Original article: role of adjuvant chemotherapy in a perioperative chemotherapy regimen for gastric cancer

Gastric cancer (GC) is the second most common cancer of the gastrointestinal tract, accounting for 6.8 % of all cancer diagnoses and 8.8 % of all cancer-related deaths. In 2012, there were 951,000 new cases of GC and 723,000 deaths due to GC worldwide [1‐5]. In Japan and Korea the survival rate of patients with GC has increased over the past decade which may partially result from increased detection rates of early stage cancer due to screening programs in this area. Nevertheless, the overall 5-year survival rate in the western world remains low with apparently 30 %, less than 50 % for stage II cancer and lower than 20 % for stage III cancer [6, 7].

Surgical resection is the only potentially curative treatment for GC. To improve the poor outcome rate many studies have examined various aspects of surgical techniques, including extended lymph node dissection, the addition of perioperative or intraoperative radiotherapy and the effect of neoadjuvant (preCTx) as well as adjuvant (postCTx) chemotherapy and radiochemotherapy [8‐19]. Conflicting results have been published for adjuvant chemotherapy. Compared to surgery alone, a survival advantage has been demonstrated in patients with adjuvant chemotherapy in Asian trials, while western studies have failed to reproduce this survival benefit [8‐16]. On the other hand, in European trials, it has been shown that the application of neoadjuvant chemotherapy lead to significantly smaller tumors, less lymph node metastases, improved curative resection and improved overall and progression free survival compared to surgery alone [17‐19]. Even so, this trails had several limitations, such as the inclusion of early stage GC, differences in lymphadenectomy and a low adjuvant CTx-rate.

Currently, the use of perioperative CTx in addition to radical surgical resection (D2-gastrectomy) is the accepted standard therapy for advanced gastric cancer, as laid down by experts and in evidence-based guidelines [23]. These perioperative CTx protocols consist of preCTx as well as postCTx. However, the role of the postoperative component of this strategy (postCTx) is not entirely clear yet.

The evidence, on which perioperative CTx has been established as standard therapy for the treatment of locally advanced gastric cancer, still underlies controversial debate.

It is well known that only a subset of patients receive postCTx due to a variety of reasons. In our study 45 % refused the CTx and 55 % did not receive post CTx due to various medical reasons.

In Europe, perioperative chemotherapy for high-risk gastric cancer is the standard therapy for high-risk gastric cancer based primarily on the results of three large, randomized trials: the UK-MAGIC Trial by Cunningham [17], the French FNCLCC/FFCD phase III trial [18] and the European Organisation for Research and Treatment of Cancer Randomized Trial 40954 [19]. In the MAGIC trial patients undergoing perioperative chemotherapy with ECF (epirubicin, cisplatin and fluorouracil) had a significant higher five-year survival rate (36 % compared to 23 % without chemotherapy) without showing differences in the postoperative complication rate. Similarly, the French FNCLCC/FFCD phase III trial showed a significant improved 5-year overall survival rate of 38 % compared to 24 % for patients receiving perioperative chemotherapy with cisplatin and fluoruracil. So far the point in time of additional chemotherapy (pre- / peri- / postoperative) has not been addressed sufficiently as starting (50-66 %) and completion (23-42 %) rates of postoperative chemotherapy is low. Although the results from the MAGIC trial constitute the basis for our current recommendations of perioperative CTx for gastric cancer, they have been severely criticized for several reasons [17]. Points of criticism have been, for example the low quality of surgery. Only a minority of patients received radical D2-gastrectomy, which is regarded as the standard for adequate radical resection. Furthermore, the trail included locally limited tumors (T1/ T2 categories), which only require radical surgery, but no CTx. With regard to this paper’s topic, the most important point of criticism of the MAGIC trail is, that only a minority of patients (<50 %) received postCTx, thereby violating the protocol of perioperative CTx. In conclusion, the impact of postoperative chemotherapy in patients with completed preoperative chemotherapy remains unclear.

In this retrospective analysis of a highly selected population of patients with completed neoadjuvant chemotherapy and curative surgery we found significant higher survival rates in patients without postoperative chemotherapy in comparison to those, who completed the perioperative therapy. This is, in several ways, surprising.

The exact reasons for the worse outcome in the group receiving postCTx are not known. It can be speculated that there is a negative selection bias for patients recieving postCTx, but this seems to be unlikely as there are no differences in the pathological UICC stage. Also, the anatomical distribution is different with more proximal located tumors in the non-postCTX group, without showing a statistical significant difference. Overall, a selection bias for the administration of postoperative chemotherapy cannot be ruled out in this analysis. Especially not addressed factors, such as the response rate to preCTX, could influence the results.

In general, perioperative chemotherapy has several advantages compared to postoperative chemotherapy. It has a higher tolerability prior to a potentially debilitating surgical procedure. Preoperative chemotherapy could lead to down staging of the tumor and improved R0 resection rates. There is an early systemic treatment of micro metastatic disease and a detection of tumors with a worse biological phenotype which lead to progression under chemotherapy. Taking in account the comparable postoperative complication rate with or without postCTx and our discussed data, it can be argued that preoperative chemotherapy should be the only admitted chemotherapy and should perhaps be extended [25].

An often-discussed potential disadvantage of preCTx is the delay of a potentially curative surgery due to neoadjuvant chemotherapy toxicity. However several points argue against this: A) only local advanced cancers should be treated with neoadjuvant chemotherapy. Patients with small tumors with a good long-term survival undergo curative surgery directly rather than receiving preoperative chemotherapy [23]. B) Tumors qualifing for neoadjuvant treatment have a very bad prognosis with surgery alone and only the administration of any kind of chemotherapy can enhance the prognosis. C) Both the MAGIC and French trial showed that 92–96 % of patients who received preoperative chemotherapy underwent surgery.

Our study has several limitations that will be addressed in the following. Firstly, since this is an uncontrolled, retrospective study, patient selection bias cannot be ruled out, as clinicians are more likely to recommend post operative therapy to younger, healthier patients, who would be expected to tolerate chemotherapy better than older patients of poorer performance status. In our cohort, patients with adjuvant chemotherapy were younger and thereby may have had worse tumor biology. However, ASA score, co-morbidities and UICC stage did not differ between the postCTx- and non-postCTX-group. Secondly, patients who died during the first 60 days postoperative were included as well. They, by history, cannot undergo adjuvant chemotherapy thereby reducing the survival rate in the “no adjuvant therapy” group. But when analyzing the survival rate without these patients, the survival benefit lies in the “no adjuvant therapy” group. Thirdly, the chemotherapy protocols have changed over the study period and cannot be compared directly to one another. Fourthly, the reason for not receiving post-CTX is not associated with acute postoperative complication rate which has so far been supposed as negative predictive factor for survival. Another independent factor for the application of adjuvant CTx is the performance and nutrition status at the 3 month check-up. This has not been archived in our system and thus cannot be evaluated.

The results presented, while speculative, question the value of post-CTx in gastric cancer patients treated with preoperative chemotherapy and curative surgery. It is worthwhile to consider prospective, randomized trials of perioperative CTx versus a purely neoadjuvant approach.