Chemoradiotherapy in Gastric Cancer Chances and Challenges. Anouk K. Trip

Transcription

1 Chemoradiotherapy in Gastric Cancer Chances and Challenges Anouk K. Trip

2 Chemoradiotherapy in gastric cancer - chances and challenges The work described in this thesis was conducted at the Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands. Financial support provided by: Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, the Netherlands. Cover, Lay-out and Printing: Gildeprint. ISBN: A.K. Trip.

3 VRIJE UNIVERSITEIT Chemoradiotherapy in Gastric Cancer Chances and Challenges ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op donderdag 13 oktober 2016 om uur in het auditorium van de universiteit, De Boelelaan 1105 door Anouk Kirsten Trip geboren te Leeuwarden

4 promotor: copromotoren: prof.dr. M. Verheij dr. E.P.M. Jansen dr. J.W. van Sandick

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7 Contents General introduction and outline of this thesis 9 Part I Multimodality treatment of gastric cancer Emerging issues in multimodality treatment of gastric cancer Recent trends and predictors of multimodality treatment for oesophageal, oesophagogastric junction, and gastric cancer: a Dutch cohort study 60 Part II Novel indications for chemoradiotherapy in gastric cancer The prognostic significance of an R1 resection in gastric cancer patients treated with adjuvant chemoradiotherapy 4. Does adjuvant chemoradiotherapy improve the prognosis of gastric cancer after an R1 resection? Results from a Dutch cohort study 5. Preoperative chemoradiotherapy in locally advanced gastric cancer, a phase I/II feasibility and efficacy study Part III Late toxicity of chemoradiotherapy in gastric cancer Intensity modulated radiation therapy limits nephrotoxicity after chemoradiotherapy for gastric cancer 7. Radiation-induced dose-dependent changes of the spleen following chemoradiotherapy for gastric cancer General discussion and future perspectives 171 Appendices Summary samenvatting 185 List of publications 190 Dankwoord 192 Curriculum Vitae 193

8 INTRODUCTION

9 General introduction and outline of this thesis

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11 General introduction General introduction Epidemiology Despite its declining incidence, gastric cancer remains one of the most common malignancies. It ranks fifth worldwide and sixth in Europe [1, 2]. In the Netherlands, gastric cancer is not found in the top 10 of most common malignancies [3]. These large geographic differences in incidence, reflects the etiologic heterogeneity of this disease [4, 5]. The highest incidence of gastric cancer is encountered in Eastern Asia; about 35 and 5 per persons per year for males and females, respectively [1]. In Europe the incidences per persons per year for males and females respectively, are 13 and 6 [1], and in the Netherlands approximately 11 and 7 [3]. Gastric cancer is worldwide the third most common cause of cancer death and responsible for 9% of cancer-related death yearly [1]. In Europe, gastric cancer is the fourth most common cause of cancer death and responsible for 6% of cancerrelated death yearly [2]. Overall, the mortality rates approach the incidence rates [4]. The 5-year overall survival for all stages of this disease combined is around 25% in the United States [6, 7] and Europe [8], and 20% in the Netherlands [8]. I Surgical treatment Surgery is the cornerstone of potentially curative treatment of gastric cancer [9]. The aim of gastric cancer surgery is to obtain a microscopically complete (R0) resection of the primary tumour with adequate margins, by a subtotal or total gastrectomy, and full clearance of possible tumour positive regional lymph nodes [10]. The patient with resectable gastric cancer without distant metastases can be treated with curative intent. In the Netherlands, 60-90% of patients with non-metastatic disease actually undergo potentially curative surgery [11], corresponding to approximately 40% of all gastric cancer patients [12]. Irresectability of the primary tumour or lymph nodes, inoperability of the patient, or early stage gastric cancer (carcinoma in situ and stage IA) for which a less invasive procedure such as an endoscopic mucosal resection is sufficient [10], are reasons to abandon an extensive surgical procedure. In 2-22% of the patients who undergo potentially curative surgery, a microscopically incomplete (R1) resection is reported [13-16] which is considered an independent poor prognostic factor [13, 16-19]. No clear guidelines for patient management are available when an R1 resection is encountered at histopathological examination 11

12 General introduction of the surgical specimen after surgery. Furthermore, the opinion as to whether an R1 resection can be considered as potentially curative surgery, differs [15, 18-21]. Further direction in patient management in this situation is therefore needed. To conclude, only less than half of gastric cancer patients are eligible for treatment with curative intent. Given the important role of surgery in the treatment of gastric cancer, further improvement of its quality has been emphasised. Nonetheless, even after optimised surgery, the prognosis of gastric cancer patients remains dismal [9, 22-24]. For example, in randomised controlled trials investigating the extent of the lymph node dissection, 5-year overall and disease-free survival rates were 33-70%, and 60-63%, respectively [23-27]. Locoregional tumour recurrence is a major problem, reported in 13-88% of patients. Peritoneal carcinomatosis and distant metastases were documented in 15-44% and 27-49% of patients, respectively [22, 26-29]. Currently, no salvage treatments for disease recurrence are available [30]. Therefore, it is of great importance to improve surgical results by developing more effective neoadjuvant and adjuvant treatment strategies. Multimodality treatment The addition of chemotherapy and chemoradiotherapy (CRT) to potentially curative surgery, i.e. multimodality treatment, improves outcome in gastric cancer patients. In 2001, the U.S. Intergroup 0116 trial demonstrated improved disease-free and overall survival for patients randomised after curative surgery to postoperative CRT (45 Gy combined with 5-FU), versus observation-only [31]. In 2006, the British MAGIC trial showed improved overall survival for patients randomised at diagnosis to perioperative chemotherapy (epirubicin, cisplatin and 5-FU), versus surgery-only [32]. In 2007, the Japanese ACTS-GC trial showed improved disease-free and overall survival for patients randomised after potentially curative surgery to postoperative chemotherapy (S-1), versus observation-only [33]. And, in 2012, the Asian CLASSIC trial demonstrated improved disease-free and overall survival for patients randomised after potentially curative surgery to postoperative chemotherapy (capecitabine and oxaliplatin), versus observation-only [34, 35]. Overall, with multimodality treatment 5-year disease-free survival rates increased by percentage points and overall survival by 9-17 percentage points [31-34]. The outcomes of these randomised controlled trials have led to a shift from an exclusively surgical approach to mul- 12

13 General introduction timodality treatment of gastric cancer worldwide [36-38]. It differs per country which of the above described multimodality approaches has been implemented as standard treatment. In the Netherlands, as in most European countries, perioperative chemotherapy has been adopted in the national guideline [39]. If preoperative chemotherapy has not been given, postoperative CRT is advised. Which of these regimens provides the best patient-specific outcome, requires further investigation. I Chemoradiotherapy The rationale for adding CRT to potentially curative surgery in gastric cancer is to improve locoregional control. Initially, this treatment modality has been administered exclusively in the postoperative setting. The first large randomised study on this subject was the Intergroup 0116 trial [31]. Since that trial, several developments regarding the concurrent delivery of chemotherapy and radiotherapy, and management of treatment-related toxicity, have taken place. Jansen et al. investigated more intensified CRT treatment regimens in a series of three phase I/II dose-escalation trials, combining radiotherapy to 45 Gy in 25 fractions, with daily capecitabine [40], with daily capecitabine and daily cisplatin [41], and with daily capecitabine and weekly cisplatin [42]. In a retrospective analysis, surgery followed by CRT according to these phase I/II studies showed a reduced local recurrence rate compared to surgery-only [43]. The CRT regimen with daily capecitabine/weekly cisplatin is currently used in the Netherlands. The additional value of postoperative CRT after preoperative chemotherapy and surgery is currently subject of study in the international multicentre randomised controlled CRITICS trial [44]. This trial has completed its target accrual of 788 patients in April 2015 and results are expected in At present preoperative CRT is not a standard treatment option in resectable gastric cancer in the Netherlands. Data from several phase I/II trials indicate that this approach is feasible and associated with favourable outcome [45-55]. In addition to improving locoregional control, preoperative CRT aims to increase the R0 resection rate. Several regimens have been investigated, most involving 45 Gy (range Gy) given in fractions of 1.8 Gy (range Gy), with a wide variety of concurrent chemotherapeutic agents. In many series, preoperative CRT was combined with induction chemotherapy [45-55]. On the other hand, for patients with resectable oesophageal cancer, preoperative CRT is currently the standard treatment [56]. In 2012, the Dutch CROSS trial showed improved disease-free and overall survival for oesophageal cancer 13

14 General introduction patients randomised at diagnosis to preoperative CRT versus surgery-only [57, 58]. In this trial, the R0 resection rate was significantly improved after preoperative CRT (82% versus 59% with surgery-only). A similar but smaller effect has been observed by administering preoperative chemotherapy in gastric cancer [59, 60]. Other advantages of administering additional treatment in the preoperative setting are: eradication of micrometastases at an early stage [32, 59], tumour sterilisation of the surgical area [61], the possibility to obtain information on the sensitivity of the tumour for treatment [45, 62], and avoidance of unnecessary surgery in case of early progressive disease [32, 59]. Last, but not least, preoperative treatment is associated with improved compliance, which is further discussed below. Taken together, preoperative CRT is an attractive approach and should be further explored as treatment option in gastric cancer. In fact, in the currently accruing international multicentre randomised controlled TOPGEAR trial patients are randomised at diagnosis for perioperative chemotherapy versus preoperative CRT plus perioperative chemotherapy [63]. And, in the Netherlands, the CRITICS-II trial is about to start in the near future, which is a phase II randomised controlled trial to identify an optimal preoperative multimodality treatment regimen for future phase III trials. Compliance with chemoradiotherapy An important challenge of multimodality treatment is sufficient patient compliance. Major limitations of postoperative therapy are the inability of patients to start adjuvant treatment, and the substantial drop-out once patients have started [31, 32]. In the Intergroup 0116 trial only 64% of the randomised patients completed the entire postoperative CRT regimen [31]. Severe acute toxicity was the most common reason for discontinuation of treatment (17% of randomised patients). Grade 3-4 haematological toxicity was reported in 54% of patients, and gastro-intestinal toxicity in 33%. In more recent postoperative CRT regimens, however, better compliance was obtained. In the phase I/II study of Jansen et al., in which patients were treated with radiation in combination with daily capecitabine and weekly cisplatin, 91% of patients completed treatment. Only 6% of patients had to stop due to acute toxicity [42]. In the three phase I/II studies combined (n=124), grade 3-4 haematological toxicity was reported in only 7% of patients, nausea in 5% and vomiting in 2% [40-42]. As mentioned before, better compliance to multimodality treatment can be achieved by giving the additional treatment before surgery [32, 52, 59]. In 14

15 General introduction the MAGIC and FNCLCC-FFCD trial, only around 40% of the patients completed postoperative chemotherapy, while around 90% completed preoperative chemotherapy. Acute toxicity was the main reason to stop preoperative chemotherapy in 5-8% of patients; reasons for discontinuation of postoperative chemotherapy were not reported. Compliance with preoperative CRT (with or without induction chemotherapy) has been reported in 74-95% of the patients included in phase I/II studies [45-55]. Acute toxicity of preoperative CRT given with or without induction chemotherapy was in up to 11% of patients the reason to cease treatment, and not proceed to surgery. Grade 3-4 gastro-intestinal toxicity was reported in 3-29%. Within the abovementioned clinical trials, it is unknown what proportion of patients was eligible for study inclusion. Moreover, it is unclear how this translates into daily clinical practice. It is important to know whether treatments that are effective in highly selected patient populations within clinical trials, are feasible in daily clinical practice as well. The identification of associated factors may guide treatment adjustments that could increase the proportion of patients who benefit from optimal neoadjuvant and adjuvant therapy. I Late toxicity following chemoradiotherapy The inherent toxicity of additional treatment to surgery is a challenge. Late toxicity following CRT becomes more relevant with the improving prognosis of gastric cancer patients. The clinical target volume of postoperative CRT in gastric cancer encompasses the preoperative tumour extension, gastric bed/remnant, draining lymph node stations, and anastomoses [64]. Thus, a large part of the upper abdomen is irradiated, and consequently, surrounding organs receive radiation dose as well and are therefore at risk for damage. Important dose limiting organs at risk in CRT for gastric cancer are the kidneys [65]. An adequate renal function should be maintained after treatment. Generally, it is possible to preserve the function of the right kidney, while impairment of the function of (part of) the left kidney progresses over time in a dose- and volume-dependent fashion [66]. However, modern radiotherapy techniques deliver a more conformal radiation dose distribution. A planning study showed that with the use of Intensity Modulated Radiation Therapy (IMRT) the dose to both kidneys was reduced while adequately covering the planning target volume [67]. Whether this also translates into less radiation-induced nephrotoxicity at long term follow up, remains to be investigated. 15

16 General introduction The spleen is another organ that is close to the radiation target volume in CRT for gastric cancer. It is usually not considered an organ at risk in abdominal radiotherapy as life without a spleen is possible. Nowadays, the unique immunological and haematological functions of the spleen are better understood and appreciated [68, 69]. Following surgical splenectomy or in case of functional hypo- or asplenia, patients are at an increased risk for overwhelming postsplenectomy infection (OPSI) by encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitides, with mortality rates up to 50-70% [68, 70, 71]. Guidelines regarding prevention of fatal infection after surgical splenectomy or hypo- and asplenia have been implemented in clinical practice, and are effective in reducing the incidence and mortality of OPSI [68, 70, 71]. Although it has been suggested that hyposplenia may occur after radiation of the spleen as well, it is largely unknown whether and to what extent the functions of the spleen are affected by irradiation [72-75]. Moreover, the tolerance dose of the spleen is unknown. Considering the severe, potentially fatal, consequences for patients in case of functional hyposplenia, and the available effective preventive measures, it is important to gather more information on this subject. To summarise, the prognosis of gastric cancer patients is poor. In the past decades, several randomised controlled trials have shown improved overall survival for patients with resectable gastric cancer treated with multimodality treatment, including postoperative CRT. The use of multimodality treatment, however, poses new issues to address. Firstly, with a wide variety of multimodality treatment regimens showing comparable benefit, tailored strategies are lacking. Secondly, there is relatively low compliance with postoperative CRT within clinical trials and how this translates into daily clinical practice is as yet unknown. Thirdly, adverse events at short and long term will increase by the addition of CRT to surgery. In this thesis, these chances and challenges of CRT in the multimodality treatment of gastric cancer are addressed. 16

17 General introduction Outline of this thesis The studies described in this thesis focus on important chances and challenges of chemoradiotherapy (CRT) in the treatment of gastric cancer patients. In the first part, the role of CRT as treatment entity for gastric cancer patients is discussed. In the second part, novel indications of CRT in gastric cancer treatment are explored. In the third part, late toxicity of the kidneys and spleen following CRT in gastric cancer patients is evaluated. I Part I. Multimodality treatment of gastric cancer CRT after gastric cancer resection improves overall survival by increasing locoregional control. The potential advantages of administering CRT in the preoperative setting are under investigation. In chapter 1, the current and future position of postoperative and preoperative CRT in the treatment of gastric cancer is discussed. In chapter 2, recent trends in the multimodality treatment of oesophageal, gastrooesophageal junction, and gastric cancer in the Netherlands are described. Part II. Novel indications for chemoradiotherapy in gastric cancer The efficacy of postoperative CRT has almost invariably been investigated after a microscopically complete (R0) resection. In chapter 3 and 4, the outcome of gastric cancer patients treated with postoperative CRT after a microscopically incomplete (R1) resection is described. To improve R0 resection rates, preoperative CRT seems a promising treatment option. In chapter 5, the feasibility and efficacy of preoperative CRT in gastric cancer patients are studied. Part III. Late toxicity of chemoradiotherapy in gastric cancer Late toxicity of CRT has become more relevant as the prognosis of gastric cancer patients gradually improves. The kidneys are among the most important dose-limiting organs at risk in external beam radiation therapy of the upper abdomen. In chapter 6, the effect of intensity modulated radiation therapy (IMRT) on radiation-induced nephrotoxicity is investigated in postoperative CRT for gastric cancer. Unlike the kidneys, the spleen has not been considered as an organ at risk in CRT for gastric cancer thus far. In chapter 7, the effects of radiation to the spleen are investigated in patients treated with postoperative CRT for gastric cancer. 17

18 General introduction Finally, the results of this thesis and future perspectives are described in the general discussion and future perspectives. 18

19 General introduction References 1. Ferlay, J., et al., Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN Int J Cancer, Ferlay, J., et al., Cancer incidence and mortality patterns in Europe: estimates for 40 countries in Eur J Cancer, (6): p Netherlands Cancer Registry. [Available from: accessed at ]. 4. Kamangar, F., G.M. Dores, and W.F. Anderson, Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol, (14): p Wu, H., et al., Stomach carcinoma incidence patterns in the United States by histologic type and anatomic site. Cancer Epidemiol Biomarkers Prev, (7): p Kunz, P.L., et al., Long-term survivors of gastric cancer: a california population-based study. J Clin Oncol, (28): p Wang, J., Y. Sun, and M.M. Bertagnolli, Comparison of Gastric Cancer Survival Between Caucasian and Asian Patients Treated in the United States: Results from the Surveillance Epidemiology and End Results (SEER) Database. Ann Surg Oncol, De Angelis, R., et al., Cancer survival in Europe by country and age: results of EUROCARE--5-a population-based study. Lancet Oncol, (1): p Jansen, E.P., et al., Optimal locoregional treatment in gastric cancer. J Clin Oncol, (20): p Rausei, S., et al., Updates on surgical management of advanced gastric cancer: new evidence and trends. Insights from the First International Course on Upper Gastrointestinal Surgery--Varese (Italy), December 2, Ann Surg Oncol, (12): p Dassen, A.E., et al., Changes in treatment patterns and their influence on long-term survival in patients with stages I-III gastric cancer in The Netherlands. Int J Cancer, (8): p Dikken, J.L., et al., Effect of hospital volume on postoperative mortality and survival after oesophageal and gastric cancer surgery in the Netherlands between 1989 and Eur J Cancer, (7): p Bickenbach, K.A., et al., Association of positive transection margins with gastric cancer survival and local recurrence. Ann Surg Oncol, (8): p Cunningham, S.C., et al., Survival After Gastric Adenocarcinoma Resection: Eighteen- Year Experience at a Single Institution. J Gastrointest Surg, (5): p Songun, I., et al., Prognostic value of resection-line involvement in patients undergoing curative resections for gastric cancer. European Journal of Cancer, A(3): p Stiekema, J., et al., Surgical treatment results of intestinal and diffuse type gastric cancer. Implications for a differentiated therapeutic approach? Eur J Surg Oncol, : p Wang, S.Y., et al., Clinical impact of positive surgical margin status on gastric cancer patients undergoing gastrectomy. Ann Surg Oncol, (10): p Kim, S.H., et al., Effect of microscopic resection line disease on gastric cancer survival. J Gastrointest Surg, (1): p I 19

20 General introduction 19. Morgagni, P., et al., Resection line involvement after gastric cancer surgery: clinical outcome in nonsurgically retreated patients. World J Surg, (12): p Papachristou, D.N., et al., Histologically positive esophageal margin in the surgical treatment of gastric cancer. Am J Surg, (5): p Chen, J.D., et al., Prognostic improvement of reexcision for positive resection margins in patients with advanced gastric cancer. Eur J Surg Oncol, (3): p Songun, I., et al., Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol, (5): p Cuschieri, A., et al., Patient survival after D1 and D2 resections for gastric cancer: longterm results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer, (9-10): p Degiuli, M., et al., Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J Surg, (2): p Bonenkamp, J.J., et al., Extended lymph-node dissection for gastric cancer. N Engl J Med, (12): p Sasako, M., et al., D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med, (5): p Wu, C.W., et al., Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol, (4): p Gunderson, L.L., Gastric cancer--patterns of relapse after surgical resection. Semin Radiat Oncol, (2): p Chang, J.S., et al., Patterns of regional recurrence after curative D2 resection for stage III (N3) gastric cancer: implications for postoperative radiotherapy. Radiother Oncol, (3): p Waddell, T., et al., Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Radiotherapy and Oncology, (1): p MacDonald, J.S., et al., Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med, (10): p Cunningham, D., et al., Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med, : p Sakuramoto, S., et al., Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med, (18): p Noh, S.H., et al., Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol, (12): p Bang, Y.J., et al., Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet, (9813): p Waddell, T., et al., Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Radiother Oncol, (1): p Brar, S.S., et al., Processes of care in the multidisciplinary treatment of gastric cancer: results of a RAND/UCLA expert panel. JAMA Surg, (1): p Fujitani, K., Overview of adjuvant and neoadjuvant therapy for resectable gastric cancer in the East. Dig Surg, (2): p Landelijke richtlijn maagcarcinoom [Available from: nl/maagcarcinoom, accessed at ]. 20

21 General introduction 40. Jansen, E.P., et al., A phase I-II study of postoperative capecitabine-based chemoradiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys, (5): p Jansen, E.P., et al., Postoperative chemoradiotherapy in gastric cancer -- a Phase I/II dose-finding study of radiotherapy with dose escalation of cisplatin and capecitabine chemotherapy. Br J Cancer, (6): p Jansen, E.P., et al., Postoperative chemoradiotherapy in gastric cancer--a phase I-II study of radiotherapy with dose escalation of weekly cisplatin and daily capecitabine chemotherapy. Ann Oncol, (3): p Dikken, J.L., et al., Impact of the extent of surgery and postoperative chemoradiotherapy on recurrence patterns in gastric cancer. J Clin Oncol, (14): p Dikken, J.L., et al., Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRIT- ICS). BMC Cancer, : p Ajani, J.A., et al., Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol, (6): p Inoue, T., et al., Pilot Feasibility Study of Neoadjuvant Chemoradiotherapy with S-1 in Patients with Locally Advanced Gastric Cancer Featuring Adjacent Tissue Invasion or JGCA Bulky N2 Lymph Node Metastases. Ann Surg Oncol, Wydmanski, J., et al., The tolerance and efficacy of preoperative chemoradiotherapy followed by gastrectomy in operable gastric cancer, a phase II study. Radiother Oncol, (2): p Roth, A.D., et al., Neoadjuvant radiochemotherapy for locally advanced gastric cancer: a phase I-II study. Ann Oncol, (1): p Lowy, A.M., et al., A pilot study of preoperative chemoradiotherapy for resectable gastric cancer. Ann Surg Oncol, (6): p Ajani, J.A., et al., Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol, (14): p Matsuda, S., et al., Phase I study of neoadjuvant chemoradiotherapy with S-1 plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis: -KOGC04. Radiat Oncol, : p Michel, P., et al., Feasibility of preoperative and postoperative chemoradiotherapy in gastric adenocarcinoma. Two phase II studies done in parallel. Federation Francophone de Cancerologie Digestive Eur J Cancer, (6): p Pera, M., et al., Phase II trial of preoperative chemoradiotherapy with oxaliplatin, cisplatin, and 5-FU in locally advanced esophageal and gastric cancer. Ann Oncol, (3): p Lee, D.J., et al., Phase I study of neoadjuvant chemoradiotherapy with S-1 and oxaliplatin in patients with locally advanced gastric cancer. Cancer Chemother Pharmacol, Stahl, M., et al., Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol, (6): p Landelijke richtlijn oesofaguscarcinoom [Available from: accessed at ]. 57. van Hagen, P., et al., Preoperative chemoradiotherapy for esophageal or junctional cancer. New England Journal of Medicine, (22): p I 21

22 General introduction 58. Oppedijk, V., et al., Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol, (5): p Ychou, M., et al., Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol, (13): p Schuhmacher, C., et al., Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial J Clin Oncol, (35): p Xiong, H.Q., et al., Chemoradiation for resectable gastric cancer. Lancet Oncol, (8): p Becker, K., et al., Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. Ann Surg, (5): p Leong, T., et al., TOPGEAR: a randomised phase III trial of perioperative ECF chemotherapy versus preoperative chemoradiation plus perioperative ECF chemotherapy for resectable gastric cancer (an international, intergroup trial of the AGITG/TROG/ EORTC/NCIC CTG). BMC Cancer, : p Jansen, E.P., et al., Interobserver variation of clinical target volume delineation in gastric cancer. Int J Radiat Oncol Biol Phys, (4): p Dawson, L.A., et al., Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys, (3 Suppl): p. S Jansen, E.P., et al., Prospective study on late renal toxicity following postoperative chemoradiotherapy in gastric cancer. Int J Radiat Oncol Biol Phys, (3): p Verheij, M., et al., Late renal toxicity following post-operative chemoradiotherapy in gastric cancer. American Society of Clinical Oncology Gastrointestinal Cancers Symposium Proceedings, 2005 (83). Alexandria (VA). 68. Di Sabatino, A., R. Carsetti, and G.R. Corazza, Post-splenectomy and hyposplenic states. Lancet, (9785): p Crary, S.E. and G.R. Buchanan, Vascular complications after splenectomy for hematologic disorders. Blood, (14): p de Porto, A.P., et al., Assessment of splenic function. Eur J Clin Microbiol Infect Dis, (12): p Rubin, L.G. and W. Schaffner, Clinical practice. Care of the asplenic patient. N Engl J Med, (4): p Knecht, H., et al., Functional hyposplenia after allogeneic bone marrow transplantation is detected by epinephrine stimulation test and splenic ultrasonography. Eur J Haematol, (4): p Weiner, M.A., et al., Vesiculated erythrocytes as a determination of splenic reticuloendothelial function in pediatric patients with Hodgkin s disease. J Pediatr Hematol Oncol, (4): p Coleman, C.N., et al., Functional hyposplenia after splenic irradiation for Hodgkin s disease. Ann Intern Med, (1): p Selby, C., et al., Bacteraemia in adults after splenectomy or splenic irradiation. Q J Med, (242): p

23

24 Part I

25 Multimodality treatment of gastric cancer

26 Chapter 1

27 Emerging issues in multimodality treatment of gastric cancer Anouk K. Trip, Marcel Verheij, Johanna W. van Sandick, Henk Boot, Edwin P.M. Jansen, & Annemieke Cats Translational Gastrointestinal Cancer 2015; 4:

28 Chapter 1 Abstract Objectives In recent years, the treatment of locally advanced resectable gastric cancer has evolved from an exclusively surgical to a multidisciplinary approach including chemotherapy and radiotherapy (RT). Worldwide several evidence-based preoperative and postoperative adjuvant strategies have been implemented in daily clinical practice. The determination of gastric cancer patients that benefit most from certain treatment modalities is a matter of debate. Methods This review covers a comprehensive analysis of outcome and toxicity of clinical trials investigating multimodality treatment for locally advanced resectable gastric cancer to provide insight in patient groups that may benefit from certain treatments. Results Postoperative chemotherapy as monotherapy and doublet therapy has mainly been evaluated in Asian countries, where its efficacy has been clearly demonstrated. Whereas the added value of postoperative chemotherapy remains to be established in Western patient populations, perioperative doublet and triplet chemotherapy has been shown to improve overall survival (OS) in this part of the world. In addition, postoperative chemoradiotherapy (CRT) as an intensive locoregional treatment has been shown to reduce local recurrence rates and to improve OS. It has been suggested that postoperative CRT may particularly be of additional value in case of a microscopically incomplete R1 resection, a limited lymph node dissection (LND), and/or in case of regional lymph node metastases. Another attractive treatment strategy is preoperative CRT. Phase II trials reported good feasibility and patient compliance, low toxicity rates, high R0 resection rates, and promising response rates. No results from randomized controlled trials applying preoperative CRT are available yet, but phase III randomized controlled trials investigating this strategy are currently accruing patients. In gastric cancer treatment, hematological and gastrointestinal toxicity are most frequently encountered in both chemotherapy and CRT either given preoperatively or postoperatively. Toxicity rates are higher with doublet and triplet chemotherapy than with monotherapy. Toxicity rates of the newer CRT regimens are lower than those of the older regimens, and lower than those of combination chemotherapy. For both chemotherapy and CRT, toxicity rates seem lower when treatment is given preoperatively, which probably explains the higher compliance with preoperative treatment. Conclusions Based on multiple adjuvant preoperative and postoperative treatment regimens that have shown efficacy in patients with locally advanced resectable gastric cancer, all patients should be considered for multimodality treatment. Today, for gastric cancer patients the choice for a specific additional modality can only be based on patient and tumor characteristics regarding preoperative treatment, and surgical and pathological results regarding postoperative treatment. Taken together, preoperative chemotherapy and/or CRT are preferable to postoperative regimens. However, this has to be further confirmed in randomized controlled phase III studies. 28

29 Emerging issues in multimodality treatment Introduction Gastric cancer is the fifth most common malignancy worldwide with large geographic differences in incidence [1-3]. The highest incidences are encountered in Eastern Asia [3], 35.4 and 5.4 per 100,000 per year for males and females respectively [2]. In descending order are the incidences per 100,000 persons per year for males and females respectively 20.3 and 0.8 in Central-Eastern Europe [2], 14.2 and 2.0 in South America [2], 5.5 and 1.1 in Northern America, and 3.3 and 0.4 in Western Africa [2,3]. Overall, gastric cancer is twice as common in men compared to women [2,3]. These differences in gastric cancer incidence reflect etiologic heterogeneity [3,4]. Gastric cancer is worldwide the third most common cause of cancer death and responsible for 9% of cancer-related death yearly [2]. Despite large geographic differences in survival [1-3], overall, mortality rates almost resemble the incidence rates [3]. Whereas, the 5-year overall survival (OS) is around 25% in Europe and the United States, this is up to 60% in Asia [2,3,5]. The higher survival rates in Asia are ascribed to mass screening programs in Japan, high accuracy of staging that is accompanied by stage migration, and high quality of surgery [3,6-9]. For gastric cancer, surgery remains indispensable for curative treatment. Patients with non-metastasized gastric cancer at diagnosis are eligible for potentially curative surgery if the tumor can be resected with free margins, i.e., resectable gastric cancer. However, even after potentially curative surgery gastric cancer patients have a high risk of locoregional recurrence, peritoneal carcinomatosis and distant metastases, in both Asian and Western countries [10-14]. This risk increases with advanced tumor stage and can be as high as 88% locoregional recurrence, 44% peritoneal carcinomatosis, and 49% distant metastases in autopsy series [10]. Recurrence patterns are also histological type dependent [15]. For example, patients with a diffuse type gastric cancer [16] have a higher risk of peritoneal carcinomatosis than patients with an intestinal type, especially when the tumor has infiltrated the serosa [15]. Different multimodality treatments added to surgery have been investigated for locally advanced resectable gastric cancer. Whereas multiple multimodality strategies have been proven beneficial, which gastric cancer patients benefit most from which treatment modality remains a matter of debate. This review covers a comprehensive analysis of outcome and toxicity of clinical trials investigating multimodality 1 29

30 Chapter 1 treatment for locally advanced resectable gastric cancer to provide insight in patient groups that may benefit from certain treatments. Surgery The obvious goal of surgery is to achieve a microscopically complete resection of the primary tumor, known as an R0 resection, and full clearance of possibly affected regional lymph nodes [17]. A microscopically tumor positive luminal resection margin, known as an R1 resection, has been reported in 2-22% of patients [18-21]. Irrespective of its association with advanced tumor stage and aggressive tumor biology, an R1 resection has frequently been identified as an independent poor prognostic factor [18,21-24], justifying the use of peroperative frozen sections [25]. Clear guidelines regarding patient management in case of an R1 resection are lacking. When an R1 resection is assessed by frozen section examination during surgery and a tumor negative resection margin can still be obtained, extended surgery is a clear option [26]. Extended surgery is, however, disputable if that entails a distal esophagectomy or pancreaticoduodenectomy both carrying substantially increased morbidity [27]. When an R1 resection is assessed postoperatively, options vary from watchful waiting [28], to re-resection in patients with limited nodal disease [23] or re-resection whenever feasible [20,24]. The possible benefit of performing a reresection is mainly based on the rationale that obtaining tumor negative margins can negate the adverse prognostic impact of tumor positive margins [29]. The development of gastric cancer surgery entailed the selection of patients who could benefit from a partial, instead of a total gastrectomy. Currently it is standard of care to perform a partial gastrectomy when tumor free margins can be obtained in distally located tumors as this is proven safely with regard to tumor control, and is accompanied by beneficial effects on nutritional status, quality of life [30,31] and reduced surgical morbidity and mortality [32,33]. However, the risk of an R1 resection in diffuse type gastric cancer according to the Lauren classification [16] is high and may be reason to extend the surgical resection or even to consider a total gastrectomy irrespective of the tumor location, especially in young patients [21]. The extent of the lymph node dissection (LND) has been subject of extensive research. Traditionally, in the East more extended LND, i.e., D2 (lymph node stations 1-11 according to the Japanese classification of gastric cancer) or D3 (lymph 30

31 Emerging issues in multimodality treatment node stations 1-14) [34], are routinely performed and their benefit regarding OS is confirmed by randomized controlled trials [13,14]. An even more extended lymphadenectomy including para-aortic lymph nodes, i.e., D4 (lymph node stations 1-16), does not seem to add to the survival benefit [13]. In Western countries, a D1 LND (lymph node stations 1-6) used to be common practice and a shift towards standard performance of a D2 LND has in recent years [12,35]. The benefit of a D2 LND was not adopted until the 15-year follow-up results of the randomized Dutch Gastric Cancer Trial showed that a D2 LND was associated with significantly less gastric cancer-related death and less local recurrences compared to a D1 LND [12]. Short term results had not shown an OS benefit for patients who had undergone a D2 LND compared to a D1 LND [36,37]. A similar observation was made in the MRC randomized trial [33]. In both trials the lack of benefit on OS was explained by the higher postoperative mortality in the D2-group that was caused by the higher percentages of pancreatico-splenectomies to enable dissection of lymph node stations 10 and 11 [33,37]; i.e., the higher short-term mortality offset the long-term benefit on OS. This hypothesis was confirmed by a subgroup analysis of patients who had undergone a D1 or D2 LND without pancreatico-splenectomy that showed a significantly higher 15-year OS in those who had a D2 LND (22% vs. 35%; HR, 1.34; 95% CI: ; p=0.006) [12]. Patients with advanced disease and lymph node metastases may benefit more from a D2 LND than those with limited disease [37,38], except for patients with lymph node metastases in the splenic hilus (lymph node station 10). Nodal metastases at this site indicate a very poor prognosis which will not improve after removal of the affected lymph nodes that necessitates a splenectomy [25,37]. At current times, surgeons are advised to perform a D2 LND involving lymph node stations 1-9 and 11 with the removal of at least 15 nodes without routine spleen and pancreatic tail resection, sometimes also nominated as a D1+ LND [12,17]. With this approach, surgical mortality and morbidity rates can be reduced, as confirmed by an Italian randomized D1-D2 trial [38]. Taken together, in recent years this has led to the adoption of the standard performance of a D2 LND in Western countries. In general, a D2 LND reduces the risk of locoregional recurrence down to 7-28% [11,13,14], but does not influence the risk of peritoneal carcinomatosis or distant metastases [11-14]. Also, although gastric cancer surgery has been optimized and the 5-year OS has been improved, the prognosis still remains dismal. Hence, disap- 1 31

32 Chapter 1 pointing long-term results after optimal surgery emphasize the need to develop multimodality treatments that are more effective. Chemotherapy Postoperative chemotherapy The rationale for adding postoperative chemotherapy to the treatment of locally advanced resectable gastric cancer is to improve OS by eradicating remaining micrometastases that upon outgrowth are responsible for relapse. Multiple, predominantly fluoropyrimidine-based, postoperative chemotherapy regimens have been investigated resulting in conflicting evidence of efficacy, with mainly positive results for trials conducted in Asia and negative results for trials conducted in Western countries (Table 1.1). One of the first clinical trials that clearly showed survival benefit by adding postoperative chemotherapy was conducted in Japan [41]. Patients (n=1,059) were randomized after potentially curative surgery including at least a D2 LND, for observation-only vs. postoperative treatment with S-1 monotherapy for 1 year. The results of the first interim analysis were disclosed because the 3-year OS in the S-1 group was significantly higher: 80.1% vs. 70.1% (HR, 0.68; 95% CI: ; p=0.003) [41]. This was later confirmed by a significantly higher 5-year OS: 71.7% vs. 61.1% (HR, 0.67; 95% CI: ) [42]. These results have led to standard postoperative treatment with S-1 after surgery for stage II and III gastric cancer patients in Japan and other East-Asian countries [45]. Another postoperative chemotherapy regimen for stage II and III gastric cancer consists of capecitabine in combination with oxaliplatin (CAPOX) that has been investigated in Korea [40,45]. Data of this so-called CLASSIC trial (n=1,035) have not been finalized yet, but the results of the first interim analysis were also disclosed because the 3-year disease free survival (DFS) was significantly higher in patients randomized for 6 months capecitabine and oxaliplatin than those randomized for observation-only after surgery in combination with a D2 LND: 74% vs. 59% (HR, 0.56; 95% CI: ; p<0.0001). A trend towards improved OS in the CAPOXarm was also observed after 3 years (HR, 0.72; 95% CI: ; p=0.0493). The data are however immature and patient follow-up is ongoing [40]. The addition of postoperative CAPOX seemed to reduce locoregional recurrences and distant me- 32

33 Emerging issues in multimodality treatment tastases, but not peritoneal carcinomatosis [40]. The addition of postoperative S-1, on the other hand, significantly reduced locoregional recurrences and peritoneal carcinomatosis, but not distant metastases [41]. Together, these large-scale Asian trials provide sufficient evidence for the efficacy of postoperative fluoropyrimidinebased chemotherapy after potentially curative surgery in combination with a D2 LND. The most recently published Asian trial investigating postoperative chemotherapy for gastric cancer, Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT, n=1,495), compared four treatment groups in a two-by-two factorial design [39]. The four treatments consisted of UFT-monotherapy, S-1 monotherapy, paclitaxel followed by UFT, and paclitaxel followed by S-1. Sequential chemotherapy treatment did not improve DFS nor OS compared to monotherapy. S-1 seemed superior to UFT (3-year DFS UFT: 53.0%; 95% CI: ; S-1: 58.2%; 95% CI: ; HR, 0.81; 95% CI: ; p=0.0048; p non-inferiority =0.151). Multiple randomized controlled trials investigating postoperative chemotherapy for resected gastric cancer have been conducted in the West [43,44,46-49]. And yet, none of these has provided similar positive results as the Asian trials. The lack of effectiveness was initially ascribed to the use of old regimens [46,47] but newer regimens did not prove to be effective either [44,48,49]. Multiple factors have been suggested to play a role in the different outcomes after chemotherapy for Asian and Western populations, among others patient- and tumor characteristics including ethnic variability in genes regarding the drug metabolizing enzymes [40,42,50,51], the poor compliance of patients to the full chemotherapy regimen [44], the use of different surgical techniques [45] or the small sample sizes. Several meta-analyses have been performed to investigate a possible positive effect of postoperative chemotherapy, but also showed conflicting results [52-56]. The (subgroup) metaanalysis that included only Western trials showed a non-significant small benefit of postoperative chemotherapy for resectable gastric cancer [53,55,57]. Hence, postoperative chemotherapy is not routinely advised for gastric cancer patients in the West [35]. 1 Preoperative and perioperative chemotherapy The main rationale for administration of preoperative chemotherapy is to improve OS by eradicating micrometastases as early as possible and to improve surgical 33

34 Chapter 1 Table 1.1. Selection of 5 most recent randomized clinical trials investigating postoperative chemotherapy for locally advanced resected gastric cancer. Trial Inclusion N Radicality of Extent of resection (%) LND (%) Tsuburaya et al (39) Bang et al (40) Sakuramoto et al and Sasako et al (41, 42) Kulig et al (43) 5-year DFS (%) 5-year OS (%) Median OS (months) 1: 12 cycles UFT 267mg/m 2 /day p.o. on days 1-28, q 4 weeks (57% of patients completed 12 cycles) 2: 16 cycles S-1 80mg/m 2 b.i.d. p.o. on days 1-14, q 3 weeks (60% of patients completed 16 cycles) 3: 3 cycles Pac 80mg/m 2 /day i.v. on days 1, 8 (and 15), q 3-4 weeks, followed by 9 cycles UFT 267mg/m 2 /day p.o. on days 1-28, q 4 weeks (65% of patients completed 12 cycles) 4: 3 cycles Pac 80mg/m 2 /day i.v. on days 1, 8 (and 15), q 3-4 weeks, followed by 12 cycles S-1 80mg/m 2 b.i.d. p.o. on days 1-14, q 3 weeks (67% of patients completed 15 cycles) T4a-T4b 1: 374 2: 374 3: 374 4: R0: NR R1: NR D1: 0 D2: year 1 + 2: 54 vs : : 53 vs : 58* 3-year 1 + 2: 56 vs : : 54 vs : 61* 1: NR 2: NR 3: NR 4: NR A: Observation, subjected to regular follow-up B: 8 cycles Cap 1000mg/m 2 b.i.d. p.o. on days 1-14, + Ox 130mg/m 2 /day i.v. on day 1, q 3 weeks (67% of patients completed 8 cycles) Stage II-IIIB A: 515 B: 520 A+B R0: 100 R1: 0 A+B D1: 0 D2: 100 D3: NR 3-year A: 59 B: 74* 3-year A: 78 B: 83* A: - B: - A: Observation, subjected to regular follow-up B: For 1 year S-1 40mg/m 2 b.i.d. p.o. on days 1-28, q 6 weeks (64% of patients completed 1 year of treatment) Stage II-III A: 530 B: 529 A+B R0: 100 R1: 0 A+B D1: <1 D2: 94 D3: 6 A: 53 B: 65* A: 62 B: 76* A: - B: - A: Observation, subjected to regular follow-up B: 3 cycles Etop 120mg/m 2 /day i.v. on days 4, 5, 6, + Dox 20mg/m 2 /day i.v. on days 1, 7, + Cis 40mg/m 2 /day i.v. on days 2, 8, q 4 weeks (65% of patients completed 3 cycles) T2-4/N- or T1-4/N+ A: 154 B: 155 A+B R0: 100 R1: 0 A: D1: 20 D2: 33 D3: 47 B: D1: 21 D2: 35 D3: 44 A: 45 B: 51 A: 40 B: 44 A: 36 B: 41 34