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Blog aimed at residents in surgery
 URL :  www.surgical-oncology.net             e mail surgoncnet@gmail.com
Recurrence following curative resection for GC.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.



July 2002.     Review Article.    To the updating


Recurrence is the main cause of treatment failure after curative gastrectomy for patients with gastric cancer. Frequency of recurrence, time to first recurrent event, and survival are strongly dependent on the stage of disease at the time of surgery and extent of surgical resection.
According to a recently described concept, it is estimated that approximately 30% of all patients who are suitable for potential curative surgery suffer from positive nodes around celiac axis (level II: stations 7 to 12). This fact clearly indicates both the necessity of D2 resection for an R0 resection and the insufficiency of D1 resection that results in residual disease and the fatal outcome in most, and perhaps all, patients with level II disease.
In fact because adjuvant chemotherapy or radiotherapy has been of little or no efficacy, the best way to improve outcome is to increase the rate of curative resection by detecting tumors early and to perform appropriate surgery to reduce the rate of recurrence. Indeed, using this strategy in Japan has increased the rates of R0 resection to about 80% and overall survival to between 50% and 60%. The rate of curative surgery in the West is still small ranging between 30% and 70%.
Classification according to the International Union against Cancer ( UICC ) accurately predicts overall survival but is unable to provide information in terms of overall recurrence, time-specific recurrence-appearance, and site-specific first recurrence. These valuable data are the basis for the development of causative recurrence-oriented and site-specific target therapies.

Recent reports from the West and Japan consistently indicate several critical key points in the mode of recurrence after curative resection.
First, pathological serosa state is the determinant and independent factor for prediction of site-specific recurrence because patients with serosa-positive cancer are at high-risk for peritoneal spread, whereas patients with serosa-negative cancers are at risk for hematogenous recurrence.
Second, the risk for recurrence after standard gastrectomy with extended ( D2 ) lymph node dissection is strongly determined by the tumor stage; it is low risk for both serosa and node-negative cancer ( first group;about 10%), moderate among those with either serosa or node-positive cancer (second group;53% ) and very high among those with both serosa and node-positive cancer ( third group; 83% ).
A pathological serosa and node-based classification is very simple and predicts accurately site-specific recurrence risks. In fact there is a strong correlation between the serosa state and peritoneal recurrences. This is the most common type of treatment failure among serosa-positive patients, but it rarely occurs among serosa-negative patients for whom a hematognous recurence is the most frequent (1, 2, 3, 4 ).

Why and how can it be explained that most ( 70% ) patients develop a secondary tumor ( recurrence ) early ( within 2 years ) after complete tumor resection?
Circulating tumor cells have been identified in peripheral blood even at earlier tumor stages by current molecular techniques ( reverse transcriptase-polymerase chain reaction RT-PCR ) This fact strongly supports the theory that clinically occult tumor cells released from origin tumor before and during surgical maneuvers, enter the blood circulation, migrate, and form metastatic tumors to distant target organs. Previous experimental studies have shown that changes in tumor cell kinetics occur within 24 hours of the removal of the origin tumor and a week later a measurable tumor size can be observed. Therefore, these cells proliferate and invade surrounding tissues in the critical early postsurgical period. They form secondary tumors ( recurrence ) in the target organs ( peritoneum, liver ) and become clinically detectable early in the follow-up. The recent controversy over prognostic significance of circulating tumor cells underlines the complexity of the metastatic process ( 1, 5, 6, 7 ).

Shiraishi et al affirm that there are few studies regarding the predictors of early and late recurrence after gastrectomy for gastric carcinoma, and it is unknown whether prognostic factors can be applied to the timing of recurrence.
The results of their study confirmed that deaths from recurrent gastric carcinoma mainly occurred within 2 years after gastrectomy ( 75% ), and death from recurrence occurring > 5 years after gastrectomy was rare ( 6% ).
Tumor size, lymphatic invasion, level of lymph node metastasis, stage of disease, and extent of lymph node dissection were the factors associated most significantly with the timing of recurrence after gastrectomy for gastric carcinoma. Of these parameters, the stage of disease and level of lymph node metastasis were the most important predictors. Patients with more advanced stage of disease ( Stage III or Stage IV ) or those with extended lymph node metastasis ( N2, N3 ) frequently died of recurrence within 2 years after gastrectomy ( 8 ).
The depth of wall invasion and level of lymph node metastasis are reported to be the most important prognostic parameters in gastric carcinoma. The Shiraishi's et al. study demonstrated that the depth of wall invasion was a predictor of recurrence but not an indicator of the timing of recurrent death after gastrectomy. Because the majority of tumors had invaded down to the subserosa or serosa in both the early recurrence group ( 92% ) and the late recurrence group ( 80% ), the depth of wall invasion was not significantly different between the 2 groups. The results were in agreement with the findings of a previous study by Adachi et al. that demonstrated that the depth of wall invasion was not a predictor of the timing of recurrent death after curative resection of gastric carcinoma. They would like to emphasize that although the depth of wall invasion is an essential and useful prognostic indicator, it does not necessarily determine the survival period for patients with recurrence ( 8, 10 ).
Otsuji et al suggest that depth of cancer invasion, regional lymph node metastasis, and tumor size were independently correlated with tumor recurrence after curative gastrectomy. But only the depth of cancer invasion independently correlated with the timing of death due to tumor recurrence. It might be possible to predict the timing of death from tumor recurrence by the depth of cancer invasion into the gastric wall. Patients were divided into two groups according to the timing of death: those who died of tumor recurrence less than 2 years after surgery and those who died more than 2 years after surgery ( 9 ).

Yoo et al demonstrated that intra-abdominal spread of the tumour ( locoregional, liver or peritoneal recurrence ) was the major feature of both single and multicomponent recurrence. Extra-abdominal, haematogenous or lymphatic spread without intra-abdominal metastases occurred rarely.
Moreover the incidence of locoregional recurrence was the lowest among the recurrence patterns. The site most prone to locoregional recurrence was the anastomosis or stump ( 157 per cent ) following distal subtotal ( n = 70 ) or total ( n = 10 ) gastrectomy; the next was the lymph nodes ( 134 per cent ), mostly at the mesenteric or para-aortic nodes rather than the regional lymph nodes. This may be due to routine D2 or D3 lymph node dissection. It is therefore possible that extended lymphadenectomy with intraoperative frozen-section examination of the resection margins may further decrease the incidence of locoregional recurrence in gastric cancer after curative resection ( 11 ).
Schwarz et al confirm that radical gastrectomy with extended lymphadenectomy may reduce loco regional recurrences, possibly affecting adjuvant treatment strategies. In fact a recent Intergroup trial demonstrated a significant survival advantage of postgastrectomy chemoradiation in gastric cancer patients, primarily because of a reduction of a relative locoregional recurrence (LRR) rate exceeding 70% in control patients. In summary, the postgastrectomy recurrences, on the basis of clinical/radiological follow-up, rarely include local or regional sites, despite an R1 resection frequency of 18%. Most failures occur systemically or peritoneally and can be predicted by simple pathologic staging criteria, namely, a large number of metastatic lymph nodes and serosal invasion by the primary tumor. These results seem similar to Asian experiences that apply the routine use of ELND at the time of gastrectomy; they seem, however, to stand in sharp contrast to those of the US Intergroup trial. A more extensive retroperitoneal dissection may well decrease the locoregional recurrence risk, thus obviating the need for postoperative radiation treatment. Systemic or intraperitoneal investigational chemotherapy approaches, dependent on the pathologic risk determination, may represent more appropriate and potentially more effective ways of postoperative adjuvant treatment for patients at high risk for diffuse relapses. In fact from 40% to 50% of patients with subserosal or serosal tumors are identified to have free intraperitoneal tumor cells. It is well understood that positive peritoneal cytology at the time of gastrectomy will lead to peritoneal recurrence in virtually all patients (12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 ).
Also Yoo et al riaffirm that a review of clinical trials suggests that no single method of treatment can efficiently address all variants of gastric cancer spread, and that no improvement in the results obtained in recurrence of gastric cancer can be expected. At present, therefore, prevention or reduction of the frequency of recurrence is probably more important than the early detection of recurrence ( 11 ).
Wayman et al note that type I and Type II adenocarcinoma of the oesophago-gastric junction have a predominantly early, haematogenous pattern of recurrence. There is a need to better identify the group of patients with small metastases at the time of diagnosis who are destined to develop recurrent disease in order that they may be spared surgery and those with micro metastases in order that they can be offered multi-modality therapy including early post operative or neo-adjuvant chemotherapy. The more radical nature of the surgery performed with perhaps greater attention to lymphadenectomy may account for the improved local disease control. The radical two-field lymphadenectomy appears to give good local disease control ( Dresner and Griffin, 2001 ) and the total gastrectomy with D1 or D2 lymphadenectomy practised for the junctional cancers may also confer better local disease control than the more traditional distal and subtotal gastric resections. There are some conflicting reports suggesting that lymphadenectomy confers no survival benefit ( Hulscher et al, 2001 ) however such studies are either too small with insufficient statistical power, not stratified by tumour stage or lack standardisation of technique (25, 26, 27, 28 ).

Kim et al suggest that the risk of ovarian metastasis after curative gastrectomy is strongly associated with the number of metastatic lymph nodes ( >6 ) and patient age ( <50 years ). Prospective studies are needed to evaluate further the role of prophylactic oophorectomy in young female gastric carcinoma patients who have multiple regional lymph nodes with metastases ( 29 ).

Maehara et al conclude that the clinicopathological characteristics of gastric cancer determine the type of recurrence ( peritoneal and local recurrences were related to infiltrative growth, in contrast to haematogenous and lymphatic recurrences). And there were no statistical differences in survival time among each type of recurrence and survival was not related to the number of sites of recurrence. Survival did not depend on factors of sex, age, tumour location, tumour size, depth of invasion, tissue differentiation, histological growth pattern, lymphatic and vascular involvement, lymph node metastasis and extent of lymph node dissection ( 30 ).

References

1) Dimitrios H. Roukos, and Aggelos M. Kappas. Limitations in Controlling Risk for Recurrence After Curative Surgery for Advanced Gastric Cancer Are Now Well-Explained by Molecular-Based Mechanisms. Annals of Surgical Oncology 8:620-621 (2001).

2) DH Roukos, M Lorenz, K Karakostas, P Paraschou, C Batsis, and AM Kappas. Pathological serosa and node-based classification accurately predicts gastric cancer recurrence risk and outcome, and determines potential and limitation of a Japanese-style estensive surgery for Western patients: a prospective with quality control 10-year follow-up study. British Journal Cancer, 2001, 84 ( 12 ), 1602-1609.

3) Roukos DH. Extended (D2) lymph node dissection for gastric cancer: do patients benefit? Ann Surg Oncol 2000; 7: 253-5.Editorial.

4) Roukos DH. Current status and future perspectives in gastric cancer management. Cancer Treat Rev 2000; 26: 243-55.

5) Zippelius A, Pantel K. RT-PCR-based detection of occult disseminated tumor cells in peripheral blood and bone marrow of patients with solid tumors. An overview. Ann N Y Acad Sci 2000; 996: 110-23.

6) Miyazono F, Natsugoe S, Takao S, et al. Surgical maneuvers enhance molecular detection of circulating tumor cells during gastric cancer surgery. Ann Surg 2001; 233: 189-94.

7) Gunduz N, Fisher B, Saffer EA. Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res 1979; 39: 3861-5.

8) Shiraishi N, Inomata M, Osawa N, Yasuda K, Adachi Y, Kitano S. Early and late recurrence after gastrectomy for gastric carcinoma. Univariate and multivariate analyses. Cancer 2000; 89: 255-61.

9) Eigo Otsuji, Shinichiro Kobayashi, Kazuma Okamoto, Akeo Hagiwara, and Hisakazu Yamagishi. Is Timing of Death from Tumor Recurrence Predictable after Curative Resection for Gastric Cancer? 2001, volume 25, number 11, pag 1373-1376.

10) Adachi Y, Oshiro T, Mori M, Maehara Y, Sugimachi K. Prediction of early and late recurrence after curative resection for gastric carcinoma. Cancer 1996; 77: 2445-8

11) C. H. Yoo, S. H. Noh, D. W. Shin, S. H. Choi and J. S. Min. Recurrence following curative resection for gastric carcinoma. British Journal of Surgery, 2000, 87, 236-242.

12) Roderich E. Schwarz, and Kathryn Zagala-Nevarez. Recurrence Patterns After Radical Gastrectomy for Gastric Cancer: Prognostic Factors and Implications for Postoperative Adjuvant Therapy. Annals of Surgical Oncology 9:394-400 (2002).

13) Hayes N, Ng EK, Raimes SA, et al. Total gastrectomy with extended lymphadenectomy for "curable" stomach cancer: experience in a non-Japanese Asian center. J Am Coll Surg 1999; 188: 27-32.

14) Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725-30.

15) Schwarz RE, Karpeh MS, Brennan MF. Surgical management of gastric cancer: the Western experience.In: Daly JM, Hennessy TPJ, Reynolds JV, eds. Management of Upper Gastrointestinal Cancer. London: WB Saunders, 1999: 83-106.

16) Ribeiro U, Gama-Rodrigues JJ, Safatle-Ribeiro AV, et al. Prognostic significance of intraperitoneal free cancer cells obtained by laparoscopic peritoneal lavage in patients with gastric cancer. J Gastrointest Surg 1998; 2: 244-9.

17) Mori N, Oka M, Hazama S, et al. Detection of telomerase activity in peritoneal lavage fluid from patients with gastric cancer using immunomagnetic beads. Br J Cancer 2000; 83: 1026-32.

18) Averbach AM, Jacquet P. Strategies to decrease the incidence of intra-abdominal recurrence in resectable gastric cancer. Br J Surg 1996; 83: 726-33.

19) Burke EC, Karpeh M Jr, Conlon KC, Brennan MF. Peritoneal lavage cytology in gastric cancer: an independent predictor of outcome. Ann Surg Oncol 1998; 5: 411-5.

20) Hirose K, Katayama K, Iida A, et al. Efficacy of continuous hyperthermic peritoneal perfusion for the prophylaxis and treatment of peritoneal metastasis of advanced gastric cancer: evaluation by multivariate regression analysis. Oncology 1999; 57: 106-14.

21) Neri B, Cini G, Andreoli F, et al. Randomized trial of adjuvant chemotherapy versus control after curative resection for gastric cancer: 5-year follow-up. Br J Cancer 2001; 84: 878-80.

22) Chan WH, Wong WK, Khin LW, Chan HS, Soo KC. Significance of a positive oesophageal margin in stomach cancer. Aust N Z J Surg 2000; 70: 700-3.

23) Kim SH, Karpeh MS, Klimstra DS, Leung D, Brennan MF. Effect of microscopic resection line disease on gastric cancer survival. J Gastrointest Surg 1999; 3: 24-33.

24) Zhang ZX, Gu XZ, Yin WB, Huang GJ, Zhang DW, Zhang RG. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)-report on 370 patients. Int J Radiat Oncol Biol Phys 1998; 42: 929-34.

25) J Wayman, M K Bennett, S A Raimes and S M Griffin. The pattern of recurrence of adenocarcinoma of the oesophago-gastric junction. British Journal of Cancer (2002) 86, 1223 1229.

26) Dresner SM, Griffin SM. (2001). Pattern of recurrence following radical oesophagectomy with two field lymphadenectomy. Br J Surg, 87: 1426-1433.

27) Hulscher JBF, van Sandick JW, de Boer AG, Wijnhoven BPL, Tijssen JGP, Fockens P, Stalmeier PFM, ten Kate FJW, van Dekken H, Obertop H, Tilanus HW, van Lanschot JJB. (2001). No survival benefit of extended transthoracic resection over limited transhiatal resection for adenocarcinoma of the mid-/distal esophagus and gastric cardia: results of a randomised study. Gut, 49: (suppl III) 1.

28) Wayman J, Dresner SM, Raimes SA, Griffin SM. (1999). Transhiatal approach to total gastrectomy for adenocarcinoma of the gastric cardia. Br J Surg, 86: 536-540.

29) Noe K. Kim, Hark K. Kim, Byung J. Park, Min S. Kim, Yong I. Kim, Dae S. Heo, Yung-J. Bang. Risk factors for ovarian metastasis following curative resection of gastric adenocarcinoma. Cancer 1999;85:1490-9.

30) Y. Maehara, S. Hasuda, T. Koga, E. Tokunaga, Y. Kakeji and K. Sugimachi. Postoperative outcome and sites of recurrence in patients following curative resection of gastric cancer. British Journal of Surgery, 2000, 87, 353-357.



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