UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Daily clinical practice and patterns of care in upper gastrointestinal cancer treatmentToxicity, quality of life and survivalHaj Mohammad, N.

Link to publication

Creative Commons License (see https://creativecommons.org/use-remix/cc-licenses):Other

Citation for published version (APA):Haj Mohammad, N. (2016). Daily clinical practice and patterns of care in upper gastrointestinal cancer treatment:Toxicity, quality of life and survival.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 22 May 2020

Chapter 1

General introduction and outline of the thesis

Chapter 112

General outline and introduction of the thesis 13

INTRODUCTION AND OUTLINE OF THE THESIS

Upper gastrointestinal (GI) cancers - esophageal, gastric and pancreatic cancer - have a

dismal prognosis. Despite treatment with curative intent, randomized clinical trials report

5-year survival rates of only 47% in esophageal cancer [1], 36 % in gastric cancer [2] and 21%

in pancreatic cancer.[3] In population-based series 5-year survival rates of patients treated

with curative intent are even lower and range from in 19-25% in esophageal cancer [4], 20-

31% in gastric cancer [5] and 11-16% in pancreatic cancer.[6]

Besides the poor results of treatment, management of upper GI cancers is further compli-

cated by the occurrence of side effects of oncological treatment. This is more prominent

in upper GI cancer due to the extent of upper GI surgery, with potentially severe compli-

cations [7-9], as well as the use of multimodality treatment (radiation, chemotherapy), which

cannot always spare vital organs. This may severely impact quality of life and functional

outcome of these patients.

Unfortunately, the majority of patients have advanced disease at the time of presentation,

rendering palliative systemic treatment combined with best supportive care as the only

treatment of choice. Median overall survival data for patients with metastatic disease in

population-based studies varies from 2 months for pancreatic cancer [10] to less than a year

for esophagogastric cancer.[11]

Trends over time show a rising incidence of both esophageal cancer [4] and pancreatic can-

cer.[12] Esophageal cancer has two histological subtypes: adenocarcinoma and squamous

cell carcinoma. The European standardized rate (ESR) increased for esophageal cancer

from 5/100 000 in 1990 to 10/100 000 in 2015. Over the past three decades, in the West-

ern world the rates of esophageal squamous-cell carcinoma have declined, while those

of esophageal adenocarcinoma have been progressively increasing.[12, 13] Gastric cancer

markedly decreased in the Netherlands with a ESR in 1998 of 25/100 000 compared to an

ESR in 2008 of 14/100 000 [5] Despite these increasing trends for esophageal adenocarci-

noma and pancreatic cancer, it should be noted that upper GI cancers are relatively un-

common in the Western World. For example, in the Netherlands in 2015 2369 new pa-

tients were diagnosed with esophageal cancer - this is six times lower than the incidence

of breast cancer in 2015. Likewise, in 2015 2284 patients were diagnosed with pancreat-

ic cancer and 1556 patients with gastric cancer.[12] This implies that individual caregivers

may have limited experience with the treatment of this disease, unless care is centralized.

In the Netherlands, high complex, low volume surgery is centralized because outcome of

patients treated in a high-volume specialized center is usually better compared to out-

come of patients treated in low volume hospitals.[14-16] However, for palliative treatment

Chapter 114

with systemic therapy this association has not been investigated in upper gastro intesti-

nal cancer.

The poor prognosis, the potentially severe toxicity of treatment and late presentation of

the disease together with the relatively low incidence pose a great challenge to the op-

timization of outcomes of patients with upper GI cancer. The main aim of this thesis is to

investigate toxicity and functional outcome of treatment of locally advanced esophageal

cancer and to investigate treatment strategies for metastatic esophagogastric and pan-

creatic cancer, with a special focus on differences in management and survival between

Dutch hospitals in daily practice.

Part 1: Treatment of locally advanced esophageal cancerNowadays the treatment of choice for locally advanced resectable (clinical tumor stag-

eT1-3, any N (with the exception of T1N0) esophageal cancer in the Netherlands is mul-

timodality treatment consisting of neoadjuvant chemoradiation followed by resection,

based on the results of the Dutch CROSS trial.[17] This treatment consists of five times

weekly intravenous chemotherapy (carboplatin area under the curve of 2 mg per milliliter

per minute and paclitaxel 50 mg per square meter of body surface area). A radiation dose

of 41.4 Gray (Gy) is given (23 x 1.8 Gy), with 5 fractions administered per week, starting on

the first day of the first chemotherapy cycle. Resection is planned six to ten weeks after

the end of neoadjuvant treatment.

The updated results of the CROSS trial [1] show a median survival of 49 months. Although

survival benefit was found for both histological subtypes, in the subgroup of patients with

squamous cell carcinomas the median survival was even 82 months.

In the light of the gradual but continuing improvement of survival of resectable esopha-

geal cancer, long-term side effects of chemoradiotherapy may become increasingly rel-

evant. During the radiation treatment, margins around the target volume are needed to

compensate for daily setup variations and daily mobility of the esophagus, leading inev-

itably to dose delivery to normal organs such as the heart. In cancers with a high propor-

tion of cancer survivors long-term effects of radiation-induced cardiotoxicity have been

investigated. For example, in breast cancer an increased rate of mortality from heart dis-

ease in the group of long-term surviving women treated with radiation therapy was report-

ed.[18] Cardiac toxicity was confirmed in population-based data [19] showing that exposure

of the heart to ionizing radiation during radiotherapy for breast cancer increased the sub-

sequent rate of ischemic heart disease. Subsequently, modern tangential techniques and

inspiration breath-hold techniques have been introduced to reduce the irradiated heart

volume and thus late cardiac toxicity. In contrast to late cardiac toxicity, limited data are

General outline and introduction of the thesis 15

available on acute cardiac toxicity of chemoradiotherapy. Acute cardiac toxicity may have

impact on treatment tolerance but may also be a predictor of late chronic cardiac toxic-

ity. Therefore, in Chapter 2 we describe the hemodynamic aspects of changes in heart

volume during neoadjuvant chemoradiation. Furthermore, we explore whether changes

in heart volume during chemoradiation have impact on the dose distribution of the tar-

get volume. if during neoadjuvant chemoradiation of esophageal cancer there are signs

of subclinical cardiac toxicity, measures will need to be taken to further minimize cardiac

toxicity and delivery of radiation dose to other organs at risk.

A clinician-reported outcome such as toxicity is a very important outcome measure used

in clinical trials and in daily practice. However, grading adverse events is not necessari-

ly identical to functional outcome and quality of life (QOL). First, some treatment side ef-

fects as pain and emotional effects are preferably defined by the patient. Second, only pa-

tients can determine how relevant toxic effects are to their functional outcome. Functional

outcome can be assessed with QOL questionnaires and measurement of functional status.

Functional status refers to routine activities of daily living such as self-care, housekeeping

and outdoors activities. They might truly reflect a patient’s day-to-day functioning. Multi-

modality treatment showed a temporary negative effect on most aspects of quality of life,

but normalized or even improved one to two years after surgery.[20] These combined find-

ings might provide patients and health workers with essential information; for patients to

guide expectations on functional status during treatment, for health workers to provide

extra support. To date, these data are lacking and, therefore, in chapter 3 we evaluate

activities of daily living and quality of life of the patient during neoadjuvant chemoradia-

tion and after surgery.

Besides physical and practical consequences, patients undergoing neoadjuvant chemo-

radiation followed by surgery must cope with numerous social and emotional challeng-

es due to treatment-related toxicity and risk of recurrence.[21] This not only poses a bur-

den on the patient, but also on their caregiver. Moreover, with the shift of delivery of care

from the hospital to the home as a result of increased use of outpatient services for can-

cer treatment and shortened hospital visits, especially family caregivers are taking more

responsibility for patient care. In general, caregivers are responsible for organizing the

appropriate food supply, for example ground food, have to manage medical emergen-

cies when they arise, are expected to understand medical information, and need to make

the time to escort the patient to the hospital.[22] Next to these responsibilities, they are

expected to provide psychological, spiritual and emotional support.[23] The broad array

of support tasks may be accompanied by high levels of distress and unmet supportive

Chapter 116

care needs.[24, 25]

In the period after treatment, persistent psychological distress and role adjustment prob-

lems experienced by caregivers of non-upper GI cancer survivors have been reported to

be higher than healthy controls.[26] In case of esophageal cancer, the burden of caregiv-

ers - defined as the extent to which caregivers feel that their emotional or physical health,

social life, and financial status have suffered as a result of caring - can be associated with

practical matters, such as adjusting the frequency of meals. Furthermore, also the par-

ticularly poor prognosis may have a large impact on caregiver burden. To possibly assist

health care providers to provide resources to the spousal caregivers most in need, we de-

scribe the spousal caregivers’ burden of esophageal cancer survivors after treatment with

curative intent. Furthermore, we explore associations for spousal caregiver burden after

neoadjuvant chemoradiation and surgery in chapter 4.

Although surgery is considered the mainstay of curative treatment for esophageal cancer,

in the period 2005-2013 in the Netherlands less than 30% of all cases with esophageal can-

cer underwent surgery with curative intent.[27] This is related to various patient- and tumor

characteristics. First, most patients present with advanced disease and are therefore treat-

ed with palliative intent without surgery. Second, patients can have an irresectable tumor

because of disease extent or a proximal localization. And third, patients may be medical-

ly inoperable because they are considered unfit for esophagectomy because of comor-

bidity. In case of irresectability or inoperability definitive chemoradiotherapy (dCRT) is an

alternative to surgery that can achieve long-term disease control and even cure.[28] Defin-

itive chemotherapy, as generally applied in the Netherlands, consists of six times week-

ly chemotherapy. A total radiation dose of 50.4 Gy is given (28 x 1.8 Gy), in 5 fractions per

week, starting on the day of the first chemotherapy cycle. Although irresectable and in-

operable patients may both be treated with dCRT, both groups are quite distinct with in-

operable patients potentially being disposed to more toxicity because of underlying dis-

ease. In a single center retrospective series of 291 patients undergoing definitive chemo-

radiation 5-year overall survival rate was 20%, grade 3 and/or 4 toxicity was 48%.[29] Oth-

er studies report grade 3 toxicity ranging from 29-56%.[30-32] In these studies, no reporting

of toxicity was made on the basis of the reason of non-surgical treatment, i.e. having an

irresectable tumor or being inoperable because of comorbidity. Next to information on

survival (the benefit of treatment) information on the extent of toxicity (the harm of treat-

ment) is essential for a patient when deciding to opt for a specific treatment. To fill the

knowledge gap on the toxicity of dCRT for inoperable patients, we describe the tolerabil-

ity of this treatment regimen for this patient group in chapter 5.

General outline and introduction of the thesis 17

Part 2: Treatment for metastatic disease of esophagogastric and pancreatic cancerIn terms of efficacy, palliative chemotherapy has been shown to be superior compared to

best supportive care for esophagogastric cancer.[33] A standard first-line treatment, howev-

er, has not been established. It is a matter of debate whether a three-drug of two-drug reg-

imen should be used. Landmark studies from the American and Asian continent general-

ly use two drug regimens consisting of a fluoropyrimidine analogue and a platinum com-

pound.[34, 35] In Europe conducted randomized phase 3 trials often use three drug-regi-

mens.[36-39] To put this in a historical context: Cullinan et al. reported in 1985 on monother-

apy 5-fluorouracil (5-FU), the doublet 5-FU and doxorubicine and the triplet 5-FU, doxoru-

bicine and mitomycine C (FAM).[40] None of the regimens showed an improvement in over-

all survival. In 1991, a randomized controlled trial, conducted by the EORTC compared the

triplet FAM vs the triplet 5-FU, doxorubicine, methotrexate (FAMTX), which showed an ad-

vantage in median survival for FAMTX (44 weeks versus 29 weeks).[41] Until the turn of the

century FAMTX was widely used in European trials.[39, 42, 43] However, since the publication

of a phase 3 randomized trial with 274 patients in which FAMTX showed a median survival

of 5.7 months compared to epirubicine, cisplatin and 5-FU (ECF) 8.7 months, ECF became

the common comparator in Europe.[39] (figure 1)

5-FU vs

5FU+

doxo

vs FAM

FAM vs

FAMTX ECF vs

FAMTX

8.7 mo

5.7 mo

21 w

44 w No difference in survival

1985 5-FU/FAM

1991 FAMTX

1997 ECF

2008 EOX/ECF/5-FU+CIS

No difference

in survival

Cullinan JCO 1997

Wills JCO 1991

Webb JCO 1997

Wagner 2008

FIGURE 1 Development of palliative systemic chemotherapy for metastatic esophagogastric cancer

Abbreviations:

5-FU=5-fluorouracil

doxo= doxorubicine

FAM=5-fluorouracil, doxorubicine, mitomycine C

FAMTX=5-fluorouracil, doxorubicine, methotrexate

ECF=epirubicine, cisplatin, 5-fluorouracil

Chapter 118

In 2008 Wagner et al.[33] published a Cochrane review investigating the optimal chemo-

therapeutical treatment consisting of a fluoropyrimidine analogue and a platinum com-

pound. Since 2008 new results from randomized trials have been published, including

two-drug combinations.

Although treatments may be effective in terms of survival, the level of side effects should

also be taken into account. In order to select the optimal treatment balancing survival

gain and toxicity, in chapter 6 we investigate the efficacy and safety of triplet versus dou-

blet chemotherapy in patients with advanced and metastatic gastro-esophageal disease

in a systematic review and meta-analysis.

In metastatic pancreatic cancer, progress in identifying effective novel treatments has

been limited. Until recently, gemcitabine was the standard of care, based on findings of a

study conducted more than fifteen years ago. In the pivotal trial by Burris et al in 1997 [44]

gemcitabine vs. 5-FU monotherapy was shown to have a small significant benefit in over-

all survival from 4.4 months to 5.7 months. The clinical benefit was a composite measure of

pain (analgesic consumption and pain intensity), performance status, and weight. Clinical

benefit required a sustained (≥4 weeks) improvement in at least one parameter without

worsening in any of the others and occurred in almost one quarter of the patients treated

with gemcitabine compared to a scarce five percent in the 5-FU arm. Since the introduc-

tion of gemcitabine as first line therapy, numerous phase III studies have evaluated differ-

ent gemcitabine-based regimens as first-line therapy, but in all cases, observed benefits,

if any, have been small.[45-49]

However, in 2011 Conroy et al.[50] published the results of FOLFIRINOX (oxaliplatin, irino-

tecan, leucovorin, 5-fluorouracil) compared to gemcitabine that resulted in longer surviv-

al (11.1 vs. 6.8 months, respectively) as well as a delay in deterioration of quality of life.

Also, nab-paclitaxel added to gemcitabine was shown to improve survival from 6.7 to 8.5

months.[51] The two trials included somewhat different patient groups: the FOLFIRINOX

regimen was administered to patients with WHO performance score 0 and 1, while the

gemcitabine and nab-paclitaxel regimen was administered to patients with WHO perfor-

mance score of 0 to 2. The two regimens have not been compared head to head; both

are considered standard of care in the first-line setting for patients with metastatic dis-

ease.[52] (figure 2)

General outline and introduction of the thesis 19

FIGURE 2 Development and usage of palliative systemic chemotherapy for metastatic pancreatic cancer

Abbreviations:

5-FU=5-fluorouracil

GEM= gemcitabine

nabP= nab-paclitaxel

Because survival is poor and treatment is complex with a wide range of local and system-

ic treatment options, variation in treatment modalities for esophageal and pancreatic can-

cer may exist. Moreover, survival from randomized studies usually does not reflect daily

practice, because patients with comorbidities and elderly patients are often underrepre-

sented in clinical trials.[53] To assess whether patterns of care and the effectiveness of treat-

ment confers to a real benefit in the general population, population-based observation-

al research can provide insight. Therefore, in chapter 7 and chapter 8 we use popula-

tion-based data to describe treatment and outcome in patients with metastatic esopha-

geal and pancreatic cancer, respectively.

The cancer care task force of the Dutch Cancer Society concluded that quality of cancer

care in the Netherlands is high. However, they posed that improvements of outcomes are

possible by reducing variation between hospitals.[16] For pancreatic and esophageal can-

cer, since 2006 it has been recommended to concentrate the surgical treatment for up-

per gastro intestinal cancer to improve quality of care. For gastric cancer in 2011 a mini-

mum volume of ten annual gastrectomies was implemented. Esophagectomies, gastrec-

GEM vs 5-FU

FOLFIRINOX

vs GEM

Clinical benefit

5.7 mo

vs 4.4 mo

11.1 mo

vs 6.8 mo

8.5 mo

vs 6.7 mo

Burris JCO 1997

Conroy NEJM 2011

von Hoff NEJM 2013

1996 GEM

2011 FOLFIRINOX

2013 GEM+nabP

Chapter 120

tomies and pancreatectomies have been referred to as highly complex, low volume sur-

gery. Surgical outcomes appear to be better in high-volume centers, related to the lower

incidence and the better management of postoperative complications.[14, 15, 54, 55] For the

association between volume and outcome, the overall hospital volume has been shown

to be even more relevant than the volume of patients treated per individual surgeon [56],

indicating the importance of experienced nonsurgical support for this specific group of

patients. Currently, it is unknown whether outcomes for palliative chemotherapy show an

identical volume association. It may be hypothesized that for treatment of patients with

metastatic cancer, the experience of medical oncologists, as defined by the number of an-

nually treated patients, as well as the combined experience of the whole multidisciplinary

team providing upper gastrointestinal cancer care may be a relevant factor determining

patient outcome. Chapters 9 and 10 describe volume outcome relations for treatment

with palliative chemotherapy in gastro-esophageal cancer and pancreatic cancer, respec-

tively, on the basis of population-based data.

Finally, chapter 11 contains a general discussion and future perspectives on treatment in

patients with upper gastrointestinal cancer in daily practice.

General outline and introduction of the thesis 21

REFERENCES

1. Shapiro J, van Lanschot JJ, Hulshof MC et al. Neoadjuvant chemoradiotherapy plus

surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-

term results of a randomised controlled trial. Lancet Oncol 2015; 16: 1090-1098.

2. Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy versus

surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11-

20.

3. Oettle H, Neuhaus P, Hochhaus A et al. Adjuvant chemotherapy with gemcitabine

and long-term outcomes among patients with resected pancreatic cancer: the

CONKO-001 randomized trial. JAMA 2013; 310: 1473-1481.

4. Dikken JL, Lemmens VE, Wouters MW et al. Increased incidence and survival for

oesophageal cancer but not for gastric cardia cancer in the Netherlands. Eur J

5. Dassen AE, Dikken JL, Bosscha K et al. Gastric cancer: decreasing incidence but stable

survival in the Netherlands. Acta Oncol 2014; 53: 138-142.

6. Sirri E, Castro FA, Kieschke J et al. Recent Trends in Survival of Patients With Pancreatic

Cancer in Germany and the United States. Pancreas 2016.

7. Hartwig W, Werner J, Jager D et al. Improvement of surgical results for pancreatic

cancer. Lancet Oncol 2013; 14: e476-485.

8. Jamieson GG, Mathew G, Ludemann R et al. Postoperative mortality following oe-

sophagectomy and problems in reporting its rate. Br J Surg 2004; 91: 943-947.

9. Luft HS, Bunker JP, Enthoven AC. Should operations be regionalized? The empiri-

cal relation between surgical volume and mortality. N Engl J Med 1979; 301: 1364-

1369.

10. Baxter NN, Whitson BA, Tuttle TM. Trends in the treatment and outcome of pancreatic

cancer in the United States. Ann Surg Oncol 2007; 14: 1320-1326.

11. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29.

12. Integraal Kankercentrum Nederland. Cijfers over kanker: incidentie slokdarmkanker,

maagkanker, alvleeskanker, borstkanker. In: www.cijfersoverkanker.nl 2015.

13. National Cancer Institute. SEER stat fact sheet: esophageal cancer. In Surveillance,

Epidemiology and End Results Program. 2016.

14. de Wilde RF, Besselink MG, van der Tweel I et al. Impact of nationwide centralization

of pancreaticoduodenectomy on hospital mortality. Br J Surg 2012; 99: 404-410.

15. Mamidanna R, Ni Z, Anderson O et al. Surgeon Volume and Cancer

Esophagectomy, Gastrectomy, and Pancreatectomy: A Population-based Study in

England. Ann Surg 2016; 263: 727-732.

16. Wouters MW, Jansen-Landheer ML, van de Velde CJ. The Quality of Cancer Care

initiative in the Netherlands. Eur J Surg Oncol 2010; 36 Suppl 1: S3-S13.

17. van Hagen P, Hulshof MC, van Lanschot JJ et al. Preoperative chemoradiotherapy

Chapter 122

for esophageal or junctional cancer. N Engl J Med 2012; 366: 2074-2084.

18. Clarke M, Collins R, Darby S et al. Effects of radiotherapy and of differences in the

extent of surgery for early breast cancer on local recurrence and 15-year survival: an

overview of the randomised trials. Lancet 2005; 366: 2087-2106.

19. Darby SC, Ewertz M, McGale P et al. Risk of ischemic heart disease in women after

radiotherapy for breast cancer. N Engl J Med 2013; 368: 987-998.

20. Akkerman RD, Haverkamp L, van Rossum PS et al. Long-term quality of life after

oesophagectomy with gastric conduit interposition for cancer. Eur J Cancer 2015;

51: 1538-1545.

21. Jacobs M, Macefield RC, Elbers RG et al. Meta-analysis shows clinically relevant

and long-lasting deterioration in health-related quality of life after esopha-

geal cancer surgery. Qual Life Res 2014; 23: 1155-1176.

22. National Cancer Institute. Family caregivers in cancer:roles and challenges for health

professionals. In: Coping with cancer. http://www.cancer.gov/about-cancer/coping/

family-friends/family-caregivers-hp-pdq2016.

23. Honea NJ, Brintnall R, Given B et al. Putting Evidence into Practice: nursing assess-

ment and interventions to reduce family caregiver strain and burden. Clin J Oncol

Nurs 2008; 12: 507-516.

24. Pitceathly C, Maguire P. The psychological impact of cancer on patients’ partners

and other key relatives: a review. Eur J Cancer 2003; 39: 1517-1524.

25. Soothill K, Morris SM, Harman J et al. The significant unmet needs of cancer pa-

tients: probing psychosocial concerns. Support Care Cancer 2001; 9: 597-605.

26. Mellon S, Northouse LL, Weiss LK. A population-based study of the quality of life

of cancer survivors and their family caregivers. Cancer Nurs 2006; 29: 120-131; quiz

132-123.

27. Henneman D, Dikken JL, Putter H et al. Centralization of esophagectomy: how far

should we go? Ann Surg Oncol 2014; 21: 4068-4074.

28. Herskovic A, Martz K, al-Sarraf M et al. Combined chemotherapy and radiotherapy

compared with radiotherapy alone in patients with cancer of the esophagus. N Engl

J Med 1992; 326: 1593-1598.

29. Gwynne S, Hurt C, Evans M et al. Definitive chemoradiation for oesophageal can-

cer--a standard of care in patients with non-metastatic oesophageal cancer. Clin On-

col (R Coll Radiol) 2011; 23: 182-188.

30. Cooper JS, Guo MD, Herskovic A et al. Chemoradiotherapy of locally advanced

esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG

85-01). Radiation Therapy Oncology Group. JAMA 1999; 281: 1623-1627.

31. Noronha V, Prabhash K, Joshi A et al. Clinical Outcome in Definitive Concurrent

General outline and introduction of the thesis 23

Chemoradiation With Weekly Paclitaxel and Carboplatin for Locally Advanced

Esophageal and Junctional Cancer. Oncol Res 2016; 23: 183-195.

32. Wang H, Ryu J, Gandara D et al. A phase II study of paclitaxel, carboplatin, and radia-

tion with or without surgery for esophageal cancer. J Thorac Oncol 2007;2:

33. Wagner AD, Unverzagt S, Grothe W et al. Chemotherapy for advanced gastric can-

cer. Cochrane Database Syst Rev 2010; CD004064.

34. Kim NK, Park YS, Heo DS et al. A phase III randomized study of 5-fluorouracil and

cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil

alone in the treatment of advanced gastric cancer. Cancer 1993; 71: 3813-3818.

35. Ohtsu A, Shimada Y, Shirao K et al. Randomized phase III trial of fluorouracil alone

versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients

with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group

Study (JCOG9205). J Clin Oncol 2003; 21: 54-59.

36. Ajani JA, Moiseyenko VM, Tjulandin S et al. Clinical benefit with docetaxel plus flu-

orouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial

of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study

Group. J Clin Oncol 2007; 25: 3205-3209.

37. Cunningham D, Starling N, Rao S et al. Capecitabine and oxaliplatin for advanced

esophagogastric cancer. N Engl J Med 2008; 358: 36-46.

38. Roth AD, Fazio N, Stupp R et al. Docetaxel, cisplatin, and fluorouracil; docetaxel

and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treat-

ment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group

for Clinical Cancer Research. J Clin Oncol 2007; 25: 3217-3223.

39. Webb A, Cunningham D, Scarffe JH et al. Randomized trial comparing epirubicin,

cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in ad-

vanced esophagogastric cancer. J Clin Oncol 1997; 15: 261-267.

40. Cullinan SA, Moertel CG, Fleming TR et al. A comparison of three chemotherapeutic

regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluoroura-

cil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA

1985; 253: 2061-2067.

41. Wils JA, Klein HO, Wagener DJ et al. Sequential high-dose methotrexate and flu-

orouracil combined with doxorubicin--a step ahead in the treatment of advanced

gastric cancer: a trial of the European Organization for Research and Treatment of

Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 1991; 9: 827-831.

42. Kelsen D, Atiq OT, Saltz L et al. FAMTX versus etoposide, doxorubicin, and cisplatin:

a random assignment trial in gastric cancer. J Clin Oncol 1992; 10: 541-548.

43. Vanhoefer U, Rougier P, Wilke H et al. Final results of a randomized phase III trial of

Chapter 124

sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide,

leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced

gastric cancer: A trial of the European Organization for Research and Treatment

of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 2000; 18:

2648-2657.

44. Burris HA, 3rd, Moore MJ, Andersen J et al. Improvements in survival and clinical

benefit with gemcitabine as first-line therapy for patients with advanced pancreas

cancer: a randomized trial. J Clin Oncol 1997; 15: 2403-2413.

45. Colucci G, Giuliani F, Gebbia V et al. Gemcitabine alone or with cisplatin for the

treatment of patients with locally advanced and/or metastatic pancreatic carcinoma:

a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Me-

ridionale. Cancer 2002; 94: 902-910.

46. Cunningham D, Chau I, Stocken DD et al. Phase III randomized comparison of gem-

citabine versus gemcitabine plus capecitabine in patients with advanced pancreatic

cancer. J Clin Oncol 2009; 27: 5513-5518.

47. Heinemann V, Quietzsch D, Gieseler F et al. Randomized phase III trial of gemcit-

abine plus cisplatin compared with gemcitabine alone in advanced pancreatic can-

cer. J Clin Oncol 2006; 24: 3946-3952.

48. Louvet C, Labianca R, Hammel P et al. Gemcitabine in combination with oxalipla-

tin compared with gemcitabine alone in locally advanced or metastatic pancreatic

cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23: 3509-

3516.

49. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with

gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of

the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25:

1960-1966.

50. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastat-

ic pancreatic cancer. N Engl J Med 2011; 364: 1817-1825.

51. Von Hoff DD, Ervin T, Arena FP et al. Increased survival in pancreatic cancer with

nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691-1703.

52. 52. National Comprehensive Cancer Network. Pancreatic adenocarcinoma version

2. In: NCCN Clinical Practice Guidelines. http://www.nccn.org/professionals/physi-

cian_gls/pdf/pancreatic.pdf 2015.

53. Booth CM, Tannock IF. Evaluation of treatment benefit: randomized controlled trials

and population-based observational research. J Clin Oncol 2013; 31: 3298-3299.

54. van der Geest LG, van Rijssen LB, Molenaar IQ et al. Volume-outcome relationships

in pancreatoduodenectomy for cancer. HPB (Oxford) 2016; 18: 317-324.

General outline and introduction of the thesis 25

55. Wouters MW, Gooiker GA, van Sandick JW, Tollenaar RA. The volume-outcome re-

lation in the surgical treatment of esophageal cancer: a systematic review and me-

ta-analysis. Cancer 2012; 118: 1754-1763.

56. Gouma DJ, van Geenen RC, van Gulik TM et al. Rates of complications and death

after pancreaticoduodenectomy: risk factors and the impact of hospital volume. Ann

Surg 2000; 232: 786-795.