Smoking and Lung Cancer

As early as 1912, scientists had begun to suspect smoking as a factor in the increased rates of death from lung cancer, but strong retrospective and prospective studies were unavailable. Through the 1940s, prominent scientific figures continued to blame everything from improved cancer detection rates to tarred roads to industrial plant fumes as the cause of increased rates of lung cancer. While the association seems obvious to us today, there was a paucity of data to support it at that time. The ubiquity of tobacco didn’t help either. During the first half of the 20th century, nearly 80% of American men noted some amount of tobacco use. Numerous retrospective studies emerged in 1950, but there was no trump card.

Doll and Hill’s seminal study attempted a broad-based, prospective approach to address the issue. In 1951, a simple survey asking for a brief smoking history was sent to each physician practicing in the UK. Of the replies received, men under 35 and all women were excluded from the analysis, leaving approximately 24,000 men aged 35 years and above. In 1954, Doll and Hill looked at a national database to determine how many of these physicians had died and the cause of death. All 36 men who died of lung cancer were smokers. The death rate was 0.48 per 1000 for those smoking approximately 1g daily and 1.14 per 1000 for those smoking more than 25g daily. Moreover, an increase in cigarette use was directly correlated to the risk of lung cancer.

The simplicity of their study proved to be genius. There were no advanced metrics – all the data analysis can be accomplished on a basic calculator. The correlation between tobacco and lung cancer could not have been made more obvious. Unfortunately, the results did not result in rapid policy changes. A joint advertising blitz by tobacco companies left the public unaware or unconvinced of the harmful effects of tobacco for a few more decades. Still, the evidence was undeniable, and the scientific community coalesced around this body of data, widely regarded as the turning point in the war against tobacco.

Doll R, Hill AB. 1954. The mortality of doctors and their smoking habits. British Medical Journal. 


Testicular Cancer: Changing Tides

Prior to 1974, localized testicular cancer was easily cured with orchiectomy, while metastatic disease was effectively a death warrant – cure rates were as low as 5% with a variety of chemotherapeutic agents. This trial, conducted by an up-and-coming researcher using an experimental drug called cis-diamminedichloroplatinum (or as we know it, cisplatin), provided a much-needed win in the battle against solid cancers. From 1974-1976, Lawrence Einhorn used a combination of cisplatin, vinblastine and bleomycin to treat patients with mild to severe metastatic disease. Some patients received adjunct surgery to remove residual tumors. Overall, at the time of publication, 38 of 47 patients were disease free. Moreover, at 13-year follow-up (which is remarkable in and of itself), over 50% of patients were disease free, an achievement stated as a “one-log increase in the cure rate.”

In addition to improved cure rates, cisplatin did not cause a pronounced myelosuppression like other chemotherapeutic drugs. It was not without its vices though. As Einhorn described, platinum had toxic effects on the kidney, manifested as a 25-50% reduction in baseline creatinine clearance. This was likely exacerbated by the dehydration caused by the intractable nausea and vomiting, which is eloquently described in Mukherjee’s Emperor of All Maladies. From a critical perspective, the study was well conducted in the context of a limited number of patients. Criteria for partial versus complete remission were well-defined, and follow-up was more than sufficient. Additional trials in the following years would cement the new findings.

Although partial results had been published in reports in Journal of Urology and American Family Physician, the complete results of the trial were ultimately published in Annals of Internal Medicine in 1977.  Given the overwhelmingly positive response to the therapy and the aggressive nature of non-seminomatous testicular cancer, it was quickly approved by the FDA in 1978 and became the standard of care. The combination chemotherapy was modified in the 80s to use etoposide instead of vinblastine, leading to additional improvements in cure rates. That same combination is in use today, and cure rates exceed 95%. Moments like this, when one can claim a logarithmic increase in cure rates, are few and far between in medicine.

Einhorn LH, Donohue J. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med. 1977. Sep;87(3):293-8.