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Evarts A. Graham and the First Pneumonectomy for Lung Cancer

Leora Horn, David H. Johnson

From the Division of Hematology and Oncology, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN

Corresponding author: David H. Johnson, MD, Vanderbilt-Ingram Cancer Center, Division of Hematology and Oncology, 777 Preston Research Building, 2220 Pierce Ave, Nashville, TN 37232-6307; e-mail: david.h.johnson{at}vanderbilt.edu

INTRODUCTION

Smoking... "a custome lothsome to the eye, hatefull to the Nose, harmefull to the braine, daungerous to the Lungs." — King James, 1604¹

On April 4, 1933, Dr James Gilmore, a 48-year-old obstetrician-gynecologist from Pittsburgh, PA, checked into the Barnes Hospital in St Louis, MO. The following day, he was scheduled to undergo a lobectomy for a recently diagnosed lung cancer. What actually transpired on April 5, however, would make both surgical and oncologic history, for Gilmore would be the first person to undergo a one-stage pneumonectomy for lung cancer—and survive.^2-4 The surgeon who performed the epochal operation, Dr Evarts A. Graham (Fig 1), was already a giant among American surgeons⁵ but the procedure solidified his claim to greatness. Nearly 25 years later, in a cruel twist of fate, Graham would die of the disease that helped make him, and the operation he pioneered, internationally renowned.^6-8 On the 75th anniversary of this historic event, the fascinating story of the first successful pneumonectomy for lung cancer bears retelling.

View larger version (57K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Dr Evarts A. Graham. Courtesy of the Becker Medical Library, Washington University School of Medicine (St Louis, MO).

Although reports of pulmonary malignancies date to antiquity, lung cancer is largely a disease of modern man. Before 1900, lung cancers were viewed as "matters of medical curiosity not known to be in any degree influenced by medicine and too rare to be of much practical importance."⁹ Adler¹⁰ compiled the world's entire experience of 374 cases in his textbook, Primary Malignant Growths of the Lung and Bronchi: A Pathologic and Clinical Study, published in 1912 (Fig 2). The association between lung cancer and cigarette smoking was not immediately obvious to early physicians and scientists. Other posited causes included effluents from industrial plants, coal fires, road tars, auto exhaust fumes, gas works, various pollutants, preceding influenza or tuberculosis, and even race and sex.¹¹ Sir Richard Doll would later note that "the ubiquity of the [smoking] habit...had dulled the collective sense that tobacco might be a major threat to health."¹²

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Faceplate of Adler's Textbook on Lung Cancer. From author's (D.H.J.) personal collection.

Ochsner's theory linking cigarette use with the development of lung cancer was widely disputed, even ridiculed by some of his peers, including Graham, ironically. Graham reportedly told his former trainee, "Yes, there is a parallel between the sale of cigarettes and the incidence of cancer of the lung, but there is also a parallel between the sale of nylon stockings and the incidence of lung cancer."^13,14 Once, after a lecture to the County Medical Society in Mobile, AL, a member of the audience rose to challenge Ochsner's radical theory linking cigarettes to lung cancer. The skeptic stated that he had found that patients with rectal cancer were more likely to be smokers and could Dr Ochsner explain that? After a momentary pause, the ever-decorous Ochsner reputedly opined that he could not, "...unless people in Mobile inhaled much more deeply than those in New Orleans."¹⁶ It was in this era of ambiguity and even open hostility vis-à-vis cigarette smoking as a cause of lung cancer that James Gilmore arrived in St Louis for a consultation with Graham and his team, as we will describe later.

Of course, what seems patently obvious to us today was not so clear 70 years ago. Even though others had suspected that cigarettes were a cause of premature death,¹¹ it was Raymond Pearl's 1938 report in Science that firmly established a linkage.¹⁷ A decade later, Graham, who eventually apologized to Ochsner for his misgivings vis-à-vis Ochsner's prescient observation,¹³ would publish a landmark article with Ernest Wynder linking cigarette smoking with lung cancer.¹⁸ Their work, along with that of Richard Doll and Austin Bradford Hill,¹⁹ sparked the formation of large cohort studies that conclusively established smoking as a causative agent of lung cancer and added heart disease, stroke, chronic lung disease, other malignancies, and decreased life expectancy to the list of injurious effects from smoking.²⁰ Regrettably, however, it would be yet another three decades before the tobacco industry publicly acknowledged the adverse health effects of smoking—but only after a long, drawn-out campaign of misinformation and deception helped along by the [perhaps] unwitting complicity of physicians.^21,22

PREOPERATIVE EVALUATION

Gilmore had suffered with a chronic cough and fever for a period of approximately 7 months before seeking consultation with Graham.^2,4 Although his physical examination was unremarkable, a chest roentgen showed "a fan-shaped shadow with the base outward in the region of the left axilla."⁴ Gilmore had been subjected to induction of an artificial pneumothorax while still in Pittsburgh in the hope that the suspected infection might respond.² The procedure produced surprising albeit temporary symptomatic relief. Eventually, however, his symptoms worsened. As a graduate of Washington University Medical School, Gilmore was familiar with Graham's work, prompting his trip to St Louis.

Gilmore visited Barnes Hospital on three separate occasions before the fateful April admission. The first visit took place in late February, followed by two subsequent admissions in March. On one visit, a liliodol bronchogram was performed, revealing an obstruction of the left upper bronchus.² Two rigid bronchoscopies were performed by Dr M.F. Arbuckle. The first was not helpful, but the second procedure revealed a tumor the "size of a pea" located at the opening of the upper lobe bronchus.⁴ The biopsy specimen revealed squamous cell carcinoma according to Dr W. Dean of the Ear, Nose and Throat Service (Fig 3).⁴ The fact that Dean was not a pathologist would later fuel a controversy surrounding the accuracy of the initial diagnosis. On learning he had cancer and would most likely require a lobectomy, the phlegmatic Gilmore returned home to consider his options.² While in Pittsburgh, Gilmore had dental worked performed and also purchased a cemetery plot. Unaware of the latter, Graham would later exalt Gilmore's decision to have dental work as an indication of his patient's optimism.^4,23 Only many years later would Graham learn of Gilmore's cemetery plot purchase.^4,6

View larger version (122K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Photomicrograph of Gilmore's tumor, a squamous cell carcinoma. Courtesy of the Becker Medical Library, Washington University School of Medicine (St Louis, MO).

Before the Gilmore operation, virtually all attempts at pneumonectomy had proved fatal mainly as a result of hemorrhage, sepsis, or a lack of durable bronchial closure.²⁴ Such procedures were usually undertaken to treat tuberculosis, bronchiectasis, suppurative pneumonias, or empyema and lung abscesses and were commonly performed in two stages.²⁴ At the initial procedure, pleural adhesions were created using talc or by abrading the plural surface with gauze. One week later, a second thoracotomy was performed, at which time the lobar hilum was tied with ligatures and the lobe excised or the hilum strangulated, allowing the lung to eventually slough. Under these conditions, a bronchial fistula was inevitable and infection and hemorrhage common.²⁴ Thoracoplasty was often needed. Operative speed was of the essence because any procedure taking longer than 45 minutes was thought to mean "almost certain loss of the patient."²⁵ Nonetheless, patients would submit to this procedure, despite operative mortality rates approaching 50%, in large part because the alternative, an agonizingly slow death, was so "intolerable."²⁵ In fact, so poor were the results of surgery for lung cancer that on the night of April 4, 1933, one of Graham's house officers reportedly advised Gilmore to sign out against medical advice.⁴ Thankfully, Gilmore did not heed the ill-timed advice, nor did he report this transgression to Graham, presumably saving the resident his job and his career.

On entering Gilmore's chest, Graham found "the carcinoma extended so closely to the bronchus of the lower lobe that it was impossible to save the latter bronchus. Moreover, there were many nodules in the upper portion of the lower lobe about which uncertainty existed as to whether they were tumor tissue or areas of inflammation. Finally, also, the interlobar fissure was not complete. For all these reasons it was decided to remove the entire lung."²⁶ However, because Graham's previous contributions to pulmonary resection were limited to the seemingly barbaric procedure he termed "cautery pneumectomy" wherein the lung was burned away with a red hot cautery,²⁷ he was perhaps understandably hesitant. Seated in the spectators' gallery that day was Dr Sidney Chalfont, a lifelong friend of Gilmore's who had come along to observe the operation. Graham claims he looked up at Chalfont and said: "I'm not going to be able to remove the cancer without removing the whole lung. What do you think about it?" "Has it ever been done before?" Chalfont asked. Graham replied, "No, but I've done it in animals and I don't see why it couldn't be done in a human. I think I'll go ahead."² With great caution Graham proceeded to secure the pulmonary artery; in his words: "There was one aspect of the operation which worried me. It was whether or not a middle-aged patient could tolerate the sudden occlusion of the pulmonary artery to a lung.... Accordingly, I told the anesthetist that I was planning to obstruct the pulmonary artery suddenly and I wanted to be told if any changes occurred in the pulse, respirations or color of the patient. I then passed a small rubber catheter around the artery, which would obstruct the artery when I pulled on the ends of the catheter, but which could be released instantly if any trouble arose."² When 90 seconds had passed and the patient remained stable, Graham felt it was safe to continue. He then removed the lung by first tying a "small rubber catheter tightly around the hilus as close to the trachea as possible" after which "crushing clamps were placed on the hilus below the catheter and the lung was cutoff with an electric cautery knife."²⁶ Chromic catgut was used to secure the bronchial stump; in addition "[7] radon seeds of 1.5 millicuries each were inserted into various parts of the stump."²⁶ "Horrified" at the size of the resulting chest cavity,² Graham next removed several ribs to allow the chest wall to collapse into the mediastinum and against the bronchial stump. The chest was then closed with catheter drainage. The entire procedure took 1 hour and 45 minutes. An episode of hypotension at the start of the surgery was treated with glucose and acacia. Gilmore maintained an excellent blood pressure for the remainder of the procedure, although he did require a transfusion of whole blood at the end of the operation.

Graham was assisted in the operating room by Kenneth Bell, his chief resident and a graduate of Emory Medical School. Bell would later return to Atlanta, GA, to establish a successful surgical practice, only to later die of heart disease at the young age of 39 while serving as an army surgeon at Camp Claiborne in Louisiana.⁴ Also assisting in the operating room that day was William E. Adams, a graduate of University of Iowa College of Medicine (Iowa City, IA). Adams would later become the first director of thoracic surgery at the University of Chicago (Chicago, IL).⁴ Interestingly, neither junior surgeon appeared as a coauthor on the article detailing the historic operation. Graham's sole coauthor would be Jacob J. Singer, a native of Leeds, United Kingdom, who immigrated to St Louis as a child.²⁸ Singer attended Washington University and medical school and was an expert in tuberculosis. He was a member of Graham's multidisciplinary chest clinic (Fig 4), the first of its kind in the United States, and funded in part by the Rockefeller Foundation.²⁸

View larger version (63K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Graham lecturing in Chest Clinic. Courtesy of the Becker Medical Library, Washington University School of Medicine (St Louis, MO).

The final surgical pathology report confirmed the tumor's location in the left upper bronchus (Fig 5). The lesion extended "over a distance of about 4 cm" and obliterated the bronchial lumen.⁴ There was also evidence of peribronchial node enlargement, although no comment was made regarding tumor involvement of the nodes in the initial pathology report.⁴ Years later, because of skepticism regarding the accuracy of the initial diagnosis, the pathologic specimen would be retrieved from storage and re-examined by the noted pathologist Lauren Ackerman. Ackerman's report states, "A tumor mass ulcerating into the upper lobe bronchus near the hilum...is well delineated and measures 3 cm in its greatest diameter. There are numerous pin point abscesses, a markedly thickened pleura and the lower lobe appears essentially normal. The superior interlobar bronchial node...adjacent to the tumor appears to be directly involved."⁴ In other words, Gilmore had a stage II squamous cell carcinoma (T2N1M0). Today, he would have been a candidate for postoperative adjuvant chemotherapy.

View larger version (43K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Original Figure 2 as it appeared in the Journal of the American Medical Association. (A) Medical illustration depicting the location of Gilmore's lung cancer. (B) Note suppurative nodules in upper lobe. Courtesy of the Becker Medical Library, Washington University School of Medicine (St Louis, MO).

Initially Gilmore's recovery proceeded uneventfully; however, on April 18, 1933, he became febrile and developed respiratory problems necessitating a return to the operating room, where a small amount of pus was drained. Nine days later he again returned to the operating suite for a two-rib thoracoplasty. Thereafter, he had no further postoperative problems. It is worth remembering that antibiotics were not generally available until the late 1940s.²⁹ Gilmore was discharged on June 18,1933, 75 days after admission. During his prolonged hospital stay he lost approximately 20 pounds. Less than a month after discharge, Gilmore wrote to Graham, stating, "Everything considered, I am improving; have gained 9 pounds in weight, am gaining in strength, dyspnea is much less than a month ago and morale is good."⁴ Gilmore went on to practice medicine for 24 years after his pneumonectomy. When he died on March 6, 1963, there was no evidence of lung cancer, even though he continued to smoke throughout his lifetime.

SUBSEQUENT EVENTS

Within weeks of the operation, Graham attended the annual conference of the American Association for Thoracic Surgery. At the meeting, Howard Lilienthal from Mount Sinai Medical School in New York presented a case of a tuberculous patient with a sarcoma in whom a pneumonectomy had been performed.²³ His patient had died. As a discussant of Lilienthal's paper Graham mentioned Gilmore's operation, stating, "Just a short time before I performed a complete pneumectomy and in my case, however, fortunately the result was successful. I do not call it pneumonectomy as Dr Lilienthal does because I have the support of the Oxford Dictionary to call it pneumectomy instead of pneumonectomy." He then proceeded to provide a fairly detailed description of the procedure.²³ What transpired next seems almost too improbable to fathom. Dr Pol Coryllos of New York rose to pose an etymologic challenge to Graham. Coryllos claimed that term "pneumectomy" was inaccurate since the word was an improper construct for resection of air, which would actually be "pneumatectomy." Coryllos asserted "pneumonectomy" was the proper term, noting that others had employed this term previously. Coryllos was no ordinary etymologic nitpicker. He was a native of Greece, where he had received his medical education, and attended the Sorbonne in Paris. He had served with distinction in the French army during the first World War, a recipient of the Croix de Guerre.²⁴ As he schooled Graham and the audience on the proper derivation of the terms "pneumectomy" and "pneumonectomy," Coryllos stood at a blackboard and wrote out the each of the terms in his native Greek.²³ Graham, who prided himself on diction and grammar and "was particularly superior about his knowledge of word roots,"⁴ must have been thoroughly chastened since neither term— pneumectomy or pneumonectomy—appears in his Journal of the American Medical Association (JAMA) article published just a few months later.²⁶ After this etymologic clash, one that thoroughly displeased Lilienthal, whose work was all but ignored, the news of Graham's success spread rapidly around the world; according to Mountain, "...it was not only one case. It was the leaven that stimulated and invigorated the whole field of lung surgery; it was the essential catalyst that set in train the development of the modern treatment of lung cancer."³⁰

NOTORIETY AND FAME

In the JAMA article, Graham actually credits Hermann Kümmell, a German surgeon, as having performed the first one-stage pneumonectomy.²⁶ However, Kümmell's report lacked appropriate detail, engendering considerable uncertainty regarding this earlier report.³¹ In any case, the patient had died. Accordingly, Graham's operation was the first one-stage pneumonectomy for lung cancer in which the patient survived.^3,30,32 In June 1933, Edward Archibald of the Royal Victoria Hospital in Montreal, Canada, also performed a successful pneumonectomy, in a 31-year-old man with a left upper lobe sarcoma.²⁴ William Rienhoff at the Johns Hopkins Medical School (Baltimore, MD) also successfully executed two one-stage pneumonectomies in July and October 1933.³³ The first involved a 3.5-year-old girl with a bronchial carcinoid, and the second patient was a 24-year-old woman with a lung sarcoma.³³ Notably, both Archibald and Rienhoff employed a technique of individual ligation of the hilar vessels and the bronchus, important advances that helped reduce postoperative morbidity and mortality. In fact, the 3.5-year-old child on whom Rienhoff operated drowned several years after her pneumonectomy. At autopsy, the bronchial stump was well healed, illustrating the importance of careful bronchial dissection and suturing, and the importance of repleuralizing the bronchial stump.²⁴

Graham clearly recognized the historical significance of his accomplishment, as evidenced by his rush to publish what amounted to a case report—then, as now, not typically the subject of a major article in a prestigious journal such as JAMA. In the 5 years after the Gilmore pneumonectomy, Graham would perform 70 such procedures for malignancies. Shockingly, he recorded 19 consecutive deaths after the Gilmore operation. As his technique improved, there were only three operative deaths in the last 25 cases.³⁴ Curiously, Graham never fully reported on his experience with pneumonectomies for lung cancer, although it is unlikely his failure to do so had anything to do with the seemingly poor results, a mortality rate of 30%, considering that others had reported death rates as high as 100%.³⁴

After Graham's JAMA publication, pneumonectomy became the operative treatment of choice for the management of lung cancer. He and other prominent contemporary surgeons were convinced that pneumonectomy represented the best chance for cure. In 1939, Ochsner and DeBakey opined, "The performance of simple lobectomy in carcinoma of the lung is just as illogical as partial removal of the breast in mammary carcinoma with no attempted extirpation of the regional lymph nodes. ...[F]rom a technical standpoint, total pneumonectomy is a much more surgical and anatomic procedure than is lobectomy. The latter at best consists more or less of a makeshift operation."¹⁵ Over time, however, the concept of limited resection began to take hold. As early as 1958, Johnson et al³⁵ challenged the need for pneumonectomy on the basis of a review of their own experience and the extant literature. These authors suggested that differences in survival rates in relation to surgical procedure could be a result of patient selection. They argued, "until it can be shown that radical pneumonectomy produces superior results, the thoracic surgeon is not obligated to perform the radical operation."³⁵ The real turning point came in 1962, when Shimkin et al³⁶ collated data from the Oschner and Overholt clinics and found that patients with localized lung cancer had improved survival compared with those with more advanced disease, regardless of the extent of the surgery (Fig 6). They opined that "more extensive operations [pneumonectomies] increase mortality and do not improve total survival figures."³⁶ Ironically, the renowned British surgeon H. Morriston Davies had performed the first anatomic dissection lobectomy for lung cancer in 1912,³⁷ more than 20 years before Graham's successful pneumonectomy.

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 6. Pneumonectomy versus lobectomy for lung cancer. Survival curves by stage and surgical procedures. Reproduced with permission.36

A DISTINGUISHED CAREER COMES TO AN END

Feeling unwell after an episode of the flu in late 1956, Graham went for a checkup at Barnes Hospital, where a chest x-ray revealed bilateral lung lesions.⁸ To establish a diagnosis, Graham submitted to a scalene node biopsy performed by his close friend and associate Thomas Burford. According to Ackerman,³⁸ Graham was found to have a small-cell cancer, although in a letter to his former colleague Ernest Wynder, Graham says it was an undifferentiated squamous carcinoma (Fig 7).³⁹ Regardless, Burford could not bring himself to deliver the diagnosis to Graham and asked Ackerman to convey the bad news.³⁸ When told of his diagnosis, Graham asked, "Lauren, are you sure? You have usually been right." He then paused and said, "You know Lauren, that cancer must have been awfully mad at me to do this to me."³⁸ On learning his fate, Graham wrote to several friends to inform them of his sad, ironic predicament (Fig 7).

View larger version (25K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 7. Graham's letter to Ernest Wynder. Reproduced with permission.39

On the morning of February 26, Graham became confused while shaving; he was admitted to Barnes Hospital for the last time (almost exactly 44 years after Gilmore's initial consultation). On March 4, 1957, at 3:38 PM, Evarts Ambrose Graham died.^6,8 His death marked the passing of a true titan in the pantheon of American surgeons. In yet another irony of almost unimaginable proportion, one of Graham's last deathbed visitors was James Gilmore (Fig 8).^6,8 The two had forged a relationship that had lasted more than four decades, and the poignancy of this final act of an enduring friendship is heart wrenching. One can only imagine the essence of that final encounter. What did Gilmore say to the man who had cured his lung cancer, and now lay dying of that same illness? Equally intriguing, what did Graham say to Gilmore, the inveterate smoker? Did he plead with him to put down his cigarettes one last time? As he left Graham's room, did Gilmore fumble to retrieve a cigarette from his coat pocket, light it and contemplate the inevitable fate of his friend and savior as smoke wafted above him? We will never know.

View larger version (42K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 8. Drs Graham and Gilmore, arm in arm. Courtesy of the Becker Medical Library, Washington University School of Medicine (St Louis, MO).

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: David H. Johnson

Collection and assembly of data: Leora Horn, David H. Johnson

Data analysis and interpretation: David H. Johnson

Manuscript writing: Leora Horn, David H. Johnson

Final approval of manuscript: Leora Horn, David H. Johnson

ACKNOWLEDGMENTS

We thank Philip Skroska, manager of the Visual and Graphic Archives and Paul Anderson, PhD, archivist at Bernard Becker Medical Library, Washington University School of Medicine. In reviewing copious materials for this article, we encountered a number of minor factual discrepancies. To the extent possible we have tried to hold as close to the facts as possible given that the different accounts of the event were written years apart by numerous authors, including some of the principals in this vignette.

NOTES

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 18, 2008; accepted March 28, 2008.

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