best practices and rationalistic perspectives in causation-based
prevention, early detection and multidisciplinary treatment
of breast and gastric cancer
Volume 1- Number 2 -October/December 2002
Comparing Recent Advances in Gastric and Breast Cancer
Moses Elisaf, MD, Dimitrios H. Roukos, MD, Evangelos Briasoulis, MD, Evangelos Paraskevaidis, MD, Niki J. Agnantis, MD, and Angelos M. Kappas, MD
From the Departments of Internal Medicine (ME), Surgery (DHR, AMK), Oncology (EB), Obstetrics and Gynecology (EP), and Pathology (NJA), Ioannina University School of Medicine, 45110 Ioannina, Greece, email@example.com
Establishment of progress against cancer is assessed mainly by the reduction of mortality. This reduction can emerge from a decrease in cancer incidence, increase of proportion of early stages and/or better treatment of clinically detectable cancer. Here, we review and compare time trends results in incidence, screening (mammography, endoscopy), early detection and case-mortality in the USA and Japan. What are the reasons for a faster progress and better results in the treatment of breast cancer in the U.S. and gastric cancer in Japan? What lessons can we take from this diverged progress?
Mortality reduction from cancer assessed by time trend results is the objective criterion that reflects the progress that has been made. Looking at cancer statistics data over the last decades impressive are some extreme differences in incidence and mortality of breast cancer and gastric cancer between western and eastern world. In the USA excellent survival results are currently reported for breast cancer with 5-year survival rate of 86% overall (all stages) and 97% for localized disease. The corresponding survival rates for gastric cancer are 22% and 59% only. From Japan however, excellent 5-year survival rates for localized gastric cancer are reported, approximately similar to the reported for breast cancer in the US. These data suggest that cancer not only in the breast but also in the stomach is a highly treatable disease in some specific countries but not worldwide. Here we review the time trend results of these two tumors in the USA and Japan to find out the reasons for this diverged progress and the potential for outcomes improvements.
Worldwide, breast cancer and gastric cancer are the most common malignancies but incidence presents a wide variation in various geographical areas.[2,3] In the USA, 203,500 new invasive cases of breast cancer are estimated to occur among women in 2002 but only 21,600 new diagnoses for gastric cancer. By contrast, breast cancer lifetime risk in Japanese women is 1/81 only as compared with 1/8 (13%) in the USA, whereas gastric cancer incidence in Japan is 50 vs. only 8.7 new cases each year per 100,000 population in the USA. These data provide evidence for extreme differences existed in incidence of these two tumors. With fact the high incidence, reduction in mortality can resulted from an increase in early detection and appropriate treatment.
Screening, Early detection, Minimal Invasive Treatment and Quality of life
Detection of a cancer at an early-stage cancer has been established as the most effective activity to improve substantially both survival and quality of life (QOL). Increasing the proportion of patients with early detection and decreasing the rate of late diagnosis we may improve not only survival but also QOL. Early detection allows management of the disease with minimally invasive approaches which result in improved QOL without increase of risks of treatment failures and death from cancer. Because early-stage cancer produces no or mild symptoms, detection of the disease can be achieved mainly by screening programs.
In the USA, mortality rates of breast cancer over the past decade have been truly decreased nearly parallel with an increase of both screening mammography and early detection. Indeed screening mammography has been dramatically increased from 30% in 1987 to 67% in 1998 in women aged over 40. Although incidence rates among women rose 1·2% per year from 1992 to 1998, due to increased detection of early-stage cancers, death rates for breast cancer decreased 3-4% per year between 1995 and 1998. This drop is probably due to better screening, increased early detection and improved treatment.
The excellent survival of patients with early-stages cancer and the large number of patients presented currently with early diagnosis, have focused the research efforts on improvement of QOL of these patients. As a result, the concept of a less radical surgery has been developed toward replacement of total mastectomy considering the strong desire of women for breast conservation and advances in the understanding of breast cancer spread mechanisms. Recently published 20-years follow-up results[6,7] confirm earlier shorter follow-up data[8,9] that survival does not differ after breast-conserving surgery plus irradiation and mastectomy. These evidence-based data from randomized controlled trials (RCTs) is expected to increase further the breast conservation therapy. This increasing trend however toward breast conservation treatment may be associated with a risk of increase of positive margins and local recurrence rate.[9,11] Indeed, local recurrence represents the main disadvantage of breast conserving treatment. In most studies the incidence of local failure after breast conservation therapy ranges from 10% to 20%[6-11] reflecting the median rate of this adverse effect. Interestingly, studies with longer follow-up suggest an increasing risk of late local failure that occurs longer than 10 years after treatment[9,11] emphasizing the need for particular consideration of this late failure during the initial decision for surgical treatment.Clear surgical margins remains the cornerstone in the treatment of breast cancer despite the use of adjuvant irradiation, chemotherapy and hormonal therapy (tamoxifen). It should be noted however, that although breast conservation is now the treatment of choice for most women with stage I or II breast cancer, in a few patients at risk of local recurrence total mastectomy may be the preferable procedure after extensive discussion with the patient about risks-benefits ratio.
Recently, the technique of the sentinel lymph node dissection (SLND) has been developed toward a further improvement of QOL. Axillary lymphadenectomy is essential for nodal staging and decision for adjuvant treatment. Over the last decade several studies have confirmed that the sentinel node is the first lymph node to receive lymphatic drainage from a primary breast cancer. Because SLND can predict axillary nodal status with less morbidity could replace axillary lymphadenectomy. Improvements in the technique and increased experience have increased the sentinel node identification rate to over 90% and reduced the false-negative rate to less than 5%.[12-14] However, several issues included sentinel node identification rates, false-negative events, optimal techniques, and learning curves need confirmation in a prospective multicenter fashion and other issues such as survival and comparative toxicity require prospective randomized trials. Two prospective randomized trials using sentinel node biopsy have been implemented in the United States: the NSABP B-32 trial and the ACOSOG Z0010/Z0011 trials. At the present time, SLND is advocated to abandon axillary lymphadenectomy only in centers with experience in SLND, while in other settings level I and II axillary dissection remains essential.
In stark contrast with dramatic advances of breast cancer in the USA, little or no progress has been occurred in the management of gastric cancer. Both early detection and case-fatality have not been improved. Surgical resection remains curative in less than 40% of cases[17,18] proportion that is about the half of that reported currently from Japan. The most likely explanation for this large difference is the steadily substantial declining incidence of gastric cancer in the US that has led to a dramatic reduction of research interest and funding. By contrast, in Japan incidence, morbidity and mortality of gastric cancer are still a major health problem attracting public health interest and research funding. Screening programs, including endoscopy in persons aged over 40, have resulted in an increased rate of early detected. Over 50% of new cases have an early-stage cancer and mortality has been reduced by roughly 50% within 4 years. In 1994, 97,991 deaths from gastric cancer were occurred versus only 49,737 deaths in 1997.
In Japan, most of early lesions detected by screening endoscopy are small intramucosal cancers that enable removal by minimally invasive approaches. The steadily increase of early detection in Japan and the need for a less invasive treatment for more patients detected early have contributed to the introduction and development over the past decade of endoscopic mucosal resection (EMR) in the management of early gastric cancer.[21-24] As a patient's highly-friendly treatment with clear benefits in quality of life and low morbidity, EMR has been become very popular in Japan and hundreds of patients have already been treated with this technique. Recent advances in technology, refinement of the technique and increased experience and skill of Japanese endoscopists have resulted in the establishment of EMR in Japan as the treatment of choice for small mucosal cancer. Currently, the Japanese Gastric Cancer Association recommends EMR for small (< 2cm) histologically differentiated mucosal cancers irrespective of macroscopic tumor type (elevated, flat, or depressed). The criterion of well-differentiated or intestinal type according to Lauren classification should be met, because diffuse type needs more aggressive resection of tumor margins for local control. However, many questions should be addressed according to the evidence-based principles of western medicine before a wider clinical implication of EMR can be advocated outsides Japan. The selection criteria (size, histological type, ulceration, macroscopic type) have not yet been standardized, recurrence rates of 15% at local sites after EMR should be taken into account, the risk of both metachronous recurrence at other stomach sites or synchronous malignant lesions overlooked at initial endoscopy seems to be substantial, and there is lack of long-term follow-up data. Although after EMR no treatment related death or death from gastric cancer during the relatively short follow-up has been reported issues as standardization of selection criteria, recurrence, risk of residual disease in lymph nodes and survival, need further evidence-based prospective evaluation and confirmation by multi-institutional randomized trials. The major advantage for the safety of EMR is the potential for a second treatment (EMR, laparoscopic surgery or conventional gastrectomy) if a careful and detailed histopathological examination of resected specimen reveals insufficient resection margins or submucosal invasion. Therefore, reliable is the indication for EMR as the initial treatment of choice for all mucosal, histologically differentiated cancers smaller than 2cm. EMR is also the ideal treatment of dysplasia increasingly detected by screening. Limitation of EMR for application in the USA and Europe is the even currently low rate of early-stage cancers detected and thus the small number of patients who might benefit from this technique.
Surgery is the cornerstone in the management of both breast cancer and gastric cancer. For both cancer sites there is a trend toward less extensive surgery for early stage-cancers, but radical surgery remains standard for advanced stages-cancer. For breast tumors with a size less than 4cm breast-conserving surgery and for greater than 5cm total mastectomy combined with axillary lymphadenectomy are the standard procedures. For gastric cancer however, the optimal extent of lymph node dissection continuous to be strongly controversial. In the USA, even currently, gastrectomy combined with limited (D0 or D1) lymph node dissection is the most frequently (90%) performed procedure. However, this limited surgery is thought unacceptable in Japan where extended lymph node dissection (D2 or more) is in routine clinical use. The reason for this discrepancy is that D2 dissection is associated with increased risk of morbidity and mortality when is performed by inexperienced surgeons, while no survival benefit could be documented by the randomized trials available.[30,31] However, credible evidence for the safety of D2 dissection, when it is performed with a standardized pancreas-preserving technique by experienced surgeons, provides a latest Japanese randomized trial. This preliminary report confirms previous results from specialized institutions not only from Japan but also from the West.[33,34] Although an evidence-based survival benefit after D2 dissection has not yet been established it should be considered the treatment of choice in centers with experience in D2 dissection because it reduces substantially the risk of positive residual lymph nodes and the overall local/nodal recurrence rate in less than 12% that may result in improved survival.
Prophylactic surgery is increasingly receiving attention since genetic testing in high-risk families enables now the identification of asymptomatic persons at high-risk of developing breast and gastric cancer, allowing targeted interventions. Bilateral prophylactic mastectomy on BRCA1/BRCA2 mutations carriers has been established by independent research teams effective to reduce significantly the risk of breast cancer.[37-38] Similarly, there is also currently increasing evidence for the value of prophylactic total gastrectomy in the prevention of hereditary diffuse gastric cancer (HDGC) syndrome, first described in 1998,  in carriers of germ-line mutations in CDH1 gene (E-cadherin).[40,41] However, surgical approaches for cancer prevention have several adverse effects. Total gastrectomy is associated with a risk of morbidity and mortality and adverse effects on quality of life (smaller meals, nutritional deficiencies, weight loss). Prophylactic bilateral mastectomy had a negative effect on self-esteem, sexual relationships, and satisfaction with body appearance. These short-, and long-term adverse effects, the difficulties to convince young asymptomatic persons for the necessity of surgery and the current uncertainty about the appropriate timing of surgical approach are some of the argues against prophylactic surgery. Even if a woman with evident BRCA1/BRCA2 mutation choose surgical approach it is controversy whether prophylactic mastectomy or oophorectomy is more beneficial and risks benefits ratio is confounded by multiple factors including the risk of cancer at other organs. However, it should be emphasized the potential lifesaving effects of surgical prophylaxis and the failure of surveillance either with mammography or endoscopy with biopsies to detect clinically occult disease for breast and gastric cancer respectively. By summarizing the data available, decision-making for prevention intervention in individuals with inherited susceptibility to cancer is extremely challenging and each individual woman should by itself choose the type of prevention after extensive counseling about risks and benefits. Clear medical decision is at the present time impossible.
Most patients even currently at diagnosis suffer from advanced or metastatic disease so that surgery with potential intent is not feasible. But even after adequate surgical resection resulting in a complete tumor removal followed by adjuvant treatment for gastric cancer or breast cancer, relapse at local or distant sites is frequent. The control of recurrence risk remains the major challenge and focus of basic and clinical research. Both long-term well-documented data after curative surgery and recent molecular research consistently indicate that circulating cancer cells before and during surgical maneuvers for the removal of the original tumor, are the most likely explanation for the formation of secondary tumors (recurrence). These limitations of surgery make clear the need for an adjuvant treatment to eliminate micrometastases and kill disseminated tumor cells.
Over the past decades effective adjuvant treatment has been developed for breast cancer whereas for gastric cancer little progress has been occurred. For breast cancer accumulating evidence indicates that adjuvant treatment after surgery improves recurrence-free and overall survival. The National Institute of Health Consensus Conference in the USA recommends currently polychemotherapy regimen including anthracyclines after surgery to most women with breast cancer combined with hormonal therapy for receptor positive subgroups and radiotherapy for patients with positive lymph nodes or advanced primary tumor. Available data regarding the use of taxanes or of adjuvant dose-intensive in high risk group are currently inconclusive, but ongoing studies will determine if these strategies have a role in adjuvant treatment. The absolute reduction in mortality at ten years after adjuvant polychemotherapy is rather small ranging between 2% and 12% depending on nodal status and age at diagnosis.
By contrast, for gastric cancer up until now there was no credible evidence for the effectiveness of adjuvant treatment after gastric resection.[48,51-55] Encouraging are the findings of a latest randomized USA trial suggested a survival benefit of chemoradiotherapy after surgery. However, this multimodality treatment was associated with high rates of major toxicity, its benefit seems to restricted to patients undergoing limited (D0 or D1) node dissection and the long-term results are worse than that reported after D2 dissection from specialized centers.
Adjuvant pre-operative (neo-adjuvant) treatment has recently received increasingly attention for patients with locally advanced breast cancer or gastric cancer. For breast cancer there is evidence from controlled trials that neoadjuvant polychemotherapy increases significantly the number of patients who can be offered breast-conserving surgery and there is some suggestion that it may also improve survival. For gastric cancer, ongoing phase III randomized trials will demonstrate whether neoadjuvant treatment increases the rate of curative resection and improve survival.
As described above, there is currently a broad spectrum of treatment options from minimally invasive treatment in early-stage cancers to combined multimodality approaches with pre- or postoperative adjuvant treatment in locally-advanced or non-early-stages cancers. Treatment decision for the individual patient with breast cancer or gastric cancer, according to the stage of the disease, has been established determinant for both survival and quality of life. Therefore, an accurate pre-treatment staging is essential for the design of the appropriate therapeutic strategy. Recent advances in staging imaging procedures, including positron emission tomography (PET), magnetic resonance imaging (MRI), computer tomography (CT), and endoscopic ultrasonography (EUS) have increased the accuracy of pre-treatment staging facilitating a stage-stratified tailored treatment for both cancer sites.
Chemoprevention is increasingly recognized as an important activity to control substantially cancer due to reduction of incidence. As our understanding of the natural progress of cancer development expands, it is assessed that a strong rationale for preventive approaches with consideration of pharmaceutical intervention at an early stage of carcinogenesis may be feasible. This strategy of arresting progression of pre-malignant cells by chemoprevention has become more and more attractive for both cancer sites. Chemoprevention for breast cancer is already used in medical practice whereas for gastric cancer although there have been substantial progress its efficacious has not yet been established.
The anti-estrogen tamoxifen was used in the first chemoprevention trials in the 1990s because estrogens are potent promotors of proliferation in normal and hyperplastic mammary epithelial cells. In the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial, women with an increased risk of breast cancer were treated daily with tamoxifen over 5 years. The results indicated a statistically significant reduction of 49% in the incidence of breast cancer. Although two other studies did not confirm this result, the Food and Drug Administration approved tamoxifen as a chemopreventive drug for women with a risk greater than 1,66 for developing breast cancer. Unfortunately, side effects dependent on age and race, like stroke, pulmonary embolism and an increased risk of endometrial cancer, have been reported after long-term treatment with tamoxifen.[58,59] A new generation of selective estrogen receptor modulators, such as raloxifene, now offer a chemoprevention potential with considerably lower side-effects profile. Like tamoxifen, raloxifene reduces the incidence of ER-positive tumors, and in addition has no growth-promoting effect on the uterine epithelium. To determine whether raloxifene has fewer side effects while being as effective as tamoxifen, a project called the Study of Tamoxifen and Raloxifene is now underway.
Efforts towards development of effective chemoprevention from gastric cancer are currently receiving major attention because the prognosis of this disease remains poor. Recent advances in cancer genetics indicate the important role of Helicobacter pylori as an environmental exposure in the gene-environment interaction that causes gastric carcinogenesis. Disrupting progression of H. pylori-attributable precancerous lesions would lead to gastric cancer prevention. Promising are the findings of the first randomized trial for chemoprevention with anti-H. pylori treatment and of vitamin supplementation. However, in an accompanying editorial it was pointed out that because of the lack of consistency, the findings should be interpreted with caution. Furthermore, recently, Dixon supports that the hope that intervention by elimination of H. pylori will lead to reversal of atrophy and intestinal metaplasia is an unrealistic expectation because these lesions have passed a "point of no return". Although the findings of chemoprevention studies available provide promises for the development of effective chemoprevention strategies, it is clear that much more work is needed to establish whether and who individuals might benefited from chemoprevention. Ongoing trials will highlight this important topic.
New biologic markers
Classic prognostic indicators, such as the tumor-node-metastasis (TNM) classification system imperfectly predict the clinical outcome of an individual patient with breast cancer or gastric cancer. Some early-stage tumors recur whereas some advanced-stage tumors do not develop recurrence after treatment. As a result, some patients are overtreated or undertreated. Now, exciting recent research using DNA microarrays provides promises for a highly accurate prediction of distant metastases and survival. Recent studies showed that DNA-microarray data distinguished primary breast tumors into a “good” and “poor” prognosis genetic signature. Cyclin E levels is another new biologic marker that may predict clinical outcome of patients with early-stage breast cancer better than the available conventional predictors currently used. Interestingly, these reports suggest that both new markers predicted clinical outcomes much better than the conventional clinical and histological criteria currently used. These data raise strong hope for clinical use of these markers in the near future not only for breast cancer but especially the microarrays can also be used for gastric cancer. The way for a highly personalized therapy that will lead to reducing of overtreatment or undertreatment and improving both survival and QOL in the individual patient with breast cancer and gastric cancer has been opened and remains the time to seen the realization of these expectations.
Time trends in mortality rates undoubtedly indicate a true reduction in deaths from breast cancer and gastric cancer in the USA and Japan respectively. This diverged progress in the two countries has been likely resulted from the different incidence, research attention and funding from public health. The improvement of the results is attributable largely to early detection due screening programs. The data also provide credible evidence that the progress in the management of advanced-stages is slow when one considers the billions of dollars that have been spent on this treatment and the decades needed for this moderate improvement. New multimodality (neoadjuvant) treatments are too expensive and the expected survival benefit rather small or unclear. Recent advances in cancer genetics, the completion of human genome sequence and the use of microarray technology for gene-expression profiling have opened the way for a molecular targeted therapy and prevention. The development of new drugs that block pathway cascade will contribute, in combination with the conventional treatment modalities available, to a faster progress against cancer. Rational are the great expectations to combat cancer by reducing cancer incidence and mortality due to effective chemoprevention but is hard to be predicted the time for a wide clinical use of preventive interventions.
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