[Gastric cancer and adenocarcinoma of the esophagogastric junction: principles of neoadjuvant therapy]. / Magen- und Adenokarzinome des ösophagogastralen Übergangs: Prinzipien der neoadjuvanten Therapie.

According to the current European and German S3 guidelines, neoadjuvant chemotherapy is now an integral part of the treatment of locally advanced gastric cancer and adenocarcinoma of the esophagogastric junction. Neoadjuvant therapy seeks to achieve downsizing of the primary tumor, lowering of the T and N categories and eradication of micrometastases. As the indications for neoadjuvant treatment are based on pretherapeutic information alone, a sophisticated clinical staging plays a central role. Despite all progress made in the field of diagnostic work-up, clinical staging often fails. Despite this fact, controlled randomized trials showed that neoadjuvant chemotherapy enhances the rate of curative (R0) resections and reduces the likelihood of systemic relapse. Overall, survival can be improved by neoadjuvant chemotherapy. The current research is focused on the molecular prediction of response and early response monitoring with functional imaging. New targeted drugs are being integrated into the peri-operative treatment.

Metabolic response evaluation by PET during neoadjuvant treatment for adenocarcinoma of the esophagus and esophagogastric junction.

Following several randomized trials, neoadjuvant therapy in adenocarcinoma of esophagus and the esophagogastric junction can be seen as an international standard. However, in a large proportion of patients the objective response achieved is unsatisfactory. These patients do not benefit from neoadjuvant therapy, but do suffer from toxic side effects; sometimes progressive and appropriate surgical therapy is delayed. For this reason, a diagnostic test that can accurately assess tumor response to neoadjuvant therapy might be of crucial importance. Response evaluation using CT scan, endoluminal ultrasound, or rebiopsy is not reliable. In recent times, response evaluation using 18FGD PET after and during neoadjuvant treatment is in the focus of clinical and scientific interest. Most studies have evaluated the diagnostic modalities for response to neoadjuvant treatment after completion of the treatment. Following the published data so far, FDG-PET seems to be less accurate after and during chemoradiation than after chemotherapy alone. The data of early response evaluation (14 days after the onset of chemotherapy) are very much encouraging; however, they have to be evaluated in an international randomized trial. Standardization of PET technology as well as defining the thresholds used for the estimation of early response is mandatory. So far, FDG-PET does not change treatment in esophageal and gastric cancer.

[Tumors of the upper gastro-intestinal tract]. / Tumoren des oberen gastrointestinaltrakts.

The appropriate extent of lymph node dissection in tumors of the upper gastro-intestinal tract continues to be debated. The basic tenet of surgical oncology that cancerous lymph nodes are indicators not governors of survival is under question and derives from the different theories of metastasis. Is the metastatic flow linear (indicators) or does it occur in parallel to tumorigenesis (governor)? If the latter theory is true there would be only a limited indication for lymphadenectomy (LA).Extended LA leads to an ameliorated staging of the N category. Following LA locoregional tumor control is significantly improved for esophageal and gastric cancer. In case of gastric cancer it is evident that there is a group of patients in which extended LA lead to improved long-term survival. This gain in prognosis affects patients in which lymph node metastasis is not or only slightly advanced. In locally advanced tumors there is no prognostic benefit. Patients who might benefit from the extended procedure cannot be assessed during preoperative staging. Therefore, the indications for the procedure should be liberally carried out by experienced hands and in experienced centers. According to randomized studies there is no indication for extended radical LA in pancreatic cancer.

[Early Barrett's carcinoma/high grade intraepithelial neoplasia (HG-IEN): pro endoscopic treatment--pro surgical treatment]. / Barrett-Frühkarzinom/Hochgradige intraepitheliale Neoplasie (HG-IEN): pro endoskopische Therapie--pro chirurgische Therapie.

Who may treat early Barrett's carcinoma of the oesophagus? The incidence of adenocarcinoma of the oesophagus developing within Barrett's mucosa has substantially risen in the past few years. Furthermore, treatment of preneoplastic lesions or early carcinoma is controversial. From an endoscopist's point of view high-grade intraepithelial neoplasia (HG-IEN) should be resected endoscopically rather than destroyed endoscopically while early Barrett's carcinoma should undergo endoscopic staging resection. Surgical resection is rarely necessary because lymph node metastases are rare and there is some morbidity and mortality associated with the procedure. However, surgeons argue that complete surgical resection is required because no imaging technique reveals the exact extent of the lesion and, ultimately, the degree of infiltration can only be determined within the resected specimen. Also, only surgical procedures may remove all potentially involved regional lymph nodes. Furthermore, only within surgical resections we can eliminate all pre-existing Barrett's mucosa easily while endoscopic clearance of Barrett's mucosa is difficult and requires multiple sessions. The Merendino-Siewert procedure may be an option with very low morbidity and mortality. It is worthy of note that new endoscopic resection procedures have not been studied in a controlled fashion against conventional surgical procedures. Therefore, patients with HG-IEN or early Barrett's carcinoma of the esophagus should be recruited into controlled studies and be treated in specialised high-volume centres.

[Carcinoma of unknown primary site (CUP syndrome)]. / Metastasen eines unbekannten Primärtumors.

Despite the growing array of sophisticated diagnostic tools for establishing a diagnosis of human neoplasia, 2-6% of all cancer patients still present metastatic cancer of which detailed investigations fail to identify the primary anatomic site. The site is found in less than 25% of patients before death and frequently goes undiscovered at post-mortem examination. At the time of first diagnosis with carcinoma of unknown primary site, usually more than 80% of patients present with dissemination. Prognosis depends on the site(s) involved and is unaffected by whether the primary site is ever found. Node dissection may be curative for patients with metastases to peripheral lymph nodes. Objective long-term response is possible in combination with chemotherapy in patients with small-cell malignancies, peritoneal carcinomatosis (in women), or poorly differentiated carcinomas involving external lymph nodes, mediastinum, or retroperitoneum but without metastases to viscera or bone. Toxic therapies are recommended only for palliation of symptoms and maintaining quality of life support in patients with good functional status. Patients should be encouraged to participate in clinical trials for novel therapies.

Delays in diagnosis and therapy of gastric cancer and esophageal adenocarcinoma.

BACKGROUND AND STUDY AIMS: In the past, there were long delays in the diagnosis of patients with cancer of the stomach or esophagus. The objective of this study was to describe current delays in the diagnosis and treatment of gastric and esophageal adenocarcinoma and to compare the findings with those from an historical control population treated at the same institutions 10 years earlier. PATIENTS AND METHODS: Patients with biopsy-proven gastric cancer or esophageal adenocarcinoma who were treated at two academic medical centers in Germany between April and October 2003 were consecutively screened for eligibility to take part in the study. Medical charts for each patient were reviewed. Additional data were obtained via structured interviews. Main outcome measures were the total delay, and the delays related to patients themselves, to doctors, and to the hospital. Data were compared with those from a historic control group assessed in 1993. RESULTS: The median total delay for patients with gastric cancer (n = 104) was 3.5 months (range 0.3 - 29.6), and in patients with esophageal adenocarcinoma (n = 22) the total delay was significantly shorter (median 2.2 months, range 1.2 - 11.7; P < 0.05). Comparing these findings with those from an historic cohort of patients with gastric cancer (n = 100) revealed a significant decrease in the total delay (3.5 versus 8.0 months, P < 0.001). CONCLUSIONS: The current findings indicate that delays in the diagnosis and treatment of gastric cancer have become significantly shorter within the last 10 years as our understanding of and ability to treat this form of cancer have improved.

[Sentinel lymph node mapping in gastric and esophageal carcinomas]. / Sentinel Lymph Node beim Magen- und Osophaguskarzinom.

During the last 5 years, the concept of sentinel lymph nodes has been investigated in a variety of solid tumors. Despite the multidirectional and complex lymphatic drainage of the stomach, early gastric cancer has been shown to be a suitable model for sentinel lymph node mapping. In contrast, sentinel lymph node mapping of esophageal cancer is compromised by the anatomic location of the esophagus and its lymphatic drainage in the closed space of the mediastinum. The technique and clinical application of sentinel lymph node mapping thus differ between esophageal and gastric cancer. Reliable detection of sentinel lymph nodes in the mediastinum requires radioisotope labelling, while blue dye and radioisotope labelling are both feasible for gastric cancer. In patients with early gastric cancer, laparoscopic resection with sentinel node negative status is already under investigation in clinical trials. In esophageal cancer, sentinel node mapping is still considered an experimental technique. Preliminary data, however, indicate that it may be reliable and feasible in patients with early adenocarcinoma of the distal esophagus.

[Extent of resection in surgery of stomach carcinoma]. / Resektionsausmass in der Chirurgie des Magenkarzinoms.

The extraluminal extent of resection in cases of advanced gastric cancer is controversial. If, however, following meticulous staging--including the detection of free abdominal tumor cells--complete resection seems possible, then multivisceral resection is justified. If complete resection is achieved, the prognosis of these patients can be improved. Left pancreatic resection should be performed only if the tumor invades the pancreas directly. Splenectomy is indicated if the tumor invades the organ directly or if there are locally advanced tumors of the proximal third of the stomach and tumors of the esophageal-gastric junction. However, it has to be kept in mind that splenectomy is an independent negative prognostic factor. The extent of lymphadenectomy (LA) in gastric cancer is still under discussion. According to the 10-year results of the Dutch Gastric Cancer Study, there might be subgroups which have a survival benefit after extended (D2) LA. These include, as the German Gastric Cancer Study corroborated, patients with very early stage II and stage IIIa lymph node metastases. As neither of these stages can at present be diagnosed before or during surgery, D2 lymphadenectomy should be the standard procedure for all patients with gastric cancer. Recent studies have shown that it might be possible with the help of the Sentinel Node Technique to individualize lymphadenectomy in locally gastric cancer as well. The beneficial effects of adjuvant chemoradiation in gastric cancer do not mean, however, that the extent of resection may be reduced. Adjuvant chemoradiation following complete resection and D2 lymphadenectomy should still not be regarded as standard therapy.

Esophageal cancer: patient evaluation and pre-treatment staging.

Improvements in the overall survival of patients with esophageal cancer can in the future only be achieved by tailored therapeutic strategies which are based on the individual histologic tumor type, tumor location, tumor stage at the time of presentation, consideration of established prognostic factors and the physiologic status of the patient. The major aim of every diagnostic strategy is to assess whether a complete macroscopic and microscopic tumor resection (i.e. an R0 resection) can be achieved by primary surgical approach with a high degree of likelihood. This requires histologic classification of the tumor type (squamous cell cancer or adenocarcinoma), the exclusion of distant solid organ metastases, localization of the primary tumor in relation to the tracheobronchial tree, and determination of the T-category and the surrounding structures of the primary tumor. This is currently achieved by a combination of contrast radiography, endoscopy with biopsy, endoscopic ultrasonography and CT scan. PET scanning will in the future be more widely used in esophageal cancer staging because it appears to be superior to current imaging modalities in the exclusion of distant solid organ and lymph node metastases and allows early assessment of response of the primary tumor to neoadjuvant treatment. Systematic risk analysis with a dedicated composite scoring system is essential to assess the physiologic status of the patient and reduce postoperative mortality. Only hospitals with a sufficient case load of esophageal cancer patients ('hospital volume') and a dedicated interest in the management of this disease ('centers of excellence') can provide the required expertise and standards for patient evaluation and tailored therapy.

Proliferation kinetics and prognosis in gastric cancer after resection.

The influence of proliferation and proliferation kinetics on prognosis in gastric cancer after complete resection are controversial. In a prospective study we investigated the tumour specimens of 111 patients after resection of gastric cancer, who received 200 mg intravenous (i.v.) bromodeoxyuridine (BrdU) pre-operatively. The following biological parameters were analysed in the tumour tissue using flow-cytometry: DNA ploidy, proportion of S-phase cells, BrdU labelling index (LI), DNA synthesis time (T(s)), potential tumour doubling time (T(pot)), proliferating cell nuclear antigen (PCNA) and Ki-67 LI. The median follow-up time was 40 months (range 19-62 months). Besides the established pathohistological prognostic factors, univariate analysis revealed a prognostic influence on survival for BrdU LI, T(pot) and the proportion of S-phase cells. By multivariate Cox analysis of the completely resected cases, only tumour stage and T(pot) had a significant, independent influence on survival. By classification and regression trees (CART) analysis, resection status, tumour stage and T(pot) defined risk groups with significantly different outcomes. A short T(pot) was a predictor of better survival in stage I, II and IIIA tumours. Ploidy and the other investigated proliferation-related parameters failed to demonstrate any influence on prognosis after resection of gastric cancer.

[Response evaluation--pathway for accurate indications development]. / Response Evaluation--Der Weg zu einer gezielteren Indikationsstellung.

Only patients, which respond to neoadjuvant therapy and in which a subsequent complete resection (R0) is possible, demonstrate a significant survival advantage compared to non-responders. Therefore, a sensitive response evaluation is of high clinical interest. Response evaluation by endoscopy, biopsy, endoluminal ultrasound or by CT scan showed unfavourable and overall nor reliable results. In recent studies, a accurate response prediction employing 18FDG-PET seems to be possible. Following neoadjuvant chemoradiation of esophageal cancer, a sensitive differentiation between responders and non-responders was possible in a retrospective study. In the beginning are investigations, to differentiate already after two weeks of therapy between both groups of patients.

Preoperative evaluation of pancreatic masses with positron emission tomography using 18F-fluorodeoxyglucose: diagnostic limitations.

Identification of pancreatic cancer in patients presenting with an enlarged pancreatic mass is a major diagnostic problem. Positron emission tomography (PET) using the radiolabeled glucose analogue 18F-fluorodeoxyglucose (FDG) has been suggested to provide excellent accuracy for noninvasive determination of suspicious pancreatic masses. We conducted a prospective study to verify these results. Forty-two patients admitted for pancreatic surgery underwent PET scanning. Image analysis was based on visual film evaluation and quantification of regional tracer uptake. PET imaging was visually analyzed by three observers blinded for the results of other diagnostic tests; they qualitatively graded the scans using a five-point scale (I = low to V = high) for the presence and intensity of focal FDG uptake. Diagnosis was proven by histology (n = 38) or follow-up (n = 4). Furthermore, the results of PET were compared with helical computed tomography (CT) and conventional ultrasonography (US), done during the routine diagnostic workup before pancreatic cancer surgery. Regarding only the results with scores of IV and V as positive for representing definite malignancy yielded a sensitivity of 71% and a specificity of 64% for film reading. Quantification of regional tracer uptake contributed no significant diagnostic advantage for differentiation between benign and malignant tumors. Helical CT revealed a sensitivity of 74% and a specificity of 45.5% and abdominal US 56% and 50%, respectively. We concluded that PET imaging provides only fair diagnostic accuracy (69%) for characterizing enlarged pancreatic masses. PET does not allow exclusion of malignant tumors. In doubtful cases, the method must be combined with other imaging modalities, such as helical CT. The results indicate that the number of invasive procedures is not significantly reduced by PET imaging.

Potential and futility of sentinel node detection for gastric cancer.

The technique and scientific background of sentinel node dissection has spread extremely rapidly over the surgical community. Following the addition of this technique to the tools of oncologic surgery for treatment of malignant melanoma and breast cancer, questions arise regarding the use of this method in gastric cancer also. While the lymphatic flow on the surface of the body can be defined easily, the lymphatic drainage of the stomach is much more complicated. Following rotation of the stomach during embryonic development, the lymphatic flow is not directed in a simple fashion. It is questionable whether a specific area of the stomach will drain into one lymph node echelon only. This is one of the essential obstacles for SLND in gastric cancer. Furthermore, skip metastasis seems to be quite common in cancer of the stomach. In gastric cancer, the value and the extent of classical lymph node dissection itself is still under scientific discussion. The rationale, aims, and extent of LA in gastric cancer are addressed. The scientific discussion on whether D1 or an extended lymphadenectomy are appropriate is not finally closed as yet. The possibilities and problems concerning an individualised indication for a selective lymphadenectomy in gastric cancer are discussed.

Multidisciplinary approach to esophageal and gastric cancer.

Despite marked advances in surgical therapy for patients with esophageal, esophagogastric, and gastric cancers, the overall prognosis of these patients has not markedly improved during the past decades. Multidisciplinary approaches using adjuvant postoperative and neoadjuvant preoperative therapeutic principles have received increasing attention with regard to the management of these patients. A series of randomized, prospective trials has demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a convincing survival advantage after complete tumor resection in esophageal, esophagogastric junction, or gastric cancer. The available data on the role of neoadjuvant preoperative therapy are not yet conclusive. Although neoadjuvant therapy may reduce the tumor mass in many patients, several randomized, controlled trials have shown that, compared with primary resection, a multimodal approach does not result in a survival benefit in patients with locoregional, that is, potentially resectable, tumors. In contrast, in patients with locally advanced tumors, that is, patients in whom complete tumor removal with primary surgery seems unlikely, neoadjuvant therapy increases the likelihood of complete tumor resection on subsequent surgery, but only patients with objective histopathologic response to preoperative therapy seem to benefit from this approach. Consequently, in the future, improvements in the overall survival of patients with esophageal, esophagogastric junction, or gastric cancer most likely will be achieved only by tailored therapeutic strategies that are based on the individual tumor location, tumor stage, and consideration of established prognostic factors. A clear classification of the underlying tumor entity, a profound knowledge of the prognostic factors applicable, a thorough preoperative staging, and identification of parameters that allow for the prediction of response to preoperative therapy will become essential for the selection of the optimal therapeutic modality for individual patients.

[New therapy approaches in tumors of the upper gastrointestinal tract (esophagus, stomach)]. / Neue Therapieansätze bei Tumoren des oberen Gastrointestinaltrakts (Oesophagus, Magen).

Despite numerous phase-II and phase-III studies investigating neoadjuvant treatment in esophageal and gastric cancer, the value of multimodal therapy in these tumors is not clearly defined yet. One reason are the different study entry criteria and different staging modalities in the investigations published so far. Concerning esophageal cancer, neoadjuvant chemotherapy does not yet have a definite role after several phase-III studies. It may be that this treatment should only be inaugurated in innovative protocols. Furthermore, in esophageal cancer it is proven that chemoradiation is superior to radiation alone in the neoadjuvant setting. Following neoadjuvant chemoradiation, there is a distinct trend in favor of multimodal therapy. In the case of locally advanced squamous cell carcinoma of the esophagus, neoadjuvant chemoradiation offers 30%-60% of the patients the possibility for a complete resection (UICC-R0); however, this is accompanied by increased postoperative morbidity and mortality. In gastric cancer, neoadjuvant chemotherapy is still an experimental approach. Intraperitoneal chemotherapy has failed to show any benefit in Western trials. Clinically related research is concentrating on the problem of distinguishing responder from non-responder at the beginning of the therapy. First results indicate that with molecular markers, response might be predicted before therapy. Using 18-FDG PET, it could be possible that the response can be recognized after only 1 week of treatment, opening the door to early response evaluation. New therapeutics like monoclonal antibodies for adjuvant therapy, which is again under discussion in gastric cancer, are only in phase-I studies.