should not be confused with overall survival, which is defined as the amount of time from initiation of a treatment until death. Overall survival is often misunderstood by patients to be synonymous with cure. Median survival benefits that are reported in studies are typically offered to patients as indicators of how long they will live, but it must be understood that medians of studies are meaningful for populations but not for individual patients. This can be further compounded by the frequent use of the phrase significant improvement in survival, in which significant refers to the statistical certainty of the finding but is often misinterpreted as a substantial improvement in survival. Many drugs have been approved with significant improvements in survival that are limited to less than 2 or 3 months, a quantity that most would agree is not substantial. Furthermore, one must be cautious about interpreting nonrandomized comparisons of older versus newer survival data, because screening and surveillance techniques are leading to more accurate staging and earlier recognition of smaller volumes of cancer recurrence, creating a lead-time bias that may appear to amplify the benefits of a newer treatment compared with an older one. Thus, randomized controlled trials are the optimal means of comparing one treatment with another.
One of the most misrepresented and misunderstood terms is progression-free survival. It is the time from when a treatment is started until that treatment is no longer controlling the tumor. Because the duration of progression-free survival is defined by cancer progression or death, whichever occurs first, the word survival is maintained in the term; however it has little to do with overall survival and is often, and sometimes deliberately, confused with it. Progression-free interval would more accurately describe what is referred to as progression-free survival.
Response rate is the percentage of patients in a clinical trial whose tumor shrinks to a prespecified degree with treatment as indicated on imaging studies, such as CT or MRI. Response rate has not been shown to correlate with other metrics, such as overall survival, but there is a strong emotional benefit to patients when the tumor is regressing, and in symptomatic patients, such shrinkage is likely to alleviate, prevent, or delay symptoms.
The classic cancer treatment modalities are surgery, radiation, and chemotherapy. As current technology has advanced, chemotherapy is best subdivided into the more classic cytotoxic chemotherapies, targeted or precision therapies, and immunotherapies.
For tumors that are localized, surgical resection remains at the center of treatment. Following resection, the patient is never at risk for harm from the tumor that has been removed but rather from microscopic tumors that may still remain in the patient. Neoadjuvant (preoperative) or adjuvant (postoperative) treatment with radiation, chemotherapy, or both, may be used to eradicate residual microscopic disease and increase the chance for cure. The nature of the treatment, in terms of chemotherapy, radiation, or both, will depend on the type of tumor and its characteristic pattern of spread. Neoadjuvant and adjuvant therapy acknowledge the fact that some patients being treated would be cured with surgery alone and are therefore exposed to needless additional toxicity. Randomized trials are crucial in determining whether, for any given population of patients, neoadjuvant or adjuvant therapy improves some important outcome, such as cure, overall survival, or disease-free survival, without unacceptable toxicity. Conversion therapy seeks to convert an unresectable tumor to a resectable one by shrinking it away from critical structures and creating a plane for resection that previously was lacking; this differs from neoadjuvant chemotherapy, which is used for micrometastases of an already resectable tumor.
Balancing therapy efficacy and toxicity—in particular, the need for adjuvant or neoadjuvant therapy or the desired aggressiveness of the primary chemotherapy, radiation therapy, or surgical therapy for populations of patients—has traditionally been based on stage, pathology, and understanding of the overall behavior of that tumor. Currently available imaging and laboratory studies are somewhat limited in terms of their ability to identify which patients will or will not be at risk for recurrence of cancer after definitive surgery. Numerous tumor markers, gene panels, and other technologies are available, but few are definitive. The preferred assay would be predictive, meaning that it could identify the subset of those patients who are at risk for recurrence and who will benefit from an intervention such as adjuvant chemotherapy to delay or prevent such recurrence. An example of this is a commercially available 21-gene assay for breast cancer that identifies a patient population who is at risk for recurrence and will have that risk lowered by chemotherapy. Such predictive tools are highly useful because they provide actionable information in terms of who to treat and who not to treat. Unfortunately, attempts to develop such predictive assays have rarely been successful. A similar multigene assay in colorectal cancer is prognostic in that it can quantitate a patient's risk of recurrence, but fails to identify which patients, if any, will have their risk lowered by chemotherapy. Therefore, it does not provide information that is definitive for decision making. Such prognostic tests are of much less value than risk factors that can be used to define better therapy, but these tests still may be of value to individual patients who may rely on that statistical information to better plan their lives.
According to the International Network on Cancer, Infertility, and Pregnancy (INCIP), prenatal exposure of children to maternal cancer with or without treatment has not been shown to impair physical or mental development in early childhood.
Current developments in chemotherapy are centered on creating agents that target specific aspects of a tumor cell. Although in theory these agents should be more selective and have fewer toxicities than older, conventional chemotherapies, this has not always turned out to be the case. Many of the signaling pathways that are hyperactive in tumor cells remain at least somewhat active in normal cells, and so disruption of these pathways can produce considerable side effects.
The goal of precision medicine is to identify specific aspects of the tumor that can guide clinicians in deciding which therapies are or are not appropriate for a particular patient. Markers can be either inclusionary, in that they include a patient in a therapy that otherwise might not be considered, or exclusionary, in that they exclude a patient from a treatment that otherwise might have been used.
An example of an inclusionary marker is the V600 BRAF mutation in melanoma. Specific BRAF inhibitors, such as vemurafenib and dabrafenib, would only be appropriate for use in melanomas that harbor this specific mutation. Melanomas lacking this mutation would not be treated with these agents. Trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2) on the cell surface, is only active in those breast or gastroesophageal tumors that overexpress HER2. In short, targeted therapy only works if the target is both present and clinically relevant.
Examples of exclusionary markers are RAS mutations. The anti–epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab were initially thought to be appropriate for treatment of all colorectal cancers. Subsequently, it was determined that any tumors harboring mutations in either the KRAS or NRAS gene were not only highly resistant to responding to these agents, but in fact the growth of the RAS-mutated tumors may even be accelerated by these agents. All metastatic colorectal cancers now require tumor genotyping for KRAS and NRAS mutations, and only those tumors lacking the mutations are appropriate for treatment with cetuximab or panitumumab.
Immunotherapy agents are drugs that do not attack the cancer directly but rather mobilize the patient's own immune system to do so. This has become possible through the identification of “immune checkpoints,” which serve as “brakes” on the immune system in order to prevent the immune system from attacking itself and causing autoimmune diseases. Antibodies that block these checkpoints release the brakes on the immune system and allow it to aggressively attack the tumor. Side effects are related to resultant autoimmunity from the less-regulated immune system. The first immune checkpoint identified was the antigen-4 (A-4) molecule on the surface of the cytotoxic lymphocyte (T cell), hence its designation cytotoxic T-lymphocyte antigen-4 (CTLA-4). Antibodies that block CTLA-4, such as ipilimumab, have been successful in mobilizing the immune system against melanoma, renal cell carcinoma, and other malignancies. The other immune checkpoint that has been successfully exploited is the programmed death 1 (PD-1) receptor. Anti–PD-1 agents, such as nivolumab or pembrolizumab, have shown substantial and durable activity against melanoma and non−small cell lung cancers, as well as other tumors. Agents against the ligand of PD-1 have also shown important clinical activity. Combinations of these agents are showing further effectiveness but with increased toxicity and also considerable expense. Many other checkpoints in the immune system are now being exploited by numerous drugs in development, and it is possible that immunotherapy will substantially change the outlook for patients with many different types of cancer in the foreseeable future.