Surveillance After Gastric Resection

Paper

Conclusions

Mikani et al. [12]

An intensive follow-up is successful in identifying asymptomatic recurrences earlier. Improvement in post-recurrence survival for the asymptomatic groups

Bohner et al. [10]

Tan et al. [11]

An intensive follow-up is successful in identifying asymptomatic recurrences earlier. Improvement in post-recurrence survival for the asymptomatic groups. No advantage in overall survival

Kodera et al. [8]

Bennett et al. [13]

Intensive follow-up does not detect asymptomatic recurrences earlier. Asymptomatic and symptomatic recurrence patterns are biologically different and associated with different survival outcomes

Kim et al. [14]

Bilici et al. [9]

All these studies focused on the possible survival benefit of early detection of recurrence by intensive postoperative surveillance.

Four studies indicated that an intense postoperative follow-up protocol was successful in identifying asymptomatic recurrences earlier than symptomatic recurrences with an improvement in post-recurrence survival [11]. Nevertheless, they could not achieve any evident advantage in overall survival [8, 10, 12]. Overall survival was reported only by two of these studies but estimated survival did not show any statistically significant difference between patients who underwent an intensive follow-up schedule.

With this purpose a study from Memorial Sloan-Kettering Cancer Center [13] showed that follow-up did not detect asymptomatic recurrences earlier than symptomatic recurrences in patients with gastric cancer who underwent a curative gastrectomy. In this report patients with asymptomatic recurrences showed better post-recurrence and disease-specific survival than those with symptomatic recurrences; in their conclusions the authors suggest that symptomatic and asymptomatic recurrence patterns are possibly different in their biological behavior and are associated with different survival outcomes. Similarly, in a paper by Kim et al. [14] median overall survival and post-recurrence survival were worse for patients with a symptomatic recurrence than for those with an asymptomatic recurrence. Moreover, in this study, multivariate analysis revealed that the presence of a symptomatic recurrence and the disease-free interval were independent prognostic indicators for post-recurrence survival. Furthermore, asymptomatic patients had a major benefit from re-resection and post-recurrence chemotherapy and at multivariate survival analysis the presence of symptoms was the only independent factor of poor survival suggesting a more biologically aggressive disease in symptomatic patients. Bilici et al. [15], in a study on 173 patients with recurrent gastric cancer, found that symptomatic recurrence is an important prognostic factor for post-recurrence survival and that presence of symptoms may be considered a marker of biologic tumor aggressiveness, which is an important determinant of survival at the time of recurrence diagnosis during follow-up for gastric cancer.

A recent systematic review by Cardoso et al. reviewed five studies enrolling a total of 810 patients and assessing outcomes of follow-up after gastrectomy for gastric cancer [16].

This review did not find any evidence suggesting that postoperative surveillance has any survival benefit; it has been also stressed that no such study has ever addressed quality-of-life issues. Major limitations in current literature were the study design and a lead-time bias in which the observed prolonged survival is due to earlier detection of recurrence, rather than to an effect on disease outcome.

International Guidelines and High-Volume Center Recommendations

The lack of evidence of follow-up is revealed by the fact that the most leading scientific societies and cooperative groups propose different schedules and that many centers apply a follow-up program dictated by past common practices in their medical center. Guidelines are generally supposed to be founded on strong evidence (therefore valid and unbiased) but to date they are based on low-level evidence or no evidence at all (Table 19.2).

Table 19.2

International guidelines recommendations

Society	Guidelines for follow-up
ASCO (American Society of Clinical Oncology)	No guidelines
JGCA (Japanese Gastric Cancer Association)	No guidelines
SSO (The Society of Surgical Oncology)	No guidelines
CCO (Cancer Care Ontario)	No guidelines
NICE (National Institute for Clinical Excellence)	No guidelines
CC (Cochrane Collaboration)	No guidelines
SSAT (Society for the Surgery of the Alimentary Tract)	No guidelines
AUGIS (Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland), BSG (British Society of Gastroenterology), BASO (British Association of Surgical Oncology)	No guidelines
NCCN (National Comprehensive Cancer Network)	Visit every 3–6 months for 1–2 years, every 6–12 months for 3–5 years and annually thereafter. Exams only if clinically indicated
ESMO (European Society for Medical Oncology), ESSO (European Society of Surgical Oncology), ESTRO (European Society of Radiotherapy and Oncology)	No guidelines. Follow-up should be performed in the identification of patients for second-line chemotherapy and in clinical trials.
GIRCG (Italian Research Group for Gastric Cancer)	Mild (risk < 10 %): tumor markers and US every 6 months, EGDS and X-ray annually, CT scan if clinically indicated or increased level of markers. Moderate (risk 10–50 %): tumor markers every 3 months, US every 6 months, EGDS and CT scan annually. Intensive (risk > 50 %): tumor markers every 3 months, CT scan every 6 months, EGDS annually. After the first 5 years visit annually and exams if clinically indicated

The American Society of Clinical Oncology (www.asco.org), the Society of Surgical Oncology (www.surgoncol.org), the Cancer Care Ontario (www.cancercare.on.ca), the National Institute for Clinical Excellence (www.nice.org.uk), the Cochrane Collaboration (www.cochrane.org), and the Society for the Surgery of the Alimentary Tract (www.ssat.com) do not provide formal guidelines or recommendations for follow-up after gastrectomy for cancer. Similarly, the Japanese Gastric Cancer Association (JGCA) guidelines offer no guidelines on follow-up [17].

The National Cancer Comprehensive Network (NCCN) guidelines include for all patients a complete history and physical examination every 3–6 months for 1–2 years, every 6–12 months for 3–5 years and annually thereafter. Other investigation should be done if clinically indicated. Patients who have undergone surgical resection should be monitored and treated as indicated for vitamin B₁₂ and iron deficiency [2].

The European Society of Medical Oncology (ESMO), the European Society of Surgical Oncology (ESSO), and the European Society of Radiotherapy and Oncology (ESTRO) guidelines state that regular follow-up may allow treatment of symptoms, psychological support, and early detection of recurrence, though there is no evidence that it improves survival outcomes. Follow-up has a role in the identification of patients for second-line chemotherapy and in clinical trials to detect symptoms of disease progression before significant clinical deterioration. Laboratory and imaging studies should be carried out when recurrence is suspected or when further chemo- or radiotherapy is indicated [1].

The Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS), the British Society of Gastroenterology (BSG), and the British Association of Surgical Oncology ( BASO) agree that regular review may identify early recurrence but there is no evidence for specific investigations nor that follow-up can affect overall survival. Endoscopy, cross-sectional imaging, and tumor markers have all been evaluated, but lack specificity or sensitivity [18].

The Italian Research Group for Gastric Cancer ( GIRCG) has proposed three different follow-up schedules (mild, moderate, or intensive) after gastrectomy for cancer in relation with a risk score calculated for each individual patient. A logistic regression model is used for the computation of the score; the coefficient Z is calculated as Z = −3.888–0.339 (middle third) + 0.917 (upper third) + 6.266 (diffuse location) + 0.027 (age) + 1.075 (pT2) + 2.013 (pT3-T4) + 1.668 (pN1) + 3.056 (pN2) + 4.971 (pN3) – 0.848 (D2–D3 dissection). The value of parametric variables was 0 (negative) or 1 (positive), whereas age was considered as a continuous variable. For each patient, the value of the coefficient Z obtained was included in the formula: ( e ^Z/1 + e ^Z) × 100 which gives risk values ranging from 0 to 100 % [19].

For patients with mild risk (< 10 % or patients over 80) they propose ultrasound of the abdomen and tumor marker assay every 6 months, endoscopy and chest X-ray annually, CT scan in case of clinical suspicion or increased level of tumor markers. For patients with moderate risk (between 10 and 50 %): tumor markers are investigated every 3 months, abdominal ultrasound after 6 months, 18 months, 30 months, and CT scan and endoscopy annually. For patients with high risk (> 50 %): tumor markers every 3 months, CT scan every 6 months, endoscopy annually.

After 5 years annual clinical monitoring, other exams if clinically indicated, any screening for second cancer (occult blood test, mammography, PSA, etc…)

To be noted that in international guidelines no nutritional or quality-of-life issues evaluation is considered.

By means of answering a questionnaire, a selected group of world-renowned experts in the field of surgical oncology were contacted via e-mail. The main portion of the survey focused on follow-up schedules and methodologies. Most questions were yes/no or multiple choice, with several text boxes included allowing for comments from participants to provide additional information or clarification.

All respondents reported having a strategy for surveillance after surgery for gastric cancer, but there was variance in strategy.

First of all we asked about the main reason for follow-up. For almost all respondents (4/6) the primary aim of the follow-up schedule is the evaluation of complications associated with surgery and quality-of-life issues and most of them perform nutritional assessment at visits. In one institution (University Hospital of Lille, France) the primary aim is the early detection of recurrence whereas in other institutions (Jagiellonian University, Krakow, Poland) it is the collection of outcome data for treatment evaluation and/or research purposes.

In 4/6 of responders follow-up schedule is carried out by a multidisciplinary team (surgeons with medical oncologists). In two institutions the follow-up is performed by the surgical team.

No significant differences were reported in terms of follow-up frequency for different disease stages. On average, advanced gastric cancer patients are followed-up every 3 months in the first year postoperatively, as opposed to follow-up every 6 months for early gastric cancer during the first year postoperatively. From the second to fourth postoperative year, the patients were usually seen every 6 months. In all cases follow-up ends at 5 years after surgery.

Table 19.3 summarizes the follow-up schedules as reported by respondents. Almost all respondents considered CT scan as mandatory for detection of all type of recurrence and PET scan as optional study.

Table 19.3

Follow-up schedules

Institution	Months after resection
	3	6	9	12	15	18	21	24	30	36	42	48	54	60
Memorial Sloan-Kettering Cancer Center, New York, USA	H&P exam	H&P exam, chest and abdominal CT, endoscopy, B₁₂		H&P exam, abdominal CT, endoscopy, B₁₂		H&P exam, abdominal CT, endoscopy		H&P exam, abdominal CT, endoscopy, B₁₂		H&P exam, abdominal CT, endoscopy, B₁₂		H&P exam, abdominal CT, endoscopy, B₁₂		H&P exam, abdominal CT, endoscopy, B₁₂
University Hospital of Lille, France	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, upper-GI x-ray	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, PET (optional)		H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, endoscopy PET (optional)		H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, PET (optional)		H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, PET (optional)	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, PET (optional)	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, endoscopy PET (optional)	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, PET (optional)	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, PET (optional)	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, PET (optional)	H&P exam, lab tests, chest and abdominal CT, CEA, CA 19.9, B₁₂, endoscopy PET (optional)
Jagiellonian University, Krakow, Poland	Liver US, chest x-ray, endoscopy	Liver US, chest x-ray, endoscopy	Liver US, chest x-ray, endoscopy	Liver US, chest x-ray, endoscopy				Liver US, chest x-ray, endoscopy		Liver US, chest x-ray, endoscopy		Liver US, chest x-ray, endoscopy		Liver US, chest x-ray, endoscopy
Odette Cancer Research, Sunnybrook Research Institute, Toronto, Canada	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron		H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron, endoscopy		H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron		H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron, endoscopy	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron	H&P exam, lab tests, abdominal CT, CA 19.9, B₁₂, iron, endoscopy
Leiden University Medical Center, the Netherlands	H&P exam,	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam	H&P exam
Städtisches Klinikum Solingen, Germany	No Schedule

H&P exam history and physical examination, CT computed tomography, US ultrasonography

One respondent left the question blank because he did not have a systematic follow-up schedule and performs advanced imaging and/or endoscopy during follow-up when symptoms arise or when there is clinical suspicion of recurrence.

Rationale for Follow-Up

Surveillance after surgery in gastric cancer includes three main purposes: detecting local or distant recurrences and or metachronous cancers in the remnant stomach; detecting long-term or late effects of surgical treatment; collection of outcome data to evaluate effectiveness of treatments and for research purpose.

Recurrence Patterns

The recurrence patterns of gastric cancer are classified as loco-regional, peritoneal, and hematogenous. Loco-regional recurrence is defined as cancer recurrence at the resection margin, within the lymph nodes (including regional, retro-pancreatic, retro-crural, and para-aortic nodes), or in the operation bed within the region of the resection (below the diaphragm and liver and above the pancreas and abdominal wound). In addition, the resection margin is divided into the proximal margin (including the lower third of the esophagus, remnant stomach, and gastrointestinal anastomosis) and the distal margin (duodenal stump). Peritoneal recurrence is defined as cancer recurrence in the abdominal cavity because of intraperitoneal distribution, including visceral metastasis and rectal shelf, peri-choledochal, and periureteral infiltration. Hematogenous recurrence has been defined as any metastatic lesion detected in distant organs [20, 21].

Timing of recurrence has been investigated by many authors and data are not uniform as reported. More than 90 % of patients relapse within 5 years after surgery, and 70 % relapse within 2–3 years [6, 7].

In early gastric cancer the rate of recurrence after gastrectomy is reported to vary from 1.3 to 12.2 %. Median time to recurrence is 16 months and hematogenous spread is probably the most common pattern of recurrence [22].

Many investigators have analyzed recurrence patterns, but the data have shown variable incidences of these patterns. This disagreement was attributed to differences in patient population, stage of the disease at the time of diagnosis, surgical treatment, and the mode and timing of recurrence detection. From literature review, in the West the pattern of recurrence tends to be local, whereas in the East the pattern is different, with more peritoneal and hematogenous recurrences [9].

Occasionally, after partial gastrectomy a second primary tumor can arise in the remnant stomach. Much of the literature relates to gastrectomies for peptic ulcer disease, which estimated a risk that is not so different from the general population [23, 24].

As regards gastric cancer, second primaries are more common after surgery for early gastric cancer because these patients have a good prognosis after curative surgery. The reported incidence of metachronous gastric cancer after partial gastrectomy for early gastric cancer is 0.6–3 % [25].

In clinical oncology practice, the detection of the recurrence in the early stage may provide an opportunity for effective treatment when patients are still fit enough to receive surgical or medical therapy.

Patients with gastric cancer recurrence are more often managed similarly to non-resectable patients because early detection of recurrence is quite difficult and peritoneal recurrence, one of the main patterns of recurrence, is usually diagnosed at an advanced stage.

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