As was presented earlier, before treatment and after initial diagnosis, staging is done. Considering signs, symptoms, cues, and clues so far and knowing the typical history of each disease, your oncologist will look where needed to assess the exact extent of the disease in exquisite detail. Some patients require bone marrow biopsies; some need scans of the brains, and so on. The goal, using internationally accepted conventions and definitions, is to stage the patient’s cancer in manner that anyone hearing the stage has an understanding of the most clinically relevant way of knowing where your tumor is and is apparently not. Thus, we can compare patients with the same stage, intelligently develop treatment regimens, and follow outcome not just for you but also for all patients with similar stages. Before we look into how we treat it, we must understand the how and why of knowing where it is as local vs. systemic therapy or some combination therein depends on that as well.
Staging gives us the extent, spread and severity of a patient’s disease. This allows a more accurate and comprehensive treatment plan and can even infer a pre treatment prognosis by comparing to others similarly staged. The systems for staging have evolved and the more we learn what really matters for each disease the more we add criteria. Staging is a living science whose goal is to have more patients living because of its work.
Typically the so called T, N, M staging rules are used ( tumor size, lymph node involvement and metastases) (spread) puts patients in various levels or sublevels of stages 0-4. Physical exam, physical condition, certain laboratory tests, imaging scans and microscopic pathology reports refine the system.
A clinically useful tumor classification would be able to compare similar cancers and similar patients. Such a schema must be tumor specific and reflect the natural history of the tumor as much as possible. A unified approach to the degree of spread and or severity of the tumor is crucial as prognosis, therapy, and the ability of scientists worldwide to talk to each other hinge on it. Thus, the staging classifications of the American Joint Committee on Cancer rely on the premise that thoroughly staged and described tumors will largely act similarly and have similar outcomes.
The T (Tumor size), N (presence or absence of lymph node involvement) and M (evidence of metastasis or spread) system attempts to organize our understanding of tumors. The system is dynamic and living and evolves with our knowledge of increasingly relevant prognostic factors. If the world categorizes tumors in detail in exactly the same way, there is no Tower of Babel effect where no single scientific language exists and is universally accepted. The problems that can occur when different languages are used disappear and physicians then pave the road for rapid accumulation of information about highly similar tumors in highly similar situations. That information leads to clinical trials. Clinical trials lead to the future of better and evolving cancer care. Thus, precise tumor staging is crucial.
The most common mistake regarding staging that I see is that patients do not understand the implications of their stage and thus labor under erroneous conclusions. A frequent misconception is demonstrated when listening to how most patients describe their cancer. There is a tendency to name the cancer according to where it has spread, rather than where it came from. This is not correct.
Let us look at a mythical explanation using the United States as our body. We name terrorists for the land they came from. They have a native culture, character and craft of terrorism they conduct. Whether they are in California or Maine, we name them from their country of origin. Where they have spread to is crucial but only tells us how advanced their spread is. A real world example of this in cancer medicine is demonstrated when patients with breast cancer that has spread to bone state they have bone cancer. This is incorrect. They have breast cancer that has spread to bone. This is not mere semantics. There are enormous differences in treatment and prognosis between breast cancer that has spread to bone and bone cancer.
The TNM classification is also identical to the Union Against Cancer schema (UICC).They both have clinical and pathologic staging. Simply put, pathologic staging is determined when a tumor is physically seen and biopsied. The site of origin determines the T stage and refers largely to the size of the primary tumor at that site. The N refers to proven evidence of lymph node spread and the M refers to proven evidence of distant spread or metastasis. Clinical staging employs multiple different non-surgical techniques such as X rays or CAT scans, MRI, ultrasounds or PET scans that may image or demonstrate findings that are extremely suggestive of spread.
Thus, clinical staging relies on what we can see and pathologic staging relies on what we can feel or have touched as a result of tissue biopsy. In some cases, biopsy may be required to confirm suspicions of the presumed clinical stage as frequently the impact of incorrect assumptions of the degree of advance can have enormous consequences. Of course, we cannot biopsy all tumors that we see. They must be safely accessible. In addition, in many cases such as breast cancer, biopsy of nearby draining regional nodes is routine. Immense knowledge is gained by systematically finding and assessing for cancer in what we call the sentinel lymph nodes regionally draining the primary cancer.
Stage grouping refers to when we combine the clinical or pathologic stage information, i.e. the T, N and M information and group them into larger numeric stages of usually 1-4 with occasional subsets. Stage 1 is the most limited and Stage 4 usually refers to being widespread. Different combinations of TNM can be in the same stage group such as a large tumor with no involved lymph nodes or a small tumor with a few involved nodes. All stage grouping is specific for each tumor. These numeric groups are not for convenience; rather they reflect the spread of the disease and have enormous influence on prognosis and therapy.
The clinical stage guides therapy. The pathological stage determined after complete surgical removal of all visible disease can determine the need for further therapy even when no remaining tumor seems to exist. Both breast and colon cancer are excellent examples where the stage seen as a result of surgery predicts the risk of future relapse from microscopic tumor cells that may still be present. As mentioned in the Diagnosis chapter, adjuvant therapy refers to when we see no remaining tumor cells but history tells us, based on the tumor type and stage, that there is a meaningful risk that viable cancer cells remain undetected. The utility of such therapy is very specific for the type of tumor. Adjuvant therapy is wise if evidence suggests that it can help improve the odds of preventing recurrence, delaying recurrence or increasing the odds of survival. It is not wise for every tumor or every stage of any tumor. It is a very specific choice based on very specific clinical evidence; the benefit is very tumor and stage specific.
Therapeutic procedures, such as partial or total surgical removal, may alter a tumors’ stage and the life history of the cancer. Thus, we have the rTNM – restaging scheme, which yields different results than the original stage. Obviously, we use the rTNM for re-estimation of prognosis and guidance for further therapy after total or partial surgical removal. Whenever patients are compared or treated in clinical studies, physicians always use the pre therapy original stage of the tumor so that everyone is on equal footing and starting at the same place. Not all patients with any given tumor type or stage will or can have surgical removal. Comparison that is more accurate can occur among patients owing to this rationale.
There are exceptions to the TNM staging criteria and they usually include the so-called liquid tumors such as leukemia and lymphomas, etc. They do not lend themselves easily to the TNM system due to how patients with them typically present at diagnosis and their natural history. Thus, there are elegant detailed criteria for staging. In the case of most leukemia, physicians use lists of definitive factors to give a prognostic score. Thus, we can group these diseases into various stages that predict response to therapy and odds and duration of survival. These factors are constantly evolving as molecular and genetic tests and knowledge that goes far beyond simple laboratory tests develop.
The beauty of such staging schemes that are internationally accepted is that they allow us to compare therapies stage for stage and design clinical trials intelligently with high likelihood of answering an important question. The staging schemes help us decide what adequate therapy is and assists in further refining treatment approaches.
In most cases, staging relies on the anatomic extent of the malignancy. We know where the tumor has physically spread. However, sometimes the degree of aberrancy – the bizarreness and abnormality in the appearance of the tumor under the microscope (histological grade) and patient age can affect staging. Thus, two very similar tumors may have slightly different stages because the cancer cells are more primitive or angry in one case or the patients are different ages. The reason for the different stage is the same reasoning for staging. In the example above, we know that more angry cells or an older age impact the prognosis of otherwise similar patients thus we name the stage differently.
Although cancer cells mimic their normal cell counterpart as discussed in The Enemy, they often have very specific identifying fingerprints or products they produce. Increasingly, molecular markers, which are the presence of highly specific molecules that identify or mark the disease, specific genetic fingerprints or abnormal proteins on the cancer cell surface and other cancer specific characteristics and tumor produced products aid in staging and directing therapy. In some cases, the degree of bizarreness of the cancer cells may be the most important staging criteria of all.
The challenge for any staging system is that it must keep up with the diagnostic advances in oncology as we find newer valid and crucial prognostic variables. Thus, original and future stages of the seemingly same tumor may not be similar. There is no widely accepted detailed staging system yet for tumors of the central nervous system owing to inherent difficulties in defining landmarks, their significance and frequent lack of biopsy material.
In conclusion, it is imperative to have an extremely accurate staging of any tumor whether it is by anatomic site only, biochemical, genetic and molecular or immunologic measurements. Patients must be certain that their tumors are precisely staged and that they know what stage it is. As mentioned, we understand treatments and prognosis largely in terms of the stage of the disease at the time of the diagnosis. Individual treatment decisions require thorough staging.
Patients must remember that they are individuals and not a group. Although the study of groups of similar patients have taught us enormously what the odds are for response, duration of response, freedom from relapse and survival, patients experience their disease as individuals. Individuals may beat or, less happily, lose against the odds.
The National Cancer Institute (NCI) has played an active role in the development of drugs for cancer treatment for over 50 years. This is reflected in the fact that approximately one-half of the chemotherapeutic drugs currently used by oncologists for cancer treatment were discovered and/or developed at NCI.
NCI’s Developmental Therapeutics Program (DTP) has over 400,000 drugs in its repository that have gone through some kind of screening process. About 80,000 compounds have been screened since 1990 using the current screening system. Compounds can enter at any stage of the development process with either very little or extensive prior testing. NCI supports about 1,500 clinical trials through a variety of programs. NCI researchers at the National Institutes of Health in Bethesda, Md., conduct some while others take place at cancer centers, hospitals, and community practices around the country.
It is far beyond the scope of this book to discuss in any depth all the nuances of the more than fifty common chemotherapy drugs available. Previously in the overview section we enumerated the major classes of drugs. Here we will delve a little more deeply into the how of the drugs we have as well as the most importance drug advances.
The first and most important concept is that typically, specific drugs work for specific tumors. However, this is this is changing as new combinations are tried. Secondly, drugs try to hit the Achilles heel(s) of the tumor. Yes, the majority of cancer cells have an Achilles heel, weak spots that theoretically drugs attempt to exploit. Although these drugs may damage normal cells in the process, such as the gastrointestinal tract, bone marrow and others, the bulk of the damage is intended to affect the tumor because of its Achilles heel(s).
One particular area of concern is off-label use. Pharmaceutical companies initially apply to the FDA for approval of a new agent for a particular tumor in a particular setting. This requires an average of 6 years of development and more than five hundred million dollars. Becoming FDA approved means a drug is known to be safe and effective. It then receives approval for its use for a specifically tested indication. Once approved, hundreds of researchers and many patients with other tumors or different stages of the original tumor type compared to the original trials, participate in carefully designed phase I-IV clinical trials of the drug either alone or in combination with other drugs or radiation.
Remember, I am using a broad definition of drug to include novel immunologic agents, typical chemotherapy compounds, vaccines and many other varieties of substances given many different ways. In this way, researchers can develop numerous extremely important uses for the original drug that go beyond the original FDA approved use. After FDA approval, it is usually only a matter of time before we know, because of more trials, if the drug has additional uses. Typically, many do. Thus, patients need not be wary if the drug(s) they are treated with are off label.
Normal cells have a life cycle. The creation of new cells from a parent cell is a reasonably well understood process with numerous genetic and biochemical markers that tell us where the cells are in that process. The phases of the process have different names. One technique of developing a new drug is to target a potential vulnerability because of the phase a tumor cell may be in.
Cells that are resting are usually in a very chemotherapy resistant phase. In the next phase or interphase, cells become very active in making the building blocks that they need to live, maintain the household and prepare to divide and have children.
The genetic material of all cells is contained in tightly coiled twisted ladders knows as chromosomes. Those ladders are made of DNA and the nucleus inside the cell is the headquarters or home for the chromosomes. This genetic material contains all the directions and all the blueprints for everything that cell is and can do. In the DNA synthesis phase, the amount of DNA doubles in preparation of the cell dividing. In the Gap 2 phases, a fine meshwork of scaffolding appears inside the cells like an old-fashioned bingo spindle. This mitotic spindle is necessary for the duplicated DNA in our chromosomes to move across the nucleus before the cell divides into two cells. In the final phase, the M phase (for mitotic) all the newly created and aggregated DNA material goes into the two daughter cells in identical amounts.
Chemotherapy drugs may be specific for a phase they affect the most. These drugs attempt to exploit the fact most, but not all cancers cells are more active than healthy cells and more prolific at having offspring. Some chemotherapy agents however are phase non-specific and kill non-dividing cells. Examples are the anti-tumor antibiotics, excepting Bleomycin. Some drugs are simply specific for the whole cycle and do not need a particular phase. Rather, these drugs require only that the tumor cell be going through the cycle of life, not just a particular phase. Thus, these drugs can inflict injury at any point along the cell cycle. Examples are the so-called alkylating agents. Generally, these types of drugs have a linear dose-response behavior in that the more you give the more tumor cells they should theoretically kill. Of course, two things limit this. One is the tolerance of normal cells (thus the patients’ body) and the other is the multiple clever ways tumor cells can either acquire or already have in-born resistance to the agent.
As mentioned above, there are phase specific drugs that are only effective if they are present during a particular phase of a tumor cell’s life cycle. This type of drug usually has a limit in cell killing ability. After a certain dose level, no further killing happens. However, if the drug is still present by the next time that specific phase occurs in a tumor cell’s life cycle more tumor cells theoretically may die.