Figure 1. Figure 1. Timeline of Pivotal Events in Cancer Treatment. CML denotes chronic myeloid leukemia.

Figure 2. Figure 2. Timeline of Pivotal Events in Cancer Prevention. BCG denotes bacille Calmette–Guérin, DCIS ductal carcinoma in situ, FDA Food and Drug Administration, and HPV human papillomavirus.

Experiments that can be done in hours in the laboratory take months and years to replicate in the clinic, so clinical advances, though plentiful, develop slowly. Figure 1 and Figure 2 depict the pace of change for the past two centuries in four areas: cancer treatment, chemoprevention, viruses and cancer-vaccine development, and tobacco control.

In the treatment of cancer, surgery was the first tool available. In 1809, Ephraim McDowell removed an ovarian tumor without the use of anesthesia, the first abdominal surgery performed in the United States, and provided evidence that tumor masses could be cured by surgery. The first public use of anesthesia, as reported by John Collins Warren in the Journal in 1846,11 and the introduction of antisepsis by Joseph Lister in 186712 paved the way for a cascade of surgical firsts in cancer treatment in the 19th and early 20th centuries. These innovative surgeons showed that any organ that was affected by cancer could be dealt with surgically.13

The most profound influence on cancer surgery occurred in 1894, when William Halsted14 introduced radical mastectomy for breast cancer. Halsted based his operation on the supposition that breast cancer spread in a centrifugal fashion from the primary tumor to adjacent structures. He recommended en bloc resection of all surrounding tissue to remove all cancer cells, even the head of the humerus if it was involved. En bloc resection became known as “the cancer operation,” and it was applied to the removal of all other cancers, despite scant evidence supporting its use. It would be 74 years before the use of radical mastectomy and en bloc resection was questioned by another surgeon, Dr. Bernard Fisher. On the basis of experiments in rodent tumors, Fisher proposed that breast cancer had early access to the bloodstream and lymphatic tissues. Lymph-node involvement, he hypothesized, was merely an indication of generalized spread of disease. Radical mastectomy was both too much and too little: too much for small tumors and too little for large tumors that had already metastasized. In a series of clinical trials conducted by what is now called the National Surgical Adjuvant Breast and Bowel Project (NSABP), which Fisher led, he clearly showed that radical en bloc removal of tissue did nothing more than could be accomplished by removing the tumor mass itself, if surgery was supplemented by chemotherapy, radiation therapy, or both. Fisher also showed that less radical surgery plus chemotherapy or radiation therapy accomplished the goal with much less morbidity. These studies15-25 revolutionized the treatment of breast cancer. Since then, most other surgical procedures have been tailored to the availability of other treatments, and cancer surgery has become more effective, with less morbidity. In the first half of the 20th century, however, surgery was the only option, and a minority of patients could be cured by surgical removal of their tumors alone.

The era of radiation treatment began in 1895, when Roentgen reported on his discovery of x-rays,26 and accelerated in 1898 with the discovery of radium by Pierre and Marie Curie.27 In 1928, it was shown that head and neck cancers could be cured by fractionated radiation treatments, a milestone in the field.28 The modern era of radiation therapy began in 1950 with the introduction of cobalt teletherapy. Since then, aided by advances in computing, the field has been driven by advances in technology that have allowed the therapeutic radiologist to deliver beam energy precisely to the tumor and to spare the normal tissue in the path of the radiation beam. Like surgery, radiation therapy has become more effective, with less morbidity, and can be used in combination with other treatments.

By the 1950s, it had become apparent that no matter how complete the resection or how good the radiation therapy or how high the dose delivered, cure rates after surgery, radiation therapy, or the two combined had flattened out. Only about a third of all cancers could be cured by the use of these two treatment approaches, alone or together.

It was Paul Ehrlich at the turn of the 20th century who first made a concerted effort to develop chemicals to cure cancer. He coined the word “chemotherapy.” After animal models of transplantable tumors were developed in the early 20th century,29 researchers devoted the first half of the century to establishing screening systems that would reliably predict antitumor activity in humans on the basis of data from murine models. However, these efforts were largely unsuccessful. Part of the problem was the limited capability for testing new agents in humans. Two events provided optimism about the future of anticancer drugs: the use of nitrogen mustard in lymphomas at Yale in 194330 and Farber's report in 1948 that folic acid antagonists could induce temporary remission in childhood leukemia.31 In 1955, these discoveries led to a national screening effort to develop and test anticancer drugs. Then the use of cancer chemotherapy, although shrouded in controversy, began in earnest. Missing was proof of principle, already established for surgery and radiation therapy, that drugs could cure any cancer. Major advances came in the mid-1960s with firm evidence that childhood leukemia32 and advanced Hodgkin's disease in adults33,34 could be cured by combination chemotherapy.

Proof of cure by chemotherapy had a permissive effect on the use of drugs as an adjuvant to surgery and radiation therapy. Doctors started to be willing to consider using chemotherapy. In the mid-1970s, two landmark studies of adjuvant chemotherapy in breast cancer were published: one from the NSABP, which tested a single drug and was reported by Fisher and colleagues in 1975,15 and one from Italy, which tested a drug combination and was reported by Bonadonna et al. in 1976.35 The latter study evaluated a combination regimen (cyclophosphamide, methotrexate, and fluorouracil) developed by the NCI but was performed under contract with the Milan Cancer Institute, despite large populations of patients with operable breast cancer in the United States, because no major U.S. center was willing to test combination chemotherapy as an adjuvant. The results of both studies were positive, and the race was on. By 1991, thanks to the availability of multiple effective chemotherapeutic agents and hormone treatments, improved diagnostic tools for early diagnosis, and intelligently designed clinical trials, the rate of death from breast cancer began to fall, a trend that has continued.36 Early diagnosis and lumpectomy coupled with systemic therapy have greatly reduced the morbidity associated with breast-cancer treatment, with good cosmetic effects. Such advances have fulfilled the mandate of the war on cancer “to support research . . . to reduce the incidence, morbidity and mortality from cancer.”

The success of adjuvant treatment of breast cancer, in turn, had a permissive effect on the use of drugs in the postoperative treatment of other major cancers, such as colorectal cancer. As a consequence of early diagnosis, prevention, and adjuvant treatment, the rate of death from colorectal cancer has fallen by 40% during the past four decades.36

Another paradigmatic change in cancer treatment occurred in 2006, when Druker et al.37 showed the efficacy of a drug (imatinib) that targeted the unique molecular abnormality in chronic myeloid leukemia. This work provided proof of principle that treatments targeting specific molecular abnormalities that are unique to certain cancers could convert them into manageable chronic illnesses. Since then, chemotherapy has become targeted therapy, and the literature has been dominated by the search for drugs to inhibit unique molecular targets, with recent success in the treatment of some very difficult-to-treat tumors, such as melanoma38 and lung cancer.39

Until recently, cancer treatment was a three-legged stool sitting on a base of surgery, radiation therapy, and chemotherapy. In the past 25 years, immunotherapy has been added as an important component of cancer treatment.

Antibodies were first described in the 1880s and dominated studies of immunology for almost 100 years but had little effect on cancer treatment. In 1975, Köhler and Milstein developed methods for producing antibodies by fusing cultured myeloma cells with normal B cells from immunized mice.40 The availability of large amounts of antibodies with a single specificity led to the successful development of therapeutic antibodies for cancer, starting with approval by the Food and Drug Administration (FDA) of rituximab for the treatment of B-cell lymphomas in 199741 and followed by the approval of many other antibodies, most of which act by inhibiting growth factor receptors on the surface of cancer cells.

In the early 1960s, it became clear that cellular rather than humoral immunity played a major role in the immune destruction of experimental cancers, although the inability to manipulate T cells outside the body severely hampered studies of tumor immunity. The description of T-cell growth factor (subsequently called interleukin-2) in 1976 was a seminal discovery that stimulated extensive studies of the cellular immune reaction to experimental and human cancers.42 The durable regression of metastatic melanoma and renal cancers in humans after the administration of interleukin-2, described in 1985, represented the first clear demonstration that immune manipulations could cause the regression of invasive metastatic disease.43 Interleukin-2 was approved for the treatment of metastatic renal cancer in 1992 and for metastatic melanoma in 1998. The subsequent development of immunomodulatory agents such as ipilimumab,44 the development of cell-transfer therapies,45,46 and the use of genetically engineered lymphocytes to treat cancer47 have provided additional evidence of the ability of immunotherapy to mediate cancer regression. With the increasing use of these agents, the cancer-treatment platform sits firmly on four legs.