Perspective

10.1586/14737140.7.10.1363 © 2007 Future Drugs Ltd ISSN 1473-7140 1363www.future-drugs.com

Need for a paradigm shift in cancer prevention and clinical oncologyMatthias P Ebert†, Roland Schmid and Christoph Röcken

†Author for correspondenceDepartment of Medicine II, Klinikum rechts der Isar, TU München, Ismaninger Str. 22, 81675 München, GermanyTel.: +49 894 140 4872Fax: +49 894 140 2259matthias.ebert@lrz.tum.de

KEYWORDS: biomarker, cancer, diagnosis, oncology, prevention, screening

Every year approximately 3 million Europeans develop a cancer. Of these patients, 20–25% will suffer from cancer of the hepatogastrointestinal tract (the largest cancer group) and most of these individuals will die from the disease. Recent analysis from the American Cancer Society indicates that disease-related mortality from heart, cerebrovascular and infectious disease has decreased dramatically in the last 60 years, whereas the mortality of cancer remains unchanged. Despite recent improvements in the understanding of the biology, development and progression of human cancers, and the development of novel diagnostic and therapeutic approaches, most cancer patients are diagnosed in an advanced stage with a limited chance of cure. We hypothesize that there has been a dramatic shift in the treatment and, more importantly, prevention of heart, cerebrovascular and infectious diseases that has not yet reached oncology practice. We think that the shift from local to systemic therapy in combination with biomarker-guided detection of patients at risk leads to a reversion of current medical management: we do not treat the end-stage disease but rather follow the course of cancer development starting with risk assessment, followed by disease treatment and prevention of disease progression. Thus, we can prevent end-stage disease that cannot be treated curatively. Our two-step hypothesis should lead to a dramatic improvement of the prognosis of cancer patients.

Expert Rev. Anticancer Ther. 7(10), 1363–1367 (2007)

Current state of cancer managementEvery year cancer is diagnosed in approxi-mately 3 million Europeans. Recent epidemio-logical analysis from the American CancerSociety indicates that the lifetime risk of devel-oping cancer is 1:2 for men and 1:3 for women[101]. Most of these individuals are diagnosedin advanced stages in which a cure is not possi-ble. Despite recent developments in the under-standing and knowledge of the biology, devel-opment and progression of cancers, and thedevelopment of novel diagnostic strategies andtargeted therapies, the prognosis remains poorfor these individuals [1]. Apart from the medi-cal challenges that are present in the manage-ment of these individuals, the burden ofhealth-related costs is substantial. Since can-cers are heterogeneous diseases with a widevariety of genetic, epigenetic, transcriptomic

and proteomic changes, it remains question-able whether the development of novel tar-geted therapies alone will lead to a substantialimprovement of cancer management and,thus, improvement of prognosis [2].

A significant number of cancers are relatedto infectious and inflammatory processes,including viral (e.g., EBV, HBV, HCV, HPV),bacterial (Helicobacter pylori) and parasitic(schistosomiasis) infection, and successful vac-cination and eradication therapies willimprove the risk of developing certain cancertypes (TABLE 1) [3,4]. In addition, other environ-mental factors, such as tobacco exposure anddietary habits, have been linked to increasedrisk of cancer. While the effect of these factorson the overall cancer incidence and prevalencehas been demonstrated, cancer is also a diseaseof the elderly. Disease-related mortality has

CONTENTS

Current state of cancer management

Winners of prevention

Future role of cancer prevention

Expert commentary

Five-year view

Financial & competing interests disclosure

Key issues

References

Affiliations

For reprint orders, please contact reprints@future-drugs.com

Ebert, Schmid & Röcken

1364 Expert Rev. Anticancer Ther. 7(10), (2007)

been reviewed by the American Cancer Society in the last sixdecades. For heart, cerebrovascular and infectious diseases, thisanalysis revealed a dramatic improvement of disease-relatedmortality (FIGURE 1). The group of cancers that were alsoassessed in this analysis demonstrated no improvement of dis-ease-related mortality in 1950 compared with 2004, althoughrecent estimates from the American Cancer Society also indi-cate that age-standardized cancer death rates among men andwomen have decreased by 13.6% between 1991 and 2004 [5].Overall, despite recent improvements in diagnosis and therapyof cancers, disease-related mortality remains poor [101]. There

are various reasons for the divergentresult of vascular and infectious diseasescompared with cancers.

Winners of preventionObviously, mortality from vascular andinfectious diseases has improved substan-tially within the last decades. We believethat, in these diseases, there has been a two-step change in disease management, whichhas led to a considerable improvement ofdisease-related mortality and prognosis:

• A shift from local to systemic therapy

• Biomarker-guided detection of patientsat risk

Earlier, infectious and vascular diseaseswere treated in patients with the full clinicalpicture of the disease (i.e., patients withabscess or myocardial infarction, respec-tively). In these patients, a local therapy wasperformed (i.e., abscess drainage or angio-

plasty) and they then received antibiotics (abscess) or anticoagu-lation (infarction) (FIGURE 2A). As soon as the systemic therapieswere established, clinicians searched for indications to administerthese systemic therapies earlier in patients who might be at riskof developing an infectious or vascular disease (FIGURE 2B) [6,7].

After the shift from local to systemic therapy, the seconddevelopment was the identification of individuals at risk whocould be treated before the disease developed fully. Risk wasassessed by both clinical symptoms and established biomarkers.For infectious diseases, identifying individuals at risk is clini-cally easy, since they may develop fever and also demonstrate

Table 1. Association of inflammation/infection with cancer development and potential interventional/preventive strategies.

Agent Disease Intervention/prevention

Helicobacter pylori and chronic gastritis Gastric cancer, MALT lymphoma Antibiotics

Epstein–Barr virus Non-Hodgkin lymphoma, Hodgkin lymphoma nasopharyngeal carcinoma

None

Human papillomavirus Anogenital carcinoma, oropharyngeal carcinoma Vaccine

Hepatitis B or C virus Hepatocellular carcinoma Vaccine and antiviral treatment

HIV/AIDS Non-Hodgkin lymphoma, Kaposi sarcoma Antiviral treatment

Liver flukes (e.g., Clonorchis sinensis) Cholangiocarcinoma Antibiotics

Schistosoma hematobium Squamous carcinoma of urinary bladder Antibiotics

Gastroesophageal reflux Esophageal adenocarcinoma Proton-pump inhibitors

Ulcerative colitis Colorectal cancer Immunosuppression

Adapted from [4].MALT: Mucosa-associated lymphoid tissue.

Figure 1. Changes in disease-related mortality in the USA, from 1950 to 2004. While there has been a dramatic improvement in disease-related mortality in heart, cerebrovascular and infectious diseases within the last decades, cancer-related mortality remained unchanged. Adapted from the American Cancer Society [101].

0

100

200

300

400

500

600

1950

2004

Ch

ang

es in

dis

ease

-rel

ated

mo

rtal

ity

per

100

,000

Heart Cerebrovascular Pneumonia Cancer

Year

Disease

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biochemical signs of infection, such as an increase in C-reactiveprotein or leukocytes (biomarkers). Then, a microbiologicaldiagnosis is pursued and the patient eventually receives anti-biotics (targeted therapy), even if the identity of the infectiousagent has not been revealed (FIGURE 2C). Furthermore, todaymany individuals receive antibiotics as a preventive agent inpatients at risk of infections or undergoing interventions.

For vascular diseases, a similar pattern of shift from local to sys-temic therapy in combination with risk assessment and diseaseprevention has taken place. Once the patient undergoes angio-plasty (local therapy), a prophylactic therapy is administered [8].Thus, these individuals receive anticoagulation agents and,depending on their risk profile, statins, antihypertensive drugs, aspecial diet and so on (systemic therapy). Again, most cardio-logists will agree that it is not ethical to withhold these preventivedrugs in individuals who present with a specific risk profile. Indi-viduals with increased lipid levels or other markers of increasedrisk of developing a coronary heart disease (markers) will receive

these drugs (targeted therapy) even before they develop a myo-cardial infarction. Cardiovascular disease is considered achronic lifelong disease that ultimately leads to cardiac andcerebrovascular insults, for example, and hence requires a sys-temic approach. The early risk assessment of disease with thehelp of clinical, biochemical or molecular markers in combina-tion with the administration of targeted therapies is the reasonfor the dramatic improvement of disease-related mortality thathas been observed in these disease groups.

Future role of cancer preventionBoth today and in the past, cancer has been mostly diagnosedin patients who develop symptoms. Patients presented withsymptomatic disease and required a diagnostic work-up,which included taking the patient’s history, physical examina-tion and invasive and/or noninvasive procedures. Finally, acancer was diagnosed and further diagnostic procedures todetermine the clinical and pathological stage of the tumor

Figure 2. (A) In the past, vascular and infectious diseases were treated with local therapy, followed by systemic therapy. Patients were treated in advanced stages of disease. (B) A dramatic change in management was the introduction of preventive therapy, which resulted from the success of systemic therapy of these diseases. Patient risk was assessed and preventive therapy administered in order to prevent the progression of disease. (C) The second critical step was the identification of biomarkers of vascular and infectious diseases, and the combination with the administration of targeted therapies. Risk assessment and disease prevention were established, leading to a dramatic improvement of disease prognosis and disease-related mortality. (D) In current oncology practice, cancer is still first treated locally, then systemically. In order to improve cancer prognosis, we must follow the same steps that were taken in other diseases long ago: first assess risk with biomarkers, then administer targeted therapy. CRP: C-reactive protein; LDL: Low-density lipoprotein; Tx: Therapy.

A

Surgery(local therapy)

Penicillin(systemic therapy)

Vascular disease

Abscess

Intervention(local therapy)

Prophylaxis(systemic therapy)

Final disease Risk assessment and disease prevention

Infection

Infarction

Prevention

B

Surgery(local therapy)

Penicillin(systemic therapy)

Vascular disease

Abscess

Intervention(local therapy)

Prophylaxis(systemic therapy)

Final disease Risk assessment and disease prevention

Infection

Infarction

Penicillin

Anticoagulation

Targeted therapyCRP, microbiology

Abscess

Infarction

Risk symptoms

C

Final disease Risk assessment and disease prevention

PreventionTargeted therapy

ChemotherapySurgery

Biomarkers

D

Cancer

Cancer

Risk symptoms

Final disease Risk assessment and disease prevention

BiomarkersLDL, CRP

Targeted therapy

Ebert, Schmid & Röcken

1366 Expert Rev. Anticancer Ther. 7(10), (2007)

were added. Ultimately, a decision with regard to treatment wasmade. Since the development of symptoms in cancer (in contrastto infectious diseases, for example) is usually the result of advancedcancerous disease, the presence of symptoms cannot be regarded asclinical markers of early cancer [9]. Today, cancer is mostly diag-nosed and treated in patients who usually present with sympto-matic disease (i.e., in an advanced stage that reflects the final stagesof the cancer development and progression process) (FIGURE 2D).

While the development of new diagnostic procedures andtailored or targeted therapies present new developments andinnovations in the management of cancer patients, their impacton the prognosis of cancer patients is only modest. We hypothe-size that, in order to dramatically improve cancer prognosis, wemust also move from local to systemic therapy and combinebiomarker-guided risk assessment with tailored preventive sys-temic therapy, thereby parallelizing the paradigm shift that hasalready taken place many years or even decades ago in infectiousand vascular diseases. This shift would lead to the reversion ofthe current clinical management, which is the symptom-guideddiagnosis of advanced disease to the holistic therapy of patientswith a high risk of cancer development or progression. The crit-ical difference in our current management in cancer patients isthe observation that, while infectious and vascular diseases areprevented from developing or progressing, cancer is still onlytreated when diagnosed. Therefore, we must identify, developand validate biomarkers that enable early, sensitive and specificdiagnosis of preneoplasia or early cancer. Furthermore, we haveto understand that a high-risk profile or the presence of pre-neoplastic lesions, which are either characterized by molecularor morphological biomarkers, should be regarded as a chroniccondition that needs continuous therapy.

The identification of biomarkers has been the focus of recentstudies throughout the scientific community. While numerousmarkers have been identified using genomic, transcriptomic,

proteomic, metabolomic and other approaches, none of thesemarkers have been sufficiently validated for clinical practice andmanagement to date. Thus, in order to obtain clinically validatedbiomarkers, more support and research activity in this field ishighly necessary. A recent review summarizes the available datafor biomarkers in various cancers (TABLE 2) [10].

Similar to diabetes or high blood pressure, which are both riskfactors for vascular diseases and usually require life-long therapy,we have to regard a biomarker-defined high-risk cancer profileas a chronic disease, which in combination with targeted andless toxic drugs could lead to a life-long treatment in order toprevent the development and progression to invasive cancer andmetachronous disease recurrence. Systemic therapy may be asso-ciated with side effects that must be carefully considered whenusing these therapies in otherwise healthy individuals. However,we should not wait for the cancer to progress to a symptomaticstage that cannot then be treated with curative intent. In orderto improve cancer prognosis, we must re-evaluate our currentapproach and strategy. Rather than treating patients withadvanced disease, we should use biomarkers to identify at-riskindividuals, and then consider them as patients with a chronicdisease who need lifelong targeted and tailored preventive medi-cal treatment. This approach should have a dramatic impact oncancer prognosis and survival in an aging population.

Expert commentaryDespite recent improvements in cancer diagnosis and therapy,most cancers are diagnosed in advanced stages that do not allowcure. Conversely, we have witnessed a dramatic improvement inprognosis for patients with cardiovascular or infectious diseases.In order to improve cancer prognosis, we must shift from localto systemic therapy and combine biomarkers with early systemicintervention in order to prevent the development of end-stagecancer and thereby improve prognosis of cancer patients.

Table 2. Overview of potential biomarkers in different cancers.

Entity Normal Risk Early IEN

Moderate IEN

Advanced IEN

Early cancer Cancer

Prostate AR, SRD5A2, CYP17, GSTP1 polymorphisms; genetic susceptibility

to infection

AR, GSTP1, TERT, NKX3.1, 8p, 13q, 10q, 16q, 7p, 7q, Xq, DNA ploidy, IGF, EGFR, HER2, PCNA, Ki67

p53, VEGF, FGF, Cadherins, MMPs, PSA

Colon APC, BCL-2, c-MYC,

hypomethylation

RAS, COX2 SMAD 2, SMAD 4,

DCC, STAT3

p53, p16, 7q, VEGF, cyclin D1

p15, Bub 1, 22q, CD44

p15, Bub1, 22q, CD44

8p, tPA, MMP, CEA, E-cadherin

Lung 3p, 9p, 13q, 5p, p16

p53, K-RAS, c-MYC, 22q, 18q, α catenin

Esophagus p16, p53, DNA content, EGFR, VEGFR, cyclin D1, APC, TGFα, VEGF, cadherin

Liver HBV, HCV, carcinogen/DNA

adducts

TGF, IGF-2, TNF-2, IL-6, genomic instability

Telomerase, c-MYC, p53, Rb, IGF2-R, PTEN, DLCI, p73, E-cadherin, cyclin D, cyclin E, p16, p21, p27, aberrant methylation

Adapted from [10].AR: Adrenergic receptor; CEA: Carcinoembryonic antigen; IEN: Intraepithelial neoplasia; MMP: Matrix metalloproteinase; PSA: Prostate-specific antigen.

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Five-year viewIn the next few years, biomarkers for the early detection of can-cer and/or prenoplasia will be validated and will guide the clini-cian in the risk assessment of individuals in order to stratifyhigh-risk of cancer individuals for cancer prevention.

Financial & competing interests disclosureSupported by the BMWi/AIF, the Else-Kröner Foundation and theWilhelm-Sander Foundation (all Germany). The authors have noother relevant affiliations or financial involvement with any organ-ization or entity with a financial interest in or financial conflictwith the subject matter or materials discussed in the manuscriptapart from those disclosed.

No writing assistance was utilized in the production of thismanuscript.

Key issues

• Prognosis of cancer patients is poor.• Improvement of prognosis will only be possible through early

or preventive intervention.• Biomarkers need to identify high-risk individuals.• High-risk individuals will receive targeted therapies based

on their risk profile and the molecular characterization of their cancer.

References

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2 Boige V, Malka D, Ducreux M. Therapeutic strategies using VEGF inhibitors in colorectal cancer. Bull. Cancer 92, S29–S36 (2005).

3 Roden R, Wu TC. How will HPV vaccines affect cervical cancer? Nat. Rev. Cancer 6, 753–763 (2006).

4 Schottenfeld D, Beebe-Dimmer J. Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA Cancer J. Clin. 56, 69–83 (2006).

5 Jemal A, Siegel R, Ward E et al. Cancer Statistics, 2007. CA Cancer J. Clin. 57, 43–66 (2007).

6 Heart Protection Study Collaborative; Mihaylova B, Briggs A, Armitage J et al. Lifetime cost effectiveness of simvastatin in a range of risk groups and age groups derived from a randomised trial of 20,536 people. Br. Med. J. 333, 1145 (2006).

7 Pignone M, Earnshaw S, Tice JA et al. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost–utility analysis. Ann. Intern. Med. 144, 326–336 (2006).

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9 Mulcahy HE, O’Donoghue DP. Duration of colorectal cancerCEA symptoms and survival: the effect of confounding clinical and pathological variables. Eur. J. Cancer 33, 1461–1467 (1997).

10 Kelloff GJ, Lippman SM, Dannenberg AJ et al. Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer – a plan to move forward. Clin. Cancer Res. 12, 3661–3697 (2006).

Website

101 American Cancer Society: Cancer Statistics 2006 Presentationwww.cancer.org/docroot/PRO/content/PRO_1_1_Cancer_Statistics_2006_Presentation.asp

Affiliations

• Matthias P Ebert, MD

Department of Medicine II, Klinikum rechts der Isar, TU München, Ismaninger Str. 22, 81675 München, GermanyTel.: +49 894 140 4872Fax: +49 894 140 2259matthias.ebert@lrz.tum.de

• Roland Schmid, MD

Department of Medicine II, Klinikum rechts der Isar, TU München, Ismaninger Str. 22, 81675 München, GermanyTel.: +49 894 140 2250Fax: +49 894 140 4871 roland.schmid@lrz.tum.de

• Christoph Röcken, MD

Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, GermanyTel.: +49 304 5053 6 115Fax: +49 304 5053 6 914christoph.roecken@charite.de