Systematic Assessment of the Patient With Cancer and Consequences of Treatment
Roland T. Skeel
I. ESTABLISHING THE DIAGNOSIS
A. Pathologic diagnosis is critical
Although it might seem obvious that the diagnosis of cancer must be firmly established before chemotherapy or any other treatment is administered, the critical nature of an accurate diagnosis warrants a reminder. As a rule, there must be cytologic or histologic evidence of neoplastic cells together with a clinical picture consistent with the diagnosis of the cancer under consideration. It is rarely acceptable to initiate treatment based solely on clinical examination, radiologic evidence, and nontissue laboratory evidence, such as tumor markers. Commonly, patients present to their physicians with a complaint such as a cough, bleeding, pain, or a lump; through a logical sequence of evaluation, the presence of cancer is revealed on a cytologic or histologic specimen. Less frequently, lesions are discovered fortuitously during routine examination, evaluation of an unrelated disorder, or systematic screening for cancer. With some types of cancer, pathologists can establish the diagnosis based on small amounts of material obtained from needle biopsies, aspirations, or tissue scrapings. Other cancers require larger pieces of tissue for special staining, immunohistologic evaluation, flow cytometry, examination by electron microscopy, or more sophisticated studies such as evaluation for genetic deletions, amplifications, or other mutations.
It is often helpful to confer with the pathologist before obtaining a specimen to determine what kind and size of specimen is adequate to establish the complete diagnosis. When a tissue diagnosis of cancer is made by the pathologist, it is incumbent on the clinician to review the material with the pathologist. This practice is good medicine. It also allows the clinician to tell the patient that he or she has actually seen the cancer and to avoid administering chemotherapy without a firm pathologic diagnosis. In addition, the pathologist often gives a better consultation—not just a tissue diagnosis—when the clinician shows a personal interest.
B. Pathologic and clinical diagnosis must be consistent
Once the tissue diagnosis is established, the clinician must be certain that the pathologic diagnosis is consistent with the clinical findings. If the two are not consistent, a search must be made for additional
information, clinical or pathologic that allows the clinician to make a unified diagnosis. A pathologic diagnosis, like a clinical diagnosis, is also an opinion with varying levels of certainty. The first part of the pathologic diagnosis—and usually the easier part—is an opinion about whether the tissue examined is neoplastic. Because most pathologists rarely render a diagnosis of cancer unless the degree of certainty is high, a positive diagnosis of cancer is generally reliable. The clinician must be more cautious if the diagnosis rendered states that the tissue is “highly suggestive of” or “consistent with the diagnosis of” cancer. Absence of definitively diagnosed cancer in a specimen does not mean that cancer is not present, however; it means only that it could not be diagnosed on the tissue obtained, and clinical circumstances must establish if additional tissue sampling is necessary. A second part of the pathologist’s diagnosis is an opinion about the type of cancer and the tissue of origin. This determination is not necessary in all circumstances but is usually helpful and may be critical in selecting the most appropriate therapy and making a determination of prognosis, and will become more relevant with precision (personalized) cancer treatment.
information, clinical or pathologic that allows the clinician to make a unified diagnosis. A pathologic diagnosis, like a clinical diagnosis, is also an opinion with varying levels of certainty. The first part of the pathologic diagnosis—and usually the easier part—is an opinion about whether the tissue examined is neoplastic. Because most pathologists rarely render a diagnosis of cancer unless the degree of certainty is high, a positive diagnosis of cancer is generally reliable. The clinician must be more cautious if the diagnosis rendered states that the tissue is “highly suggestive of” or “consistent with the diagnosis of” cancer. Absence of definitively diagnosed cancer in a specimen does not mean that cancer is not present, however; it means only that it could not be diagnosed on the tissue obtained, and clinical circumstances must establish if additional tissue sampling is necessary. A second part of the pathologist’s diagnosis is an opinion about the type of cancer and the tissue of origin. This determination is not necessary in all circumstances but is usually helpful and may be critical in selecting the most appropriate therapy and making a determination of prognosis, and will become more relevant with precision (personalized) cancer treatment.
C. Treatment without a pathologic diagnosis
There are rare circumstances in which treatment is undertaken before a pathologic diagnosis is established. Such circumstances are clearly exceptions, however, and involve less than 1% of all patients with cancer. Therapy is begun without a pathologic diagnosis only when the following conditions are met:
The clinical features strongly suggest the diagnosis of cancer, and the likelihood of a benign diagnosis is remote.
Withholding prompt treatment or carrying out the procedures required to establish the diagnosis would greatly increase a patient’s morbidity or risk of mortality.
Two examples of such circumstances are (1) a primary tumor of the midbrain and (2) superior vena cava syndrome from a large mediastinal mass with no accessible supraclavicular nodes and no endobronchial disease found on bronchoscopy in the occasional patient in whom the risk of bleeding from mediastinoscopic biopsy is deemed greater than the risk of administering radiotherapy for a disease of uncertain nature.
II. STAGING
Once the diagnosis of cancer is firmly established, it is important to determine the anatomic extent or stage of the disease. The steps taken for staging vary considerably among cancers because of the differing natural histories of the tumors.
A. Staging system criteria
For most cancers, a system of staging has been established on the basis of the following factors:
Natural history and mode of spread of the cancer
Prognostic import of the staging parameters used
Value of the criteria used for decisions about therapy
B. Staging and therapy decisions
In the past, surgery and radiotherapy were used to treat patients with cancer in early stages, and chemotherapy was used when surgery and radiotherapy were no longer effective or when the disease was in an advanced stage at presentation. In such circumstances, chemotherapy was only palliative (except for gestational choriocarcinoma), and in the absence of exquisitely sensitive tumors or strikingly potent drugs, the likelihood of increasing the survival was low. As knowledge has increased about the genetic determinants of cancer growth, tumor cell kinetics, and the development of resistance, the value of early intervention with chemotherapy has been transposed from animal models to human cancers. To plan this intervention and evaluate its effectiveness, careful staging has become increasingly important. Only when the exact extent of disease has been established can the most rational plan of treatment for the individual patient be devised, whether it is surgery, radiotherapy, chemotherapy, or molecular targeted therapy alone or in combination.
Although no single staging system is universally used for all cancers, the system developed jointly by the American Joint Committee on Cancer and the TNM Committee of the International Union Against Cancer is most widely used for staging solid tumors.1 It is based on the status of the primary tumor (T), regional lymph nodes (N), and distant metastasis (M). For some cancers, tumor grade (G) is also taken into account. The stage of the tumor is based on a condensation of the total possible TNM and G categories to create stage groupings, usually stages 0, I, II, III, and IV, which are relatively homogeneous with respect to prognosis.
III. PERFORMANCE STATUS
The performance status refers to the level of activity of which a patient is capable. It is a measure independent from the anatomic extent or histologic characteristics of the cancer and of how much the cancer or comorbid conditions have affected the patient, and a prognostic indicator of how well the patient is likely to respond to treatment.
A. Types of performance status scales
Two performance status scales are in wide use:
The Karnofsky Performance Status Scale (Table 4.1) has 10 levels of activity. It has the advantage of allowing discrimination over a wide scale, but the disadvantages of being difficult to remember and perhaps of making discriminations that are not clinically useful.
The Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO)/Zubrod Performance Status Scale
(Table 4.2) has the advantages of being easy to remember and making discriminations that are clinically useful.
TABLE 4.1 Karnofsky Performance Status Scale | ||||||||
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According to the criteria of each scale, patients who are fully active or have mild symptoms respond more frequently to treatment and survive longer than patients who are less active or have severe symptoms. A clear designation of the performance status distribution of patients in therapeutic clinical trials is thus critical in determining the comparability and generalizability of trials and the effectiveness of the treatments used.
B. Use of performance status for choosing treatment
In the individualization of therapy, the performance status is often a useful parameter to help the clinician decide whether the patient will benefit from treatment or will be made worse. For example, unless there is some reason to expect a dramatic response of a cancer to chemotherapy, treatment may be withheld from many patients with an ECOG Performance Status Scale score of 3 or 4, particularly those with solid tumors, because responses to therapy are infrequent and toxic effects of the treatment are likely to be great.
TABLE 4.2 ECOG/WHO/Zubrod Performance Status Scale | ||||||||||||
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C. Quality of life
A related but partially independent measure of performance status can be determined on the basis of patients’ own perceptions of their quality of life (QOL). QOL evaluations have been shown to be independent predictors of tumor response and survival in some cancers, and they are important components in a comprehensive assessment of response to therapy. For some cancers, improvement in QOL measures early in the course of treatment is the most reliable predictor of survival time.
IV. RESPONSE TO THERAPY
Response to therapy may be measured by survival (with or without disease), objective change in tumor size or in tumor product (e.g., immunoglobulin in myeloma), and subjective change.2
A. Survival
One goal of cancer therapy is to allow patients to live as long and with the same QOL as they would have if they did not have the cancer. If this goal is achieved, it can be said that the patient is cured of the cancer (though biologically, the cancer may still be present). From a practical standpoint, we do not wait to see if patients live a normal lifespan before saying that a given treatment is capable of achieving a cure, but we follow a cohort of patients to see if their survival within a given timespan is different from that in a comparable cohort without the cancer. For the evaluation of response to adjuvant therapy (additional treatment after surgery or radiotherapy that is given to treat potential nonmeasurable, micrometastatic disease), survival analysis (rather than tumor response) must be used as the definitive objective measure of antineoplastic effect. With neoadjuvant therapy (chemotherapy or biologic therapy given
as initial treatment before surgery or radiotherapy), tumor response and resectability are also partial determinants of effectiveness.
as initial treatment before surgery or radiotherapy), tumor response and resectability are also partial determinants of effectiveness.
B. Definitions
The overall survival rate is used to describe the percentage of people in a cohort who are alive for a specified period of time after diagnosis or initiation of a given treatment. The median survival time is the time after either diagnosis or treatment at which half of the patients with a given disease are still alive. Disease-free survival, the length of time after treatment for a specific disease during which a patient survives with no sign of the disease, is often a useful comparator in clinical studies of adjuvant therapy, as return of disease most often represents loss of curability. Progression-free survival (PFS) is the length of time during and after treatment in which a patient is living with a disease that does not get worse. It is used primarily in studies of metastatic or unresectable disease.
C. Other considerations
It is, of course, possible that a patient may be cured of the cancer that was treated but dies early owing to complications associated with the treatment, including second cancers. Even with complications (unless they are acute ones such as bleeding or infection), survival of patients who have been cured of the cancer is likely to be longer than if the treatment had not been given, though shorter than if the patient had never had the cancer.
If cure is not possible, the reduced goal is to allow the patient to live longer than if the therapy under consideration were not given. It is important for physicians to know if, and with what likelihood, any given treatment will result in a longer life. Such information helps physicians to choose whether to recommend treatment and the patient to decide whether to undertake the recommended treatment program.
It is important to learn from the patient what his or her goals of therapy are and to have a frank discussion about whether those goals are realistic. This can avoid unnecessary surprises and anger at some later time, which can occur when the patient has set a goal that is not realistic and the physician has not discussed what may or may not reasonably be expected as a consequence of therapy.
D. Objective response
Although survival is important to the individual patient, it is determined not only by the initial treatment undertaken but also by biologic determinants of the patient’s individual cancer and subsequent treatment; thus, survival does not give an early measurement of a given treatment effectiveness. Tumor regression, on the other hand, when measurable, frequently occurs early in the course of effective treatment and is therefore a readily used determinant of treatment benefit. Tumor regression can be determined by a decrease in size of a tumor or the reduction of tumor products.
1. Tumor size. When tumor size is measured, responses are usually classified by the Response Evaluation Criteria in Solid Tumors
(RECIST) methodology first published in 2000 and revised in 2008 (RECIST 1.1), reported by Eisenhauer et al.3 in the European Journal of Cancer in 2009, and available online at http://www. eortc.be/recist/documents/RECISTGuidelines.pdf, and for the iPad from the APP Store (RECIST 1.1)
(RECIST) methodology first published in 2000 and revised in 2008 (RECIST 1.1), reported by Eisenhauer et al.3 in the European Journal of Cancer in 2009, and available online at http://www. eortc.be/recist/documents/RECISTGuidelines.pdf, and for the iPad from the APP Store (RECIST 1.1)
a. Baseline lesions are characterized as “measurable” or “nonmeasurable.” To be measurable, non-lymph node lesions must be 20 mm or more in longest diameter and measurable by calipers using conventional techniques, or 10 mm or more in longest diameter using computed tomography (CT). On CT scan, lymph nodes must be more than or equal to 15 mm for target lesions or 10 to 15 mm in short axis for nontarget lesions. Smaller lesions and truly nonmeasurable lesions are designated nonmeasurable. To assess response, all measurable lesions up to a maximum of two per organ and five in total are designated as “target” lesions and measured at baseline. Except for lymph nodes, only the longest diameter of each lesion is measured. The sum of the longest diameters of all target lesions is designated the “baseline sum longest diameter.”
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