Introduction

As our understanding of cancer has grown, medical oncology has evolved as a subspecialty of internal medicine since the 1960s. Initially, few treatments beyond surgery and a handful of toxic chemotherapy agents were available to cancer patients. Medical oncologists now have hundreds of chemotherapeutic agents to choose from for hundreds of separate diseases, with many new targeted agents in clinical development.

The primary tool of the medical oncologist is chemotherapy; however, the role of the medical oncologist in the treatment of cancer is best accomplished when a multidisciplinary approach is used. The medical oncologist must work closely with the surgical oncologist, radiation oncologist, radiologist, pathologist, and primary care physician.

The medical oncologist is typically involved in the final decisions concerning management and frequently coordinates implementation of these decisions. The decision whether to take a curatively aggressive or a palliative measured approach, the timing of localized therapies, such as surgery and radiotherapy, and the decision whether therapy is required or whether supportive care is most appropriate are often made by the medical oncologist. The oncologist must also strike the balance between expected treatment sequelae and desire to cure. If there is a reasonable expectation for cure, treatment-related toxicity becomes more acceptable. If there is a reasonable expectation for prolonging survival or improving quality of life, some toxicity is acceptable. If the chance of significantly altering the course of the disease is low, most oncologists and their patients will feel that only minimal toxicity is acceptable.

Epidemiology

As medicine, nutrition, and improved sanitation continue to further extend the average life expectancy, more people are surviving long enough to develop a malignancy. Thankfully, this is being tempered with an overall decrease in incidence and mortality from the most common cancers.¹

Cancer screening has become a routine part of the health maintenance performed on healthy individuals. Mammograms, fecal occult blood tests, colonoscopy, Papanicolaou smear, and digital rectal examinations have the potential to detect a malignancy at an early, asymptomatic stage and perhaps change the disease outcome. With increased screening, more early-stage, potentially curable cancers are being detected. Many of these cancers are amenable to local therapy (surgery and/or radiation), but a large portion continue to require systemic therapy.

The Rationale for Chemotherapy

Most cancers have 20% to 40% of cells in active cycling at any one time, which explains why the doubling time for a tumor is significantly longer than the cell cycle. Tumor growth would be exponential if all cells were dividing or constant if the fraction of actively cycling cells remained fixed; however, this does not correspond to clinically observed tumor doubling time. In 1825, Benjamin Gompertz described the nonexponential growth pattern he observed of disease in cancer patients. He noted the doubling time increased steadily as the tumor grew larger, a phenomenon now described as Gompertzian growth. This has been postulated to occur owing to decreased cell production, possibly related to relative lack of oxygen and of growth factors in the central portion of the large mass.² A smaller tumor, conversely, would have a larger portion of actively cycling cells and, thus, be potentially more sensitive to cytotoxic chemotherapy.

A clinically or radiographically detectible tumor that measures at least 1 cm in diameter contains already 10⁸ to 10⁹ cells and weighs approximately 1 g. If derived from a single progenitor cell, it would have undergone at least 30 doublings before detection. Further growth to a potentially lethal mass would only take 10 further doublings. Thus, the clinically apparent portion of the growth of the tumor represents only a fraction of the total life history of the tumor. With the long undetected portion of the growth of the tumor, occult micrometastases have often developed by the time of diagnosis.

Cytotoxic chemotherapy has the ability to kill more cancer cells than normal tissue, likely due to impaired DNA damage repair mechanisms in the former. This is relevant because most cytotoxic agents damage actively cycling cells. Typically, the more aggressive the cancer, the higher the proportion of its tumor cells that are in active phases of cell cycle.

As a result of the preferential anticancer activity in rapidly dividing malignant cells, rapidly proliferating cancers that, in the past, were associated with a shorter survival may have a better chance for cure from systemic chemotherapy than more indolent disease, as long as the tumor cells are sensitive to the chemotherapeutic agents. An example of this paradox is Burkitt’s lymphoma, which is sensitive to chemotherapeutic agents and which is curable in the majority of patients in spite of having an extremely rapid proliferation rate. Conversely, a slow-growing follicular lymphoma, even when sensitive to chemotherapy as defined by the complete disappearance of the tumor, will relapse and ultimately cause death.

Early studies of the ability of chemotherapy to kill cancer cells were conducted on leukemia cell lines in the 1960s.³ These studies noted log-kill kinetics, meaning if 99% of cells were killed, tumor mass would decrease from 10¹⁰ to 10⁸ or from 10⁵ to 10³. The fraction of cells killed was proportional, regardless of tumor size; thus, even though a given treatment would appear to have eradicated the tumor, both clinically and radiographically, there would be a high probability of residual cells that would eventually proliferate and show up as a clinically evident tumor (relapse). One explanation for the achievement of sustainable complete remission following this argument would be that other factors such as host immune response may be important at low levels of residual tumoral cells.⁴

Clinical prognostic models are, in part, based on risk of disease relapse and, thus, take into account features that might suggest micrometastatic undetectable disease at the time of diagnosis. As an example, a large tumor may suggest a longer clinically silent tumor lifetime or higher doubling rate. Clinically apparent nodal involvement demonstrates the tumor has gained the capability to spread, at a minimum regionally.

Indications for Chemotherapy

If the decision is made that the patient will benefit from chemotherapy, the treatment strategy devised by the medical oncologist will be largely determined by the stage of the cancer. The initial medical treatment of cancer can be thought of as requiring (1) preoperative (neoadjuvant) chemotherapy, (2) postoperative (adjuvant) chemotherapy, or (3) chemotherapy without localized therapy, either for metastatic, inoperable disease (either due to locally advanced stage and/or comorbid medical conditions) or a hematologic malignancy. Chemotherapy without surgical therapy was historically thought of as a palliative measure; however, improved efficacy of chemotherapy and radiotherapy is changing this notion. Many hematologic and epithelial malignancies are now approached in curative fashion with chemotherapy alone or combined with radiotherapy.