Danish Perspectives in Oncology: Profiles From Aarhus

While in Denmark under an ASTRO/ESTRO fellowship travel grant, Dr. Brian Kavanagh spoke with a number of oncologists at the University of Aarhus about their research and the practice of oncology in Denmark. In this essay, he skillfully weaves Danish history, philosophy, customs, and landscape into his interviews with four eminent Danish physicians.

Under a blue Aarhuvian sky in late September, the climbing ivy reddens over the yellow brick walls of the university (Figure 1) and splashes color on a small pond nearby. It’s a good time for thoughtful reflection in a country whose cultural landscape includes a legacy of Viking warriors, kindly toymakers, and existential philosophers.

Denmark is a small but exceedingly well-organized country that boasts an outstanding health care system overall, and within this system, its oncology sector clearly ranks among the world’s elite. The Danish achievements in this field are easily found in myriad scientific studies published in all the major international journals. But although oncologists in Denmark face many of the same challenges as their American colleagues, their approach to solving problems can sometimes assume a distinctly Danish focus.

A Modern Prince’s Battles

Four hundred years before Shakes-peare shaped his tragic legend of the angst-ridden avenger who would become the most famous character in English literature, Saxo Grammaticus had recorded in Latin the earliest surviving transcript of the traditional oral myth of Amleth [Hamlet], Prince of Denmark.

In the earlier version, Amleth pretends to be a fool to avoid the wrath of his uncle, Feng, who had murdered Amleth’s father. Amleth eventually retaliates by encouraging Feng and his lords to become stuporously drunk at a royal celebration, restraining them with the hanging tapestries knit by his mother, and then setting fire to the palace.

Cai Grau, MD, PhD, was recently appointed to the faculty of the Department of Clinical Oncology at Aarhus University Hospital. Tall and fit, never raising his voice above the tone of polite conversation, he could play the role of the prince but not the fool. And a millennium later, the drink that served Amleth well in retaliation now hangs over Denmark to drown out some of the progress made by Dr. Grau and others in the fight against cancer. Alcohol and its insidious partner in oncogenesis, tobacco, remain the scourge of Danish oncologists.

Disturbing trends of increasing cancer incidence and mortality as a consequence of increasing tobacco and alcohol consumption in Denmark have been well documented over the past decade.[1-4] And, at the same time, Danish researchers have recognized the detrimental effect of continuing these habits during cancer treatment.[5]

With regard to tobacco use, the Danish government’s drug regulatory policies have been fairly supportive of consumer-initiated smoking cessation efforts. Potentially helpful nicotine replacement therapy products, such as the Nicorette/Nicotrol Inhaler, are sold in Denmark as over-the-counter products, whereas the same items in the United States are prescription medications.

Nevertheless, it is widely believed that the most important interventional ingredient in a successful smoking cessation program is a structured schedule of counseling and follow-up evaluation to monitor patients’ behavorial changes. But, at least among primary care specialists in the United States, there appears to be very little physician initiation of follow-up evaluations and counseling in situations such as HMO-based patient care where there is no clear reward for the physician for this type of effort.[6]

Unfortunately, at Aarhus University Hospital, a state-of-the-art facility equipped for everything from genetic testing to PET scanning, Dr. Grau has thus far been unable to generate much funding support for even a small-scale smoking cessation program for patients receiving treatment for head and neck cancers.

“A few of the nurses and I have recently been working with some patients after hours in counseling sessions to try to help them stop using tobacco products,” Dr. Grau said. “But we really don’t presently have the time and the personnel who specialize in behavior modification techniques to do it properly.”

Why should this be the case, when the governing Social Democrats readily sponsor such a wide range of health care services?

American Humorist Garrison Keillor has described Denmark as the “World’s Most Nearly Perfect Nation,”[7] where personal freedom of choice is upheld as a vitally important societal value. It might, therefore, be tempting to suspect that there is an ironic ideological bias against trying to influence the behavior of another individual in this setting, because such action would imply infringement of individual liberty.

Alas, Dr. Grau offers a more mundane explanation: “It really all becomes a question of money and political expediency. Decisions about allocating resources toward programs to counsel people about the dangers of tobacco use are made by elected officials whose primary goals typically include winning re-election within the next few years. And programs such as those are unlikely to attract immediate support because the beneficial effects will not necessarily be demonstrable before the time of the next election.”

Legoland and Mother Earth

The city of Aarhus is located in Central Jutland, the large midsection of the Danish peninsula that includes Legoland, the most popular Danish tourist attraction outside Copenhagen. The amusement park features elaborate miniature replicas of famous buildings and even whole cities fashioned from many millions of the Lego toy blocks so popular with children worldwide.

Elsewhere in the region, a few small industrial towns and some historic port cities along the eastern coast are scattered through and around richly fertile land where Stone Age burial mounds (Figure 2) can be found in the midst of patchwork manor farms, a testament to the perennial regeneration of agrarian resources that has nourished Denmark and her neighbors for thousands of years.

Dr. Marie Overgaard is a senior member of the oncology department at Aarhus. She has nurtured and cultivated clinical research efforts there for more than two decades, but she does not appear to have aged at all during that time. Like many of her colleagues at the University, Dr. Overgaard maintains a healthy lifestyle and opts for the quiet efficiency of a bicycle for transit around Aarhus (see Figure 3).

While returning home from work one evening after dark, she was apprehended by an officer of the law for the high crime of riding without a working headlight on her bicycle. She had no ID cards with her, and the policeman became quite skeptical listening to someone who looked and sounded like a schoolgirl claim to be a faculty physician at the hospital.

After a phone call, the matter was resolved, but not before the doctor received a stern lecture about the dangers of poor bike visibility at night and the importance of being able to prove that she is who she says she is.

One of Dr. Overgaard’s more recent publications is a report of a randomized comparison of observation vs radiotherapy following mastectomy for node-positive breast cancer. The results, analyzed after more than a decade of patient observation, revealed a survival benefit for the adjuvant treatment.[8] In Dr. Overgaard’s opinion, the trial represents some of the best features of the Danish system and some of the most exasperating.

“Because there are only a limited number of cancer treatment centers within Denmark, it’s relatively easy to start a clinical study and then recruit large numbers of patients within a short time, especially when the study is being conducted nationwide. It’s also highly advantageous that we have very good cancer registries with reliable post-treatment follow-up information,” Dr. Overgaard said.

But in a different sense, she continued, “it is frustrating that in this breast cancer study so many patients had received mastectomy for early-stage breast cancer.”

Dr. Overgaard noted that “it has taken a long time for breast-conserving surgery to become as frequently utilized here as it is in the United States. Surgeons and others involved in the care of breast cancer patients have been a bit slow to let go of some of the old biases about needing to do mastectomy, even though we’ve known for a long time that outcomes can be equivalent for early-stage breast cancer patients with more limited resection and radiotherapy.”

The issue of preventive care again arises, and Dr. Overgaard is quick to add a qualified defense of the surgeons in that regard. “We have to consider that one reason why we’ve had many patients requiring postmastectomy radiotherapy might be that their cancers weren’t detected at a size appropriate for lumpectomy because there hasn’t been a strong nationwide policy for routine screening mammography.”

At present, the national discussion about breast cancer screening in the United States has begun to shift from a debate about who should and should not have screening mammography toward the more complex matter of when it might be appropriate to conduct genetic screening to determine breast cancer risk estimates.[9,10]

Although preparations to evaluate genetic screening programs are underway in Denmark,[11] there is more immediate concern to assure good access to screening mammography across all socioeconomic strata.[12]

Within the 22 regional health care administrations, there are only two districts that have formal screening programs that include both educational materials and scheduled mammography within the health care system. Dr. Overgaard said that “the excuse that’s given in the other places is that women who really want a mammogram will be able to request one and obtain it, anyway.”

But the problem with this approach, she said, “is that only younger women will tend to take advantage of screening programs, and older women, who probably have the most to gain from screening, are unlikely to have mammograms routinely. This is because, over the years, they’ve grown to trust the health care system and don’t feel a need to ask for more from it than is already being given to them.”

A Future of Dansk Design

After the overnight transatlantic flight, a sleepy traveler arriving in the Copenhagen airport awakens to a quiet, clean, mechanized world of stylized utilitarianism. Tall windows arc around corners opposite spotless white walls with neatly framed artwork, and escalator steps pace slowly until they sense the weight of a passenger, when their cadence quickens to hasten transit up or down. Multicolored neon lights are bright against the ambient morning gray to beacon newsstands and coffee shops near the main concourse area.

From here, a transfer to a domestic flight is a straight walk through another long, white corridor where the only sound is the whisper of the glass and polished steel doors automatically ushering entry to the departure gates.

The intellectual epicenter of cancer-related academic endeavors in Aarhus is found in the person of Jens Overgaard, professor and head of the Department of Experimental Clinical Oncology (Figure 4). The husband of Marie Overgaard, Prof. Jens Overgaard is a kinetic visionary who oversees a wide range of laboratory investigation and also has direct or indirect involvement in almost all of the clinical trial designs and analyses.

His black Labrador retriever hustles to keep up with the master’s long, loping strides when they go for a walk; fellow scientists must think fast to remain in step with one of the most active minds and prolific researchers in the field.

The author of nearly 300 scientific articles and editor of a major international journal (Radiotherapy & Oncology), Prof. Overgaard is a future-oriented savant who is also wise enough to appreciate that progress tomorrow is the result of yesterday’s hard work. His own father initially established the department Prof. Overgaard now chairs, and the entire Overgaard family respect the history and culture of the place in which they live.

For example, before entering university studies, the two older sons of Jens and Marie both spent time at a folkeh (jskole, one of the “folk high schools” pioneered by Nikolaj Frederik Severin Grundtvig). A 19th century theologian and social reformer, Grundtvig wanted to create an educational system where anyone could obtain at least some training in an employable skill and learn about Danish history and culture at the same time. The youngest son will likely follow in his older brothers’ footsteps when he completes his conventional secondary school education.

Although, in the past, his scientific efforts have been focused almost exclusively on improving treatment strategies for a variety of cancers, Prof. Overgaard and many of his colleagues still question whether aggressive therapy for some cancers is always in the best future interest of the country as a whole. The Danish approach to the management of prostate cancer is an obvious example.

In the United States, there is an overwhelming bias toward aggressive therapeutic intervention for locally confined disease, and most investigational protocols are designed to compare variations on the themes of hormonal and/or radiotherapeutic or surgical interventions. Yet it is only very recently that radical prostatectomy was introduced into common practice in Denmark for the management of localized prostate cancer.[13]

The proper selection of patients for potentially curative radiotherapeutic or surgical treatment is a topic of great interest to Prof. Overgaard, as he explains: “I’m very proud of the fact that we’ve been able to use hypoxic radiosensitizers and other treatment modifications to achieve substantial improvements in outcome for patients with head and neck cancer, for instance.”

But for prostate cancer, “which is certainly much more common,” he thinks it is “very troublesome that we just don’t have enough information to decide who would really benefit from treatment and who wouldn’t, especially when you consider the tremendous amount of health care resources involved in the debate.”[14-16]

‘Truth Is Subjectivity’

Visitors to Denmark who purchase durable goods for their personal use do not have to pay the 25% sales tax required of Danish residents. Tax rates such as these would be unacceptable to most Americans but are necessary to support the gamut of Danish government-sponsored programs, not the least costly of which is medical research. Of course, Americans and others outside Denmark may take advantage of the generous Danish taxpayers if they wish, since results of the investigations are freely distributed internationally.

Hans von der Maase, professor of clinical oncology at Aarhus, with his sharp Van Dyke beard and small round spectacles, would be well cast as a scholar walking the cobblestone streets of Copenhagen during its Golden Age in animated conversation with Grundtvig, Soren Kirkegaard, Hans Christian Andersen, or any of the other luminaries of that era.

It is relevant that one of the tenets of the existential philosophy put forth by Kirkegaard at the time was the notion that “truth is subjectivity,” ie, it is only the individual’s active, subjective belief in a certain idea that renders it true for that person.

Prof. von der Maase has learned from experience that this particular existentialist concept might apply quite directly to the transfer of medical knowledge from one country to another. He cites the example of adjuvant therapy for stage I germ-cell tumors.

“I used to go to the international meetings and engage in sometimes heated discussions about what, if anything, would be the best adjuvant therapy for early-stage germ-cell tumors,” he said. “Even though we had performed randomized studies that support the alternative of observation alone as an equivalent strategy, there were always colleagues from other countries for whom this choice just wouldn’t fit into their belief system about how to treat cancer. So now I just resign myself to knowing that there are always things about which we’ll simply have to agree to disagree.”[17,18]

What’s considered a good approach to cancer treatment in Denmark will certainly not always be viewed the same way in other countries. But in their orderly 5-million-person clinical laboratory, the Danes can be expected to continue to conduct thoughtfully designed investigations seeking the most efficient and effective ways to treat cancer. Oncologists elsewhere would ignore the results at their patients’ peril.

References:

1. Guenel P, Moller H, Lynge E, et al: Incidence of the upper respiratory and digestive tract cancers and consumption of alcohol and tobacco in Denmark. Scand J Soc Med 16:257-263, 1988.

2. Moller H, Boyle P, Maisonneuve P, et al: Changing mortality from esophageal cancer in males in Denmark and other European countries, in relation to changing levels of alcohol consumption. Cancer Causes Control 1:181-188, 1990.

3. Tonnesen H, Moller H, Andersen JR, et al: Cancer morbidity in alcohol abusers. Br J Cancer 69:327-332, 1994.

4. Dreyer L, Winther JF, Andersen A, et al: Avoidable cancers in the Nordic countries: Alcohol consumption. APMIS 76(suppl):48-67, 1997.

5. Bundgaard T, Bentzen SM, Wildt J, et al: The prognostic effect of tobacco and alcohol consumption in intra-oral squamous cell carcinoma. Eur J Cancer B Oral Oncol 30B(5):323-328, 1994.

6. Goldstein MG, DePue JD, Monroe AD, et al: A population-based survey of physician smoking cessation counseling practices. Prev Med 27(5 Pt 1):720-729, 1998.

7. Keillor G, et al: Civilized Denmark. National Geographic 194:56-73, 1998.

8. Overgaard M, Hansen PS, Overgaard J, et al, for the Danish Breast Cancer Cooperative Group 82b Trial: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997.

9. Malone KE, Daling JR, Thompson JD, et al: BRCA1 mutations and breast cancer in the general population: Analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 279:922-929, 1998.

10. Newman B, Mu H, Butler LM et al: Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279:915-921, 1998.

11. Gerdes AM, Rasmussen K, Graversen HP, et al: Clinics for counseling on cancer genetics. Experiences with genetic studies and counseling on familial breast cancer and colorectal cancer. Ugeskr Laeger 160:1145-1151, 1998.

12. Norredam M, Groenvold M, Petersen JH, et al: Effect of social class on tumour size at diagnosis and surgical treatment in Danish women with breast cancer. Soc Sci Med 47:1659-1663, 1998.

13. Brasso K, Iversen P, et al: Radical prostatectomy for localized prostatic cancer. Ugeskr Laeger 160:4505-4509, 1998.

14. Overgaard J, Hansen HS, Overgaard M, et al: Randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma: Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother Oncol 46:135-146, 1998.

15. Borre M, Nerstrom B, Overgaard J, et al: The dilemma of prostate cancer—a growing human and economic burden irrespective of treatment strategies. Acta Oncol 36:681-687, 1997.

16. Borre M, Nerstrom B, Overgaard J, et al: The natural history of prostate carcinoma based on a Danish population treated with no intent to cure. Cancer 80:917-928, 1997.

17. von der Maase H, Specht L, Jacobsen GK, et al: Surveillance following orchiectomy for stage I seminoma of the testis. Eur J Cancer 29A:1931-1934, 1993.

18. Rorth M, Jacobsen GK, von der Maase H, et al, for the Danish Testicular Cancer Study Group: Surveillance alone versus radiotherapy after orchiectomy for clinical stage I nonseminomatous testicular cancer. J Clin Oncol 9:1543-1548, 1991.