Michael Fatouros

The Predominant Role of Surgery in the Prevention and New Trends in the Surgical Treatment of Women With BRCA1/2 Mutations

BackgroundAdvances in understanding molecular and genetic mechanisms underlying cancer promise an “individualized” management of the disease. Women with a BRCA1 or BRCA2 germ-line mutation are at very high risk of breast and/or ovarian cancer. Because high-quality data are lacking from randomized trials, prevention strategies and treatment of patients with BRCA-associated breast cancer are complex.MethodsThe data for this review were obtained by searching PubMed and Medline for articles about optimizing prevention and treating women with familial susceptibility to breast and ovarian cancer.ResultsProphylactic surgery is the rational approach for women who carry the BRCA mutation; chemoprevention and/or intensified surveillance represent alternative approaches. Prophylactic bilateral salpingo-oophorectomy is superior to bilateral prophylactic mastectomy. However, reaching a definitive clinical decision is complex, and several variables should be considered for an individualized approach. Accumulating data support the concept of more extensive surgery for newly diagnosed breast cancer in women with a BRCA mutation but new unbaised studies are needed for an evidence-based approach . Such patients treated with breast conservation therapy for early-stage breast cancer are at higher risk of contralateral breast cancer than noncarriers. Primary bilateral mastectomy could also be considered and discussed with these patients. Breast tumors from BRCA1 mutation carriers are predominantly of basal subtype (i.e., triple negative), and BRCA2 mutation carriers are of luminal subtype (i.e., estrogen receptor positive). Decisions on adjuvant treatment are based on estrogen receptor, progesterone receptor, and HER2 status. ConclusionsThe complex management of healthy women and breast cancer patients with familial susceptibility to breast and ovarian cancer requires an individualized prevention or treatment strategy by an experienced team.

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

Level I Evidence in Support of Perioperative Chemotherapy for Operable Gastric Cancer: Sufficient for Wide Clinical Use?

Primary surgery with gastrectomy and, if feasible, with extended D2 node dissection is the current standard treatment of operable gastric cancer. However, it is widely accepted that without adjuvant systemic treatment, the high relapse and death rates can hardly be improved. Despite research efforts, neither a chemotherapeutic regimen nor the timing of chemotherapy administration (i.e., before or after surgery) has been standardized. For the first time now, the MAGIC trial provides level I evidence for a survival benefit of perioperative chemotherapy over surgery alone in patients with localized gastric cancer. However, this study raises several questions: given that it was designed to assess an overall benefit and not a stage-specific survival benefit, it remains unknown as to which subgroups (II, IIIA or IIIB) mostly benefit from a perioperative regimen of epirubicin, cisplatin, and infused fluorouracil (ECF). Another key question is the impact of the MAGIC study in daily clinical practice. As several treatment options become available, uncertainty of oncologists for selecting an optimal adjuvant chemotherapy between perioperative, neoadjuvant and postoperative setting increases. Gastric cancer is an aggressive malignancy with nearly 700,000 deaths annually (the second leading cause of cancer death) and a prevalence of around 930,000 new patients annually worldwide. Even the most appropriate local therapy, as an extensive D2/ D3 surgery, which increases the rate of a true complete surgical pathologic R0 resection, is associated with a substantial proportion of recurrence and death. Particularly in patients with advanced serosa-positive, node-positive gastric cancer, the 10year survival rate ranges between 10% and, at best, 30%. Overall, less than 30% of Western patients are cured with local therapy alone as an R0 resection. Systemic adjuvant treatment is required for survival improvements. The biological and clinical heterogeneity of gastric cancer represents a major challenge of current and future molecular and clinical research. 14,15 Clinical data provide differential outcomes among patients with same TNM stage (I, II or III) and treatment and thus there is a clear requirement for tailoring adjuvant systemic therapy in treating specific subgroups of patients. Clinical models converted into a software program using conventional clinicopathologic prognostic factors have been developed and validated, but both these nomograms and the surgical pathologic TNM staging system have two major limitations: First, they cannot identify patients with local disease who could spare the toxic effects of unnecessary chemotherapy. Second, these conventional models cannot predict the response to certain chemotherapeutic regimens among patients with systemic disease who truly require adjuvant systemic treatment to reduce disease relapse and death rates. In contrast to the proven efficacy of adjuvant cytotoxic chemotherapy in other adenocarcinomas including colorectal, lung and breast cancer, no conclusive data exist for gastric cancer. Many phase III clinical trials have explored this approach in Received November 30, 2006; accepted January 12, 2007; published online: July 26, 2007. Address correspondence and reprint requests to: Dimitrios H. Roukos; E-mail: droukos@cc.uoi.gr, info@gastricbreastcancer.com

Assessment of local stage in rectal cancer using endorectal ultrasonography (EUS).

BackgroundPreoperative staging of rectal cancer is essential for the selection of the optimal treatment. This study aims to evaluate the accuracy of endorectal ultrasonography (EUS) in local staging of rectal cancer.Patients and methodsDuring a 4-year period, 33 patients with biopsy-proven rectal cancer underwent evaluation of the invasion of the rectal wall, the mesorectal lymph nodes status and the pelvic organs using EUS. We compared the EUS findings (uTN) to the histopathology examination of the resected specimens (pTN) according to TNM classification.ResultsMost patients had T3 tumours. Overall accuracy in assessing the depth of rectal wall invasion (T) and the lymph node status was 79% and 59% respectively. Two patients previously treated by preoperative chemoradiation were correctly staged only for N stage.ConclusionsEUS is a valuable diagnostic tool in local staging of rectal cancer. Progressively increasing experience will overcome the obstacles in accurate interpretation of ultrasound images.

Non-toxic megacolon due to transverse and sigmoid colon volvulus in a patient with ulcerative colitis

Intestinal volvulus in patients with inflammatory bowel disease is rare. A 83-year-old woman diagnosed with ulcerative colitis five years ago was referred to our hospital due to abdominal distension. The patient had been diagnosed with pancolitis and dolichocolon and was started on mesalazine 1.5 g/day treatment resulting in long-term remission. Physical examination showed abdominal distention with no rebound; however on auscultation abdominal sounds were absent. Patient had no signs of toxicity. Temperature was 38.2 °C, heart rate was 82 bpm and respirations were 16/min. Laboratory investigation showed elevated white blood cell count (20,000/mm(3)) with hemoglobin at 13.2 g/dl and C-reactive protein at 310 mg/dl. Radiology was suggestive of megacolon and volvulus. Patient underwent endoscopy, which revealed normal rectal mucosa; there were however present areas of bowel gangrene. Urgent laparotomy was performed which revealed double transverse and sigmoid colon volvulus. A left hemicolectomy and transversectomy were performed. A case of a patient with ulcerative colitis is being presented here, exhibiting a non-toxic megacolon, resulting from a double transverse and sigmoid volvulus probably stemming from congenital dolichocolon. This case is stressing the importance of prompt differential diagnosis in such cases of megacolon as any symptom misinterpretation may result in unfavorable outcomes.

Controversy in the Treatment of Gastric Cancer

To the Editor: Following the most recent positive results from large-scale randomized controlled trials (RCTs) that adjuvant chemotherapy improves survival of patients with localized gastric cancer,one could suppose that the long-term debate about the challenges of treating gastric cancerhave now been overcome. However, two of these reports support primary chemotherapywhile the third supports primary D2 surgery followed by chemotherapy.Thus, they raise more questions than answers and surgeons and oncologists are more confused than ever. Should patients with localized gastric cancer receive adjuvant chemotherapy? If yes, when: before (preoperative or neoadjuvant) or after surgery (postoperative)? Should adjuvant treatment include radiotherapy in the preoperative or postoperative setting? Currently, there is no standard treatment or a worldwide consensusand the therapeutic strategy differs between Western and Eastern countries. In a recent issue of the Journal a report by Mansour et al.from the Memorial Sloan Kettering Cancer Center and an accompanying editorial by Ajanifrom the University of Texas MD Anderson Cancer center address the interesting topic of selecting patients for the most beneficial treatment. Prognosis for gastric cancer still remains poor. Although high survival rates have been reported with adequate local therapy (surgery) in early-stage gastric adenocarcinomaor lymphoma,most patients in the West and a substantial proportion in the East are diagnosed at advanced tumor stage for which cure even today is rare. To improve treatment results and poor outcome, two completely different approaches are currently recommended. Standard treatment for localized gastric cancer in Japan and Korea is primary D2 surgery,supported by a recent RCT, followed by adjuvant chemotherapy in selected patients.In contrast in the USA and Europe, after the positive results of the MAGIC trial with perioperative chemotherapyand of the INT-0116 trial with postoperative adjuvant chemoradiation,more emphasis is given to adjuvant treatment and little attention to the extent of surgery. Faced with these contradictions, how should patients with localized gastric cancer currently be treated: primary D2 surgery and then careful decisionmaking on adjuvant chemotherapy on the basis of clinicopathological features,or primary systemic chemotherapy followed by surgery, usually D1 node dissection?Despite randomized evidence, there are weaknesses in both settings, namely the neoadjuvant and postoperative approaches. In the neoadjuvant setting, the response rate is approximately 40%. Given the toxicity of neoadjuvant chemotherapy and the delay in surgical treatment, it is likely that about 60% of patients are harmed by this strategy. Particularly for patients with stage II disease, who have a relative good prognosis after adequate D2 surgery,preoperative chemotherapy may have a negative impact on survival. Primary D2 surgery followed by postoperative chemotherapy also has several limitations and weakness. In the West, despite positive results by descriptive studies with D2 surgery from specialized institutions,there is still controversy given that Published online January 15, 2008. Address correspondence and reprint requests to: Dimosthenis Ziogas, MD; E-mail: deziogas@hotmail.com

Fournier's gangrene complicating ulcerative pancolitis

Fournier gangrene is a very rare and a rapidly progressing, polymicrobial necrotizing faciitis or myonecrosis of the perineal, perianal and genital regions, with a high mortality rate. Infection is associated with superficial traum, urological and colorectal diseases and operations. The most commonly found bacteria are Escherichia coli followed by Bacteroides and streptococcal species. Diabetes mellitus, alcoholism, and immunosuppression are perpetuating co-factors. Fourniers gangrene complicating inflammatory bowel disease has been reported in three patients so far, two with Crohns disease. A 78-year-old man diagnosed with ulcerative pancolitis was referred for fever, and painful perianal and scrotal swelling after perianal surgery for a horseshoe-type perianal abscess. Since bowel disease diagnosis, patient was on mesalazine and achieved long-term remission. Perianal abscess occurred suddenly one week before perianal surgery without any evidence of pre-existing fistula or other abnormalities. Physical examination showed extensive edema and crepitus of perineum and genitalia and patient had symptoms of significant toxicity. The diagnosis of Fourniers gangrene was made and patient underwent emergency surgery with extensive surgical debridement of the scrotal and perianal area and Hartman procedure with a diverting colostomy. In addition, patient started on therapy with mesalazine 3gr, methylprednisolone 16 mg, parenteral nutrition and broad spectrum of antibiotics. Two days after the first operation the patient needed a second operation for perianal debridement. On the fourth day, blood cultures showed E. coli. Patient had an uneventful recovery and was discharged after 34 days of hospitalization. On follow up, disease review is scheduled and colostomy closure is planned.

Prophylactic Surgery in the Complex Decision-Making Management of BRCA Mutation Carriers

To the Editor: In a recent issue of the journal, Heemskerk-Gerritsen et al. provided clinical useful data supporting the efficacy of genetic testing and prophylactic mastectomy (PM) in unaffected and affected breast cancer carriers who had mutations in BRCA1 and BRCA2. No breast cancer occurred among 358 BRCA carriers (unaffected women, n = 177; affected, n = 181) after PM in a median follow-up of 4.5 years. However, is it PM the optimum preventive intervention, just as data on other preventive options, including prophylactic salpingo-oophorectomy chemoprevention and intensified surveillance, have become available? Given the lack of randomized trials, it is not surprising that the management of BRCA1/2 mutation carriers is debated. In contrast to another recent study and data from many other reports, a new study published recently reported no difference in survival between BRCA and non-BRCA mutation carriers. If this finding is true, neither genetic testing at diagnosis of a new breast cancer or after completion of treatment, nor prophylactic interventions are required. However, this study has been criticized for possible biases and methodology errors. Live-saving preventive interventions are required for BRCAmutation carriers because these women are at high risk of breast and ovarian cancer. However, there is no standard approach. Decision-making management of these women is complex. Prophylactic salpingo-oophorectomy seems to be better than PM or chemoprevention and surveillance, but high-quality measurable comparative data on the safety and efficacy of all these options and their effect on both survival and quality of life are not available yet. Another challenge is how to deal with women who have a family history of breast cancer but who test negative for a BRCA mutation. To address these challenges a comprehensive decision-making algorithm for individualizing management of these women was developed at the Ioannina University. Testing for CDH1 mutations in women with BRCA-negative test result who have a family history of both breast cancer and gastric cancer as well as for the CHEK2 mutation facilitates decisionmaking prevention strategies for these non-BRCA mutation carriers. Women with CDH1 mutations have a 40% lifetime risk of breast cancer, but they face a much higher risk gastric cancer (70%). The first priority for CDH1 carriers is the prevention of gastric cancer. A riskreducing prophylactic total gastrectomy is now increasingly accepted. Given the overall poor survival of gastric cancer, with exceptionally high cure rates for early-stage stomach tumors, despite adequate D2 lymphadenectomy, D1 gastrectomy plus chemoradiation, or perioperative adjuvant systemic treatment, prevention strategy seems to be the most rational way to reduce the incidence of and mortality from gastric cancer. The feasibility and assessment of genetic testing for women with breast cancer and increased familial risk before definitive therapy have begun to influence the Published online January 15, 2008. Address correspondence and reprint requests to: Dimosthenis Ziogas, MD; E-mail: deziogas@hotmail.com