Osteogenic sarcoma, while it is the most common type of bone cancer, is nevertheless not common—there are only about 1,000 new cases annually in the U.S. It has a bimodal distribution, i.e., two peaks in incidence. About half the tumors develop in adolescents, when the growth spurt occurs, and the other half occur in middle age and older.
While osteogenic sarcomas can occur in any bone, the bulk of these tumors occur in the long bones of the extremities—the humerus, femur, etc. If we go back to the pre-chemotherapy era, i.e., the 1950s and 1960s, upon diagnosis of such a tumor, the usual approach would be to stage it by doing a chest X-ray, since it was well recognized that, as was typical of most sarcomas, they almost always metastasize or spread to the lungs first. If the chest X-ray was “clean” and the tumor was localized to the bone, then the standard treatment would be amputation at the joint above the tumor.
With this strategy, the general survival or cure rate for localized osteogenic sarcoma was about 20-25%. A famous victim of this disease was Ted Kennedy, Jr., the son of Senator Ted Kennedy and nephew of President John Kennedy, who was diagnosed in 1973 at the age of 12 with a tumor in his right leg. He underwent an amputation and survived to the age of 51.
In 1963, Paul Carbone, who at the time was head of medical oncology at the National Cancer Institute, coined the term “adjuvant therapy” for the use of additional treatments, typically chemotherapy, to follow surgical resection of localized cancers. The purpose of such treatments was in the setting of various cancers where it was recognized that, despite potentially curative surgery, there remained a high probability that the tumor would recur. This was presumed to be due to residual microscopic tumor cells following the surgery and that chemotherapy (or hormonal therapy or radiotherapy, depending on the tumor) could possibly eradicate them and render the patient truly disease-free. By 1970, such adjuvant treatments were starting for breast cancer and other cancers. Nowadays, they are routine for breast, colorectal, lung, ovarian, pancreatic and other malignancies.
Two drugs, Adriamycin (doxorubicin) and high-dose methotrexate, were known to be effective for metastatic osteogenic sarcoma. As a result, given the high recurrence rate for localized disease, they were introduced as adjuvant therapy in 1973. Their use increased the survival for localized osteogenic sarcoma from 25% to 50% by 1978.
Taking the lead in this research was Gerald Rosen, a pediatric oncologist at Memorial Sloan-Kettering Cancer Center in New York. He added further drugs to the combination regimen and gradually the survival rate improved even further, bringing survival rates well past the 50% mark, under some circumstances as high as 70%.
Nonetheless, these dramatic changes and improvements remained controversial. Why? For one thing, these chemotherapy regimens were extremely toxic and dangerous with severe sepsis, nausea and vomiting, and hair loss among the side effects.
More importantly, the Mayo Clinic was highly conservative with the use of these toxic chemotherapy regimens. They had never introduced chemotherapy as adjuvant treatment for their osteogenic sarcoma patients undergoing amputation. In a 1978 paper, they reported that their patients with osteogenic sarcoma of the extremities treated with surgery alone achieved a survival of 50% without chemotherapy. This was not quite as good as the Rosen group, but dramatically better than the 25% pre-1970 and without the significant toxicity and long-term effects of the chemotherapy regimens.
What was going on? The answer is what is known as stage migration. This results from the introduction of new diagnostic technology—in the case of osteogenic sarcoma, the introduction of CT scans. While previously staging was done with plain chest X-rays, these were replaced for staging purposes by the more sensitive chest CT scans. As a result, smaller lung metastases could be identified; therefore, when patients were declared to be localized and metastasis-free, they were even more “clean.” As a result, the localized osteogenic sarcoma group had a better overall prognosis, as reported by the Mayo Clinic, independent of any changes in treatment.
Simultaneously, these patients with smaller metastases were added to the metastatic osteogenic sarcoma group; as a consequence, the metastatic group was enhanced by patients with much smaller metastatic tumors who had a better prognosis than the metastatic group of earlier years. The result was that the overall metastatic group also had an improved prognosis compared to the past. But, in truth, overall nothing had changed.
Stage migration has come to be known as the Will Rogers phenomenon after a humorist of the early twentieth century (no space to discuss why) and may occur whenever new diagnostic technology is introduced. In the case of osteogenic sarcoma,
while it was responsible for some of the perceived improvement in survival, the truth is, based on subsequent randomized trials, that adjuvant chemotherapy does indeed improve survival as well over and above the perceptions of stage migration. It remains the standard of care for osteogenic sarcoma until today.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
