Angelos M. Kappas

Perspectives in the treatment of gastric cancer

The overall 5-year survival of patients with gastric cancer is only 23% in the US compared with 60% in Japan. For Western patients, detecting the disease earlier and applying treatment quality control could substantially improve clinical outcome. For the treatment of gastric cancer, complete tumor resection, whenever feasible, is the standard treatment. Resection of the primary tumor (partial or total gastrectomy) is based on standardized criteria of the tumor, such as location, stage, histology, and surgical margins. The extent of regional lymphadenectomy required, however, has been a matter of considerable debate. Emerging evidence from the latest randomized controlled trials show that extended (D2) lymphadenectomy is safe and able to cure 20% of patients with N2-disease compared with 0% treated with limited D1 dissection, provided that the optimal surgical technique is used. Estimates suggest that this N2-specific subgroup advantage reflects a potential absolute overall survival benefit of 3–6%. Postoperative decisions about adjuvant chemotherapy and radiotherapy are based on pathologic staging, the extent of surgery performed (D0/D1 vs D2/D3) and the risk–benefit ratio. Recurrence-risk and mortality-risk reduction is achievable with a carefully planned relapse-prevention guided therapeutic strategy. Patient-related factors (tumor features and expected recurrence-risk magnitude) and treatment-related factors (surgical experience, adjuvant treatment risk–benefit ratio) should be considered on an individual basis. In future, genomic-based approaches will help to provide a more personalized therapeutic approach and improve patient outcome.

Perspectives and Risks of Breast-Conservation Therapy for Breast Cancer

Although breast cancer, with 211,300 new cases expected in 2003 in the United States, continues to be the most common malignant tumor among women, it is a highly treatable disease with a 5-year survival rate of 97% for localized disease in the United States.1 Logically, scientific efforts have been focused on the improvement of quality of life of these women. 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. Total mastectomy has been the standardized primary treatment in all stages, early or late, of breast cancer although there is little or no evidence that it is superior to breast-conservation treatment. Earlier results from randomized controlled trials have suggested that there is no significant difference in survival after breast-conservation treatment or total mastectomy.2a However, because of the long natural history of breast cancer and the lack of long-term follow-up results, breast-conserving treatment has not yet been established the treatment of choice. Therefore, the recently published 20-year follow-up results of two landmark studies3,4 are relevant for treatment decision-making. They confirm earlier results that total mastectomy is not superior to breast-conservation treatment with respect to survival, but the rate of local failure was 14.3%3 and 8.8%,4 respectively. In an accompanying editorial, it was pointed out that it is time to declare the case against breast-conserving therapy closed and to increase the current low rate of breast-conserving surgery.5 These reports and the better quality of life after breast conservation will lead to wider clinical use of breast conservation treatment increasingly replacing total mastectomy in the management of early breast cancer during the next years. What will be the consequences of this expected trend in the treatment strategy of early-stage breast cancer? Is breast-conservation treatment beneficial in all women with stage I/II breast cancer or are there risks from an over simplicity in decision-making? Can these risks be minimized and how? Randomized controlled trials (RCTs) provide the highest level of evidence but they are limited by the lack of generalizability in each individual patient. What lessons can we take from RCTs available for breast-conserving treatment with respect to their pitfalls and the risks for each individual woman enrolled in these studies? Scientific data report that breast-conserving surgery is associated with higher rates of close or positive margins than mastectomy. The rate of positive margin on the final excision has been consistently high and ranges from 10% in the National Surgical Adjuvant Breast and Bowel Project (NSABP B-06) trial3 to 48% in the European Organization for Research and Treatment of Cancer (EORTC) trial.6 In recent nonrandomized studies a similar high overall rate of close ( 2 mm) or positive margin has also been reported ranging from 22%7 to 41%.8 This variation is attributable to the selection criteria, definition of margin status, extent of conservative surgery (lumpectomy, quadrantectomy, local/wide excision), tumor size, adjuvant treatment, and institution. Close or positive margin on final resection specimens is clearly associated with increased risk of local failure although the magnitude of this risk cannot accurately be estimated. Long-term data on the use of breast-conserving therapy in patients with positive margins is obviously limited and recurrence rate varies considerably.9 In most Received May 23, 2003; accepted June 10, 2003. From the Departments of Surgery (DHR) and Pathology (NJA), Ioannina University School of Medicine, Greece. Address correspondence to: Dimitrios H. Roukos, MD, Department of Surgery, Ioannina University School of Medicine, GR-451 10 Ioannina, Greece; Fax: 30-26510-97094; E-mail: droukos@cc.uoi.gr.

Factors increasing local recurrence in breast-conserving surgery.

From 20-year follow-up results of two pioneering randomized controlled trials demonstrating equal survival after mastectomy and breast-conservation therapy, recent high-quality, evidence-based clinical practice recommendations have been made. Breast-conservation therapy undoubtedly represents substantial progress for a better quality of life for women with early-stage breast cancer. However, lumpectomy is associated with a substantial proportion, approximately 10–20%, of local recurrence in long-term follow-up studies even after accounting for postoperative radiotherapy. Risk factors for local failure include margin status, young age and an extensive intraductal component. Young age and family history strongly suggest the need for genetic testing before initiation of treatment. Women with BRCA1 or BRCA2 mutations should be informed about the increased risk of contralateral breast cancer and ipsilateral failure after breast-conservation therapy. Bilateral mastectomy should also be offered as a treatment option. There is controversy over whether current effective adjuvant treatment, including chemotherapy and endocrine therapy, beyond appropriate local treatment as surgery and radiotherapy, can improve local control. Instead of debate over whether an ipsilateral tumor after breast-conservation therapy is local recurrence or a new primary cancer by analyzing conflicting data lacking strong evidence, efforts should be focused on reducing this risk irrespective of origin. Selecting women for breast-conservation therapy and achieving margin control can reduce ipsilateral failures.

Selecting a specific pre- or postoperative adjuvant therapy for individual patients with operable gastric cancer.

Although the very high locoregional recurrence rates reported with limited D0/D1 surgery can be reduced with extended D2 gastrectomy for operable gastric cancer, overall relapse and survival rates remain poor and can only be improved with adequate perioperative adjuvant treatment. However, despite intensive research, no regimen has been established as standard. Meta-analyses have demonstrated a marginal survival benefit with adjuvant chemotherapy. Two recent large randomized trials for operable gastric cancer, the MAGIC trial and the INT-0116 trial, provide evidence that some patients may benefit from perioperative chemotherapy and chemoradiation, respectively. However, while both trials suggest an overall survival benefit with adjuvant treatment, they don’t provide the harm–benefit ratio for specific subsets of patients wih different extent of surgery (D1 or D2) and tumor stage (early [T1,2]/advanced [T3,4]). This lack of evidence complicates current therapeutic adjuvant decisions. Estimating the risk of local and distant recurrence (high, moderate or low) after D1 or D2 surgery in various tumor stages and the expected harm–benefit ratio, the authors provide useful information for decisions on adjuvant chemotherapy with or withour radiotherapy in individual patients. Research on newer cytotoxic and targeted agents may improve treatment efficacy. Simultaneously, advances with microarray-based gene-expression profiling signatures may improve individualized treatment decisions. However, the validation and translation of these genomic classifiers as biomarkers into a completed ‘bench-to-bedside’ cycle for tailoring treatment to individuals is a major challenge and limits inflated expectations.

Is it time to change surgical strategy for gastric cancer in the United States

During the past several decades, survival of patients with gastric cancer in the United States has remained poor. Less extensive surgery consisting of gastrectomy with limited D0/D1 lymph node dissection has been the routine clinical practice in the treatment of gastric cancer.1,2 This surgical undertreatment is a serious problem in the treatment of gastric cancer in the United States and may partially explain1 the overall 5-year survival rate of only 23%.3 The corresponding rate in Japan, with extensive D2 dissection as the standard of care, is over 50%.4,5 Limited surgery, particularly in advanced-stage cancer, may be associated with high residual disease and recurrence rates,6 as it has recently been demonstrated in the Intergroup study (INT-0116).2 In this United States multicenter randomized controlled trial (RCT), the rates of local (29%) and regional (72%) recurrence were very high in the surgery-alone group with a limited D0/D1 node dissection. With more extensive D2/D3 node dissection, lower local and nodal recurrence rates have been reported following nonrandomized studies not only in Japan4,5 but also in Europe.7 Could residual disease, recurrence, and mortality be improved with appropriate, more extensive, D2 surgery? On the basis of the better survival with postoperative chemoradiotherapy (fluorouracil plus leucovorin and local-regional radiation) observed in the INT-0116 study conducted by the Intergroup/South West Oncology Group,2 current research efforts in the United States have focused on the development of a more effective regimen using newer agents such as cisplatin and taxanes and similar preirradiation and/or postirradiation regimens. Since the two large European RCTs have failed to demonstrate a survival benefit in favor of D2 over D1 node dissection,8,9 limited D0/D1 surgery continues to be the most common surgical procedure in several ongoing phase II and III trials. Is this the best way—namely, using as a platform a limited D0/D1 surgery—for the development of a more effective adjuvant treatment? Or should priority be given to more extensive D2 surgery, which ensures minimal residual disease and may increase the effectiveness of systemic chemotherapy and radiotherapy? Indeed, on the basis of credible evidence of the safety and effectiveness of extensive D2 dissection provided from new RCTs10–12 and the longer survival revealed in the Dutch trial,13,14 reevaluation of the extent of surgery in both clinical practice and research appears to be an important step toward realization of the efforts to improve survival in the United States and Europe. There are two major arguments, based on the findings of two previous European RCTs,8,9 against wider clinical use of D2 dissection in the United States and Europe. First, D2 versus D1 node dissection increases in-hospital morbidity and mortality. Second, it does not significantly improve recurrence and survival rates.8,9 The safety of D2 dissection has become clearer. The Japanese experience,4,5,15 Western experts’ opinions,16,17 and most recent RCTs10 –12 reflect worldwide agreement that D2 node dissection, performed by high-volume surgeons, is a safe procedure. In general, recent scientific evidence indicates that high-risk cancer surgery, including pancreatic resection and esophagectomy18 as well as D2 dissection,19 is associated with low rates of hospital mortality, provided that high-volume surgeons perform the surgical procedure. The message is so clear that patients who are undergoing such surgical procedures are advised to carefully choose20 experienced surgeons with technical skill, to ensure the lowest possible operative mortality risk.20 Received May 3, 2004; accepted May 25, 2004. From the Department of Surgery, Ioannina University School of Medicine, Ioannina, Greece. Address correspondence to: Dimitrios H. Roukos, MD, Department of Surgery, Ioannina University School of Medicine, 45110 Ioannina, Greece; Fax: 3

Quality of surgery determinant for the outcome of patient with gastric cancer.

Curative surgery, the complete removal of the tumor (R0 resection), has long been considered the treatment of choice and the only treatment modality able to provide cure in localized gastric cancer. But until now, the optimal extent of this surgical resection still remains highly debated. Several factors, including tumor stage and difficulties in accurate preor intraoperative staging prediction, surgical complications, risks of residual disease and recurrence, as well as quality of life (QOL) differentially influence and complicate the selection of the appropriate extent of surgery. The term quality of surgery under a wide description should involve both decision making about the optimal extent of surgery and the safe performance of the selected less or more extensive surgery. But until now the interest has almost exclusively been focused on the discussion as whether limited (D1) or extended (D2) node dissection should be performed in all stages, early or late, of cancer and not a tumor stage-oriented approach. Here we discuss the risks and benefits of a tumor stagetailored surgical strategy that is increasingly receiving attention. Approximately 40% 2 to 70% of the patients in the Western world t and up to 85% in Japan 3 have a potentially completely resectable tumor at diagnosis. Formation of secondary tumor(s), recurrence, in these patients after surgical removal of the primary tumor is the cause of treatment failure and death. Recurrence occurs in the gastric bed and perigastric lymph nodes (locoregional), in the peritoneal surface (peritoneal carcinomatosis), and

Approaching the dilemma between prophylactic bilateral mastectomy or oophorectomy for breast and ovarian cancer prevention in carriers of BRCA1 or BRCA2 mutations.

Despite advances in the genetics of familial breast and ovarian cancer, the clinical management of women with established mutations in BRCA1 or BRCA2 genes remains controversial. For women who decide for prophylactic surgery and not for a conservative approach, it is highly debated whether they are benefited more by a prophylactic mastectomy rather than a prophylactic oophorectomy. Although BRCA mutation carriers are at a substantially higher risk for developing breast cancer rather than ovarian cancer, medical decision-making is a major challenge. Penetrance estimates of breast and ovarian cancer considerably vary and substantially differ between BRCA1 and BRCA2 mutation carriers. This variation is important in decision-making. Here we balance risks and benefits of these two surgical procedures regarding cancer risk estimates, effectiveness, morbidity, and quality of life. Since the first description of breast cancer susceptibility in women carrying mutations in BRCA1 or BRCA2 genes 8 years ago, important advances have been made in cancer genetics and several clinical studies with surgical or conservative preventive approaches have been published. But the clinical management of these women has not yet been established. Surgical prophylaxis in BRCA mutation carriers seems to offer higher protection against cancer than conservative approach, but it is associated with a series of limitations and risks.~ Clinicians

Expression patterns of dysadherin and E-cadherin in lymph node metastases of colorectal carcinoma

Reduction/loss of E-cadherin is associated with the development and progression of many epithelial tumors, while in a limited number of neoplasms, E-cadherin is re-expressed in metastases. Dysadherin, recently characterized by members of our research team, has an anti-cell–cell adhesion function and downregulates E-cadherin in a posttranscriptional manner. Colorectal cancer (CRC) is one of the most common tumors in the developed world, and lymph node metastases are harbingers of aggressive behavior. The aim of the present study was to examine the dysadherin and E-cadherin expression patterns in lymph node metastases vs primary CRC. Dysadherin and E-cadherin expression was examined immunohistochemically in 78 patients with CRC, Dukes’ stage C in the primary tumor and in one lymph node metastasis. Dysadherin was expressed in 42% while E-cadherin immunoreactivity was reduced in 45% of primary tumors. In lymph nodes, 33 and 81% of metastatic tumors were positive for dysadherin and E-cadherin, respectively. Dysadherin expression was not correlated with E-cadherin expression in the primary tumor with a reverse correlation evident in the lymph node metastases. Our results suggest that different mechanisms govern E-cadherin expression in the primary tumor and the corresponding lymph node metastases.

Prognostic evaluation of metallothionein expression in human colorectal neoplasms.

AIM: To investigate the role of metallothionein in colorectal tumours and the possible relation with other factors associated with tumour progression: expression of cathepsin D (CD), CD44, p53, Rb, bcl-2, c-erbB-2, epidermal growth factor receptor (EGFR), proliferation indices (Ki-67, proliferating cell nuclear antigen (PCNA)), and conventional clinicopathological variables. METHODS: The immunohistochemical expression of metallothionein was investigated in 23 cases of colorectal adenoma and 94 adenocarcinomas. Metallothionein expression was examined by the avidinbiotin peroxidase immunoperoxidase (ABC) using the monoclonal mouse antibody E9, on formalin fixed, paraffin embedded tissue. RESULTS: Positive metallothionein expression (> 5% of neoplastic cells) was observed in 30.4% of adenomas and 25.5% of adenocarcinomas, while 8.7% of adenomas and 14.9% carcinomas showed focal metallothionein positivity. In contrast, 60.9% of adenomas and 59.6% of carcinomas almost completely lacked metallothionein expression. In the series of adenocarcinomas, metallothionein expression was inversely correlated with CD44 in neoplastic cells (p = 0.01). There was no statistically significant difference of metallothionein expression, or the other variables examined, between adenocarcinomas and adenomas. CONCLUSIONS: Metallothionein expression does not seem to indicate aggressive biological behaviour in colorectal adenocarcinomas, in comparison with the other types of carcinoma. The inverse correlation with CD44 could suggest that the decreased metallothionein expression may contribute to the metastatic spread of the lymph node involvement in colorectal cancer. Metallothionein expression does not seem to represent an independent prognostic marker in colorectal cancer.

Rectal Epstein-Barr virus-positive Hodgkin's lymphoma in a patient with Crohn's disease: case report and review of the literature.

We present the case of a 35-year-old man with Crohns disease diagnosed at the age of 27, several months after an operation for small-bowel adenocarcinoma. Seven years after the adenocarcinoma diagnosis, the patient presented with severe continuous anal pain and diarrhea. In parallel with antibiotic administration, the patient was given treatment with Infliximab, but without clinical symptom amelioration. Sigmoidoscopy and subsequent biopsies from an ulcerated rectal area supported the diagnosis of Epstein-Barr virus-positive (EBV(+)) primary Hodgkins lymphoma. Infliximab administration was immediately discontinued and the patient underwent oncological follow-up and began a course of chemotherapy. Only a few cases with primary gastrointestinal Hodgkins lymphoma in Crohns disease patients have so far been reported, including a variety of scenarios on the causal relationship including disease duration, presence of EBV, long-term immunosuppressive treatment and, recently, anti-TNFα administration.