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Oesophagogastric cancer: exploring the way to an individual approach
Stiekema, J.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Stiekema, J. (2015). Oesophagogastric cancer: exploring the way to an individual approach.
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The care for oesophagogastric cancer patients has undergone significant changes and improvements over the last decade. In the Netherlands, the surgical treatment of oesophageal cancer has been centralized since 2006 and post-operative mortality rates have dropped from approximately 12% before 2000 to 4% in 2013.1-3 The increasing use
of preoperative chemoradiotherapy has led to radical (R0) resection rates exceeding 90%, compared to R0 resection rates of 70% in historical surgical series. In gastric cancer, surgical treatment has been centralized since 2012. The introduction of several multimodality approaches has been shown to improve survival. It has become clear that not every patient has the same benefit from a given treatment and adequate patient selection is of the utmost importance. An individualized therapeutic approach can contribute to the improvement of care and will become more complex in a multimodality treatment environment.
Surgical treatment
The centralization of oesophageal cancer surgery has contributed to an improvement in short-term outcome in the Netherlands.4 In contrast, gastric cancer surgery was still
performed mainly in low-volume centres and the post-operative mortality rate remains high compared to other European countries.5 This has led to the centralization of
gastric cancer surgery in 2012, with a minimum annual volume of 10 gastrectomies per centre, which was further increased to 20 procedures per centre in 2013. In addition, a clinical audit of surgically treated patients with oesophagogastric cancer has started in 2011.2 The majority of studies on volume-outcome relations in oesophageal cancer
surgery include patient populations treated in time periods before the introduction of a multimodality approach as a standard of care. The use of different modalities in the treatment of oesophagogastric cancer has made the care for these patients more complex and it is likely that this complexity will only increase in the future. Combined with the notion that improving the quality of care in the treatment of oesophagogastric cancer is a multidisciplinary team effort in which surgical technique is only one of the contributing factors, it is questionable whether volume-limits and clinical audits should remain limited to surgery.
Next to the improvement of surgical treatment, there are many other challenges in the treatment of gastric cancer. In the Netherlands, the prognosis of gastric cancer has not improved over the last decades.6 A large Italian patient series showed a similar trend,
despite the fact that more extensive lymph node dissections were performed in recent years without compromising post-operative mortality.7 One explanation of this trend in
survival is an epidemiological shift towards the diffuse histological subtype.8 Although
only limited data is available on the prognostic impact in a multimodality treatment setting, some retrospective studies and subgroup analyses from randomized trials suggest that diffuse type histology remains an independent adverse prognostic factor.9-12
The association with microscopically irradical (R1) resections and early peritoneal dissemination, calls for a differentiated diagnostic and therapeutic approach with a liberal use of diagnostic laparoscopy and extended surgical margins with routine
intra-operative frozen sections.13 The high rate of peritoneal recurrences in the studies
presented in this thesis has also initiated a prospective phase I/II trial in which the feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients with limited peritoneal carcinomatosis is investigated (PERISCOPE trial, the Netherlands Trial Registry number NTR4250).14
Patient selection
The introduction of successful preoperative treatment modalities has given rise to new questions regarding patient selection for surgical treatment. Given the extremely poor prognosis of patients with metastatic disease and the considerable morbidity, an oesophagectomy should only be performed in patients who might be cured or have a benefit in terms of improved long-term local control.15 Currently, PET/CT is advised at
some point in the preoperative staging of locally advanced oesophageal cancer.15,16 The
results from this thesis suggest that performing a PET/CT before and after CRT prevents some patients from undergoing futile surgery since early progression to disseminated disease is detected. Still, it is an expensive technique and a large, prospective side-by-side comparison including the newest generation CT-scanners and MRI for the detection of interval metastasis is warranted. Another unanswered question is whether PET/CT is able to assess the pathological response after the completion of CRT. Published results, including those presented in this thesis, are conflicting. In future prospective studies, an increased time period between the end of CRT and the response evaluation PET/CT might reduce the effects caused by radiation oesophagitis. Maybe this will indeed lead to reliable diagnostic parameters for response evaluation. Still, discriminating patients with a pathological complete response (pCR) from patients with just a few viable tumour cells left (near complete response) is virtually impossible. It should also be noted that some patients with a pCR at the primary tumour site still have viable lymph node metastasis. The real question might very well be whether avoiding the morbidity of oesophagectomy in patients with a pCR weights against decreased local control by refraining from surgery in patients with a near complete response.
For gastrointestinal stromal tumours (GIST), downsizing tumours with imatinib has greatly improved the prognosis of patients with large tumours or metastatic lesions. Through the resection of residual resistant disease, surgery can have a complementary role to the most successful targeted treatment in a solid tumour so far. The value of surgery in GISTs progressive during imatinib treatment seems limited, but this has to be confirmed in future prospective studies.
Multimodality treatment
After the results of the CROSS trial were presented, CRT has quickly been implemented as the preferred preoperative treatment of oesophageal cancer in the Netherlands.17
In gastric cancer, the results of the MAGIC trial have prompted the use of preoperative chemotherapy.18 Still, only 50% of surgically treated gastric cancer patients received
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in 2001, postoperative CRT has only been used sparsely.19 This striking difference in the
implementation of a multimodality treatment between oesophageal and gastric cancer might be a reflection of the absence of treatment guidelines for gastric cancer until 2009, the degree of centralization or differences in patient populations and co-morbidities. Currently, there is still much debate on the optimum multimodality approach in gastric cancer patients. The results of the CRITICS trial will hopefully shed more light on this issue, but these are still several years away.20
One problem in the surgical treatment of gastric cancer is the occurrence of a microscopically irradical (R1) resection. Despite the use of preoperative chemotherapy in 50% of surgically treated gastric cancer patients, the R1 resection rate in the Netherlands was still high at 10% in 2013.2 There are different opinions on the preferred strategy after
an R1 gastric cancer resection. Some advocate considering a re-resection in every patient, while others believe this has little added value in patients with advanced nodal disease, given the high risk of peritoneal and distant metastasis.21,22 Supported by the results as
described in chapter 8 and 9, adjuvant CRT is a good alternative for re-resection in these patients. So far, the value of surgical re-intervention after an R1 gastric cancer resection has only been evaluated in a retrospective, small, single centre patient cohort.23 There
was a small benefit of surgical re-intervention, but 5-year overall survival was less than in the studies presented in this thesis. Furthermore, due to the added morbidity of a re-resection, the possibility of completing any adjuvant treatment is also decreased. Patients who undergo an R1 resection are likely to have locally advanced, lymph node positive disease. These patients benefit most from adjuvant CRT.24 Still, R1 resections
are preferably prevented. The favourable results from the CROSS trial with respect to the R0 resection rate, give rise to the question whether CRT followed by surgery is also an attractive treatment sequence for gastric cancer patients. So far, the number of studies published on preoperative CRT in gastric cancer is limited. The preliminary results from the NARCIS study, in which CRT was administered to gastric cancer patients with non-metastatic, unresectable T4 disease, show that 72% of patients had undergone a radical R0 resection, which is a promising figure given the poor patient characteristics in this group.25
Genetic Profiling
The developments in microarray and next-generation sequencing technology have been one of the major advances in biomedical science in the last decade. The possibility to analyse not only tumour DNA and RNA, but also epigenetic factors such as DNA-methylation and microRNAs on a genome-wide scale have led to numerous new insights and are, albeit slowly, making its way into the clinic. Application of genetic profiling allows for the identification of tumour subtypes, enabling better treatment stratification and for the identification of aberrations that might serve as therapeutic targets. Treatment can be individualised by either a prognostic (good versus poor prognosis) or predictive (good versus poor therapeutic response) genetic signature. In oesophageal adenocarcinoma, this could implicate withholding preoperative CRT in patients who have a good prognosis
with surgery-only or are unlikely to respond. Ong et al. recently validated a 3-gene immunohistochemical prognostic signature, which was developed using (mRNA) gene expression profiling.26 Patients with stage II and III disease could be further stratified in
prognostic different subgroups, but unfortunately the survival rate in these subgroups did not justify any clinical decision regarding treatment. Perhaps a more attractive approach is the development of a prognostic genetic signature, identifying patients who have a poor prognosis despite CRT and surgery. These patients can then be considered for trials with alternative treatment regimes. The study described in chapter 12 of this thesis might lead to the first step towards such a genetic signature.
The development of a gene signature predictive for the response to CRT has also gained some attention.27,28 Although the first study in which it was suggested that gene
expression profiling could be used for predicting the pathological response to CRT was published in 2006, this has not led to a validated gene signature. Also in other solid cancer types, no validated genetic signatures of any kind exist which predict the response to CRT.29,30 One possible reason might be the technical difficulties associated with the
collection and work-up of pre-treatment biopsy samples, as presented in chapter 11 of this thesis. The most likely explanation however, might be that tumour characteristics leading to resistance to CRT are very complex and poorly reflected by gene expression profiles of tumours. In this case, the promising results from earlier studies are frequently the result from overtraining, leading to gene signatures that have a high predictive value in the datasets on which they are trained, but lose their predictive value in external validation cohorts.31,32 This validation step is preferably done in a large patient cohort
with well-documented clinical data. One of the greatest challenges in oesophagogastric cancer research will simply be the collection of a large number of pre-treatment tumour samples. Despite the increase in oesophageal cancer in recent years, it is still a relatively uncommon cancer type and only a nationwide or even European wide biobanking effort can facilitate the necessary tissue repository.
Next to prognostic and predictive profile development, genetic profiling can also be used to identify possible therapeutic targets. Currently, only trastuzumab has been shown to give a modest improvement in survival in HER2-positive gastric- and oesophagogastric junction adenocarcinoma.9 The results from recently published trials with anti-EGFR directed
therapies for oesophagogastric adenocacinoma are disappointing.33 These results are
especially disappointing since EGFR is one of the most commonly overexpressed known potentially therapeutic targets in oesophageal adenocarcinoma. This emphasizes the need to explore other candidate targets, but also to perform functional studies in which possible resistance mechanisms are evaluated. As an example, the results described in chapter 12 and other studies show that KRAS is amplified in approximately 20-25% of oesophageal adenocarcinomas. The consequences of KRAS amplification for EGFR directed therapy are not well investigated, but recent data suggest that this could lead to anti-EGFR resistance.34 Less straightforward resistance mechanisms can also occur.
In BRAF-mutated colon cancer cell lines, resistance against vemurafenib was shown to develop through feedback activation of EGFR, thereby supporting proliferation.35 The
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concurrent use of vemurafenib and an EGFR inhibitor was shown to work synergistically and is currently tested in a phase I trial in colon cancer patients. Another challenge is the notion that each individual target is only shared by a limited number of patients. This leads to a low accrual for any study with a targeted agent in oesophagogastric cancer patients, thereby endangering the completion of these trials. One way to overcome this obstacle is an approach in which cancer patients are not treated according the anatomic location of the primary tumour, but to their genetic profile. The increasing use of next-generation sequencing technology in research and in future clinical practice, could lead to a tumour geno- and phenotype driven therapeutic approach in the near future. In conclusion, the way to an individualized approach in oesophagogastric cancer treatment will be long and costly, but, with the use of continuously advancing technology and collaborations between clinical and fundamental scientists, it will be paved.
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