doi:10.1111/codi.12560
Original article
A prospective pilot study to assess neoadjuvant chemotherapy for unresectable peritoneal carcinomatosis from colorectal cancer D. Hompes*, A. Aalbers*, H. Boot†, M.-L. van Velthuysen‡, W. Vogel§, W. Prevoo¶, H. van Tinteren** and V. Verwaal* *Department of Surgical Oncology, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, †Department of Digestive Oncology, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, ‡Department of Pathology, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, §Department of Nuclear Medicine, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, ¶Department of Radiology, Antoni van Leeuwenhoek-Hospital/ the Netherlands Cancer Institute, Amsterdam, the Netherlands and **Department of Statistics, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands Received 2 September 2013; accepted 13 December 2013; Accepted Article online 16 January 2014
Abstract Aim Twelve to 13% of patients with colorectal cancer (CRC) develop peritoneal carcinomatosis (PC), the majority of whom present with unresectable disease. This study aimed to document the actual response rate to and response characteristics of preoperative modern systemic chemotherapy in this patient group. Method Patients underwent a positron emission tomography (PET)/CT scan, laparoscopy and peritoneal biopsy to document unresectable PC. After four courses of preoperative chemotherapy (capecitabine/ oxaliplatin bevacizumab), the extent of PC was re-evaluated by PET/CT(or CT), laparoscopy and peritoneal biopsy (if considered safe). Results Ten patients (seven men, three women) with good performance status of median age 60.3 (45.6– 72.8) years were studied. The first laparoscopy documented unresectable PC. One patient was excluded because of systemic metastases on PET/CT. Nine proceeded to follow the trial protocol. Of these, one developed early progressive disease, two had macroscopically
Introduction Peritoneal carcinomatosis (PC) occurs in 12–13% of patients with colorectal cancer (CRC) [1–3]. The majority present with unresectable PC, unfit for complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Unresectable Correspondence to: D. Hompes, MD, PhD, Department of Surgical Oncology, University Hospitals Gasthuisberg Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected]
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stable disease and five had progressive disease at second laparoscopy. One patient developed a small bowel perforation at first laparoscopy and received palliative chemotherapy outside the protocol, after which progressive disease was found at an explorative laparotomy. Thus, 7 (78%) patients with unresectable PC from CRC developed progressive disease under neoadjuvant chemotherapy and 2 (22%) patients remained stable. No clear macroscopic response to chemotherapy could be demonstrated. Conclusion Unresectable PC from CRC does not respond well to systemic chemotherapy. Keywords Peritoneal carcinomatosis, colorectal cancer, unresectable, neoadjuvant chemotherapy, response What does this paper add to literature? To our knowledge, this is the first trial that has prospectively assessed and documented the response of unresectable peritoneal carcinomatosis from colorectal cancer to systemic chemotherapy.
PC from CRC has a prognosis with a median overall survival (OS) of 5–6 months [4–9]. Currently these patients are treated with systemic chemotherapy. For unresectable metastatic CRC a median OS of almost 2 years has been reported in patients being treated with modern chemotherapy regimens, with a 5-year OS of about 13% [10], but without any chance of cure [11,12]. There is little information on systemic therapy for PC from CRC [1,4,5,13–15]. After 5-fluorouracil (5-FU)/leucovorin-based chemotherapy median OS of 5.2–12.6 months have been reported [13–15]. It is
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suggested that patients with PC have a longer survival with systemic treatment, but the available data are difficult to interpret because studies often include patients with resectable as well as unresectable PC [1,4,5,13– 15] and PC often accompanies other metastatic sites in liver or lung [1,4,5,16]. The patient’s performance status and comorbidity at diagnosis probably influence the treatment and outcome [2,9,16]. This prospective observational pilot study aimed to document the actual response rate and response characteristics of preoperative modern systemic chemotherapy in patients with initially unresectable PC from CRC, by laparoscopy before and after chemotherapy.
Method
Neoadjuvant chemotherapy for peritoneal carcinomatosis from CRC
erations applied to the biopsy procedure. Before the start of the systemic chemotherapy a positron emission tomography (PET)/CT scan was performed to search for systemic metastases.
Trial step II: preoperative chemotherapy In step II patients received four cycles of systemic chemotherapy.
Trial step III: chemotherapy
re-evaluation
after
neoadjuvant
In step III a re-evaluation of the extent of PC was performed by PET/CT or CT and there was a second laparoscopy, for which the same safety considerations applied as for step I.
Assessment of the extent of PC
Chemotherapeutic agents
The trial aimed to evaluate the efficacy of preoperative chemotherapy with capecitabine, oxaliplatin and bevacizumab in patients with unresectable PC from CRC. Response was assessed by laparoscopic evaluation of the intra-abdominal extent of disease using the seven-region count described by Verwaal et al. [17] and, when a peritoneal biopsy was considered safe, by histopathological examination of a PC-affected region of peritoneum. Unresectable PC is defined as a tumour load of more than five of the seven regions [17,18] and/or extensive involvement of the small bowel by PC.
Every 3 weeks patients received capecitabine (1000 mg/ m² twice daily on days 1–14) and oxaliplatin (130 mg/ m2 on day 1) with or without bevacizumab (7.5 mg/kg on day 1). In patients for whom oral intake was difficult 5-FU (400 mg/m2 in bolus form + 600 mg/m2 as a infusion over 22 h on days 1 and 2) and oxaliplatin (85 mg/m2 on day 1) with or without bevacizumab (5 mg/kg on day 1) were administered every 2 weeks.
Inclusion and exclusion criteria
Patients who had initially been excluded from CCRS + HIPEC due to the extent of their disease were eligible for this trial. Patients had to be fit enough to undergo the entire course of treatment. Patients with systemic metastasis (lung, liver, bone or other extraabdominal sites) were excluded. See Table S1 for more details. Trial schedule
Trial step I: diagnostics At step I of the trial a blood sample was taken, and carcinoembryonic antigen (CEA) and cancer antigen 19–9 (CA19-9) determined. Then the first laparoscopy was performed, with documentation of all seven abdominal regions with digital photographs. A biopsy of a PCaffected peritoneum (1.5 9 1.5 cm) was taken and a similar area of peritoneum was marked with clips. For safety reasons, regions that were inaccessible due to tumour or extensive adhesions were not documented but registered as inaccessible. These same safety consid-
Medical ethics committee
The trial protocol was revised and approved by the local medical ethics committee of the Netherlands Cancer Institute/Antoni van Leeuwenhoek-Hospital and by the National Research Authorities. All patients gave written informed consent. Statistical analysis
The primary objective was to assess the efficacy of preoperative chemotherapy in reducing the number of regions affected from more than five to less than or equal to five. Because experience with the proposed chemotherapeutic regimen already existed and this regimen was given to patients with inoperable PC, a onetailed (rather than a two-tailed) design was considered to be more efficient and practical. The highest response rate, which if true would imply that the treatment did not warrant further investigation, was set at 20%. The smallest rate that would imply that the treatment had potential and would be investigated further was set at 40%. The hypothesis was tested at a = 0.05 and a 90% power. Applying the method of A’Hern, a sample size of 47 (evaluable) patients was
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needed with 15 being the minimum number of responses required for the conclusion of ‘efficacy’ [19].
Results Patient and tumour characteristics
Ten patients were included into the trial. Table 1 summarizes patient characteristics, the Eastern Cooperative Oncology Group (ECOG) performance status (PS) [20] and the tumour characteristics (localization, pGTNM data). PC was already present at diagnosis of
the primary tumour in all patients. One patient in whom the primary tumour and the PC had both been resected 28 months previously presented with recurrent PC. The median interval between the diagnosis of the primary tumour and inclusion into this trial was 2.1 (0.0–28.0) months. In half of the patients the primary tumour was still in situ at inclusion in the trial. Intra-operative findings before and after neoadjuvant chemotherapy
All patients included had histopathological proof of PC from CRC. The median CEA value at inclusion was 11.5 lg/l (range 1.0–256.0 lg/l1). See Table 2.
Table 1 Patient and tumour characteristics. Patient or tumour characteristic Male/female Median age at inclusion (years) Patient’s general condition ASA score
ECOG performance status Primary tumour Localization
G stage T stage
N stage Cell type In situ at inclusion Peritoneal carcinomatosis (PC) Synchronous Previous PC?* Interval between diagnosis of PC and inclusion (months)
No. of patients (n = 10) 7/3 60.3 (range 45.6–72.8)
1 2 3 0 1
4 3 3 7 3
Appendix Right colon Left colon Rectosigmoid Rectum G2 Gx T3 T4 Tx N1 Nx Mucinous type Signet cells
4 1 1 3 1 2 8 1 4 5 3 7 4 1 5
10 1 2.1 (range 0–28.0)
*One patient had a medical history of primary CRC and PC, which was resected earlier: that patient was included in this trial with recurrent PC.
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Trial step I In nine patients PET/CT showed PC without systemic metastases. In seven of them laparoscopy showed six or seven abdominal regions and the small bowel to be affected by PC. In two patients the pelvis was inaccessible for assessment and in two others extensive invasion of the small bowel was the main reason for unresectability. One of these patients had an inaccessible right hemiabdomen. A peritoneal biopsy could be taken in eight patients, showing adenocarcinoma in seven and mucin without cells in one; in this patient, the primary tumour was found to be a moderately differentiated adenocarcinoma of the transverse colon. For logistical reasons, PET/CT could only be performed after laparoscopy in patient G (see Table 2 for patient designations). Unfortunately, liver metastases were found. Hence, this patient was excluded from the trial and started on palliative chemotherapy. Patient I developed a small bowel perforation during laparoscopy, resulting in a postoperative enterocutaneous fistula. She was also excluded from the protocol and, after recovery from this complication, she was started on palliative chemotherapy (5-FU/leucovorin/oxaliplatin).
Trial step II Of the eight patients who went on to have preoperative chemotherapy, four received capecitabine/oxaliplatin with bevacizumab and four received capecitabine/oxaliplatin only. Seven patients received four cycles of chemotherapy, with dose reduction due to chemotoxicity in six. In patient H the systemic therapy was stopped after two cycles, owing to clinical disease progression with bowel obstruction. An early CT scan showed liver metastasis, enlarged mediastinal lymph nodes and progression of PC, and the patient died shortly after discontinuing treatment.
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68.7 52.9 45.6 62.5 58.2 72.8 63.5 52.7 49.8 65.2
Patient
A B C D E F G H I J
M M M F M M F M F M
Gender a, a, a, a, b a, a, b a, a, b b
b b
b b b b
Reason for unresectability* Capox/BV Capox Capox/BV Capox/BV Capox/BV Capox Palliative chemo Capox Folfox Capox
Preop. chemotherapy 20.0 23.0 2.0 20.0 3.0 121.0 3.0 256.0 1.0 3.0
Preop.
CEA (lg/l)
2.0 69.0 6.0 13.0 13.5 156.0 – – – 5.0
Postop. 1† 0 1 0 1 0 NA 0 NA 1
Response on PET/ CT or CT? 0 NA‡ 0 0 0 0 NA NA‡ NA 0
Response at laparoscopy? PD PD SD SD PD PD NA PD PD PD
Stable or progressive disease
No No No No No No Yes§ No Yes– No
Trial stopped
1 1 0 0 1 1 0 1 0 0
Cancerrelated death
M, male; F, female; CEA, carcinoembryonic antigen; SD, stable disease; PD, progressive disease; Capox, capecitabine/oxaliplatin; Fofox, 5-fluorouracil/leucovorin/oxaliplatin; BV, bevacizumab; NA, not applicable; 0, no; 1, yes. *a, PC in 6–7/7 abdominal regions; b, extensive small bowel invasion. †Slight response on positron emission tomography (PET) but slight progression CT. ‡Laparoscopy not performed because of clinical progressive disease (ileus) and systemic metastases/progressive disease on CT. §PET/CT was performed after laparoscopy: trial was stopped because of liver metastases. ¶Trial stopped because of small bowel perforation at laparoscopy: extensive PC.
Age (years)
Table 2 Intra-operative findings before and after preoperative chemotherapy.
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Trial step III After the end of preoperative chemotherapy the median CEA value was 13.0 (2.0–156) lg/l. For patient B the second CT scan showed evident progression of the PC, and for this reason no second laparoscopy was performed. In the other six patients, who all completed the preoperative chemotherapy, the second PET/CT or CT showed stable disease in three and suggested slight regression of PC in the other three. At second laparoscopy all six patients had PC in six or seven abdominal regions and extensive small bowel involvement. PC had remained stable in two patients and progressed in four. The subhepatic space was inaccessible in two patients and the pelvis in one. Due to safety considerations peritoneal biopsies were only taken in three patients: two showed adenocarcinoma and one showed mucin only. Patient I was found to have progressive PC disease during laparotomy performed outside the protocol, despite the palliative chemotherapy she had received. As an example, Fig. 1 shows intra-operative laparoscopic views of the seven abdominal regions in two patients before and after chemotherapy. The histopathological images of the peritoneal biopsies taken in Patient A show a mucinous tumour in which cellularity almost disappeared after chemotherapy, whereas in patient C, chemotherapy barely changed the cellularity of the tumour (Fig. 2).
Trial closure No response to chemotherapy could be demonstrated in any of the included patients. For this reason, is would have been unethical to include further patients in the trial. The median OS for the included patients was 8.3 (range 1.4–16.8) months.
Discussion The majority of patients with PC from CRC present with unresectable disease [4,16] and have a very poor prognosis [4–9]. Currently, systemic chemotherapy is the only available treatment option for these patients. Under modern chemotherapy regimens, there are reports of a median OS of of 23.9 months and a 5-year OS of 13% for metastatic CRC [11,12]. It is difficult to determine whether this finding for metastatic CRC in general also applies to PC. Preoperative chemotherapy is accepted as a down-sizing technique for initially unresectable systemic metastases from CRC, especially liver metastases, with response rates as high as 50% [21–25]. Conversion to resectability occurs in 10–20% [21–24], which results in 5-year OS rates of 30–40% [21]. At present, reported data on the efficacy of systemic chemotherapy for PC are scarce and difficult to interpret.
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Three important observations should, however, be made. First there are few data on the effect of chemotherapy for PC, although there is some information in the literature on the difference between chemotherapy and CCRS + HIPEC. Thus, in a multicentre study, Elias et al. compared the outcome of patients with resectable PC from CRC treated by palliative chemotherapy with that of patients with a comparable extent of PC undergoing CCRS + HIPEC. In these highly selected patients with limited PC, the median survival was 23.9 months in the chemotherapy group compared with 62.7 months in the HIPEC group [10]. In a retrospective study by Passot et al., 90 patients received preoperative chemotherapy before undergoing CCRS + HIPEC. The authors found a response in 36% of patients, stable disease in 21% and progressive disease in 21%, but it should be noted that response was assessed on data from previous explorative surgery and/or radiological imaging [26]. The literature on systemic chemotherapy is far less optimistic when patients with resectable and unresectable PC are combined in one trial [13,14,27,28]. The randomized controlled trial by Verwaal et al. [14] reports a disease-specific survival of 12.6 months. A retrospective trial by Zani et al. [28] reports a median OS of 16.3 months under modern chemotherapy and Klaver et al. [27] reported a median OS of 18.2 months after adding a biological agent to the chemotherapy, but no clear data on the extent of PC are given and this retrospective study included patients who were rejected for CCRS + HIPEC based on the presence of systemic metastases or advanced age. For unresectable PC, results are even worse. A retrospective analysis by Hompes et al. [9] showed a median OS of 6.3 months, with a median OS of 9.3 months after chemotherapy vs 3.1 months without chemotherapy. Pelz et al. [15] reported comparable findings, with 12.0 months under modern chemotherapy regimens vs a median OS of 5.0 months without chemotherapy. Thus, with a median OS of 8.3 months (range 1.4–16.8 months) the results of this trial concur with the literature data on patients with unresectable PC undergoing systemic chemotherapy. It is important to note that, because the few published data on systemic therapy for PC from CRC are heterogeneous and because there are no clear data available on the ‘natural history’ of PC from CRC (i.e. the outcome without chemotherapy), no clear conclusions can be drawn on the potential benefit to OS of systemic chemotherapy for PC from CRC. In the present trial, systemic chemotherapy does not convert unresectable PC into resectable PC, thus turning these patients into candidates for cure by CCRS + HIPEC. Nevertheless, systemic chemotherapy might still result in a benefit to OS for some.
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Abdominal region
Before Chemotherapy
After Chemotherapy
Right subprenic space [Patient J]
Left subphrenic space [Patient J]
Subhepatic space [Patient A]
Omentum / Transverse colon [Patient A]
Right lower abdomen [Patient A]
Small bowel / Mesentery [Patient A]
Pelvis
[Patient J]
Figure 1 Digital photographs of peritoneal carcinomatosis in the seven abdominal regions before and after preoperative chemotherapy. The figure shows laparoscopic views from different abdominal regions in patients A and J before and after systemic chemotherapy in order to document the response to chemotherapy.
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Patient A
Patient C
Before Chemotherapy
After Chemotherapy
Figure 2 Histopathology of peritoneal carcinomatosis from colorectal cancer before and after preoperative chemotherapy in patients A and C to document the response to chemotherapy.
Secondly, performance status (PS) is an important clinical predictive factor for survival in patients with Stage IV disease [16,17]. PS, age and American Society of Anesthesiologists (ASA) score, and postoperative morbidity and mortality after palliative surgery are important prognostic factors for OS in patients with unresectable CRC metastases [9,29]. Furthermore, treatment differed significantly for different extents of PC in Pelz’s study [15]. Patients who did not receive chemotherapy more frequently had a high tumour load. Also, low tumour load initially showed a tendency toward benefit from chemotherapy, but after 3 years survival was similar for different extents of disease. The best results with chemotherapy were reached in patients with low tumour load and in patients with PC only (i.e. without systemic metastases) [15]. There are several Indications that PC as a local phenomenon has a higher influence on OS than systemic dissemination [5,9,15]. PC is a major cause of disease-specific mortality in patients with metastatic CRC [5]. According to Pelz et al. [15] the biologically aggressive nature of PC impairs the functional status of patients to an extent that they are only eligible for best supportive care. Thirdly the difficulty of assessment of PC lies in the inability to image lesions < 1 cm in diameter and to assess tumour response on the RECIST criteria. Thus the extent of PC and the treatment response cannot be accurately documented or monitored [15]. This makes retrospective evaluation of PCI (the peritoneal carcinomatosis index according to Sugarbaker) very difficult. For this reason Pelz et al. [15,30] used the terms ‘low’, ‘moderate’ and ‘extensive’ to describe the tumour burden, analogous to the PCI. Still, this remains only an estimate of the extent of PC. Laparoscopy is the only reliable tool that is currently available to assess the extent of PC.
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This observational pilot study provides the first prospective assessment of unresectable PC from CRC under modern systemic chemotherapy. Laparoscopy was performed to assess the extent of PC before and after combined chemotherapy with capecitabine/oxaliplatin with or without bevacizumab. All included patients had a good PS and ASA score at PC diagnosis. One patient had to be excluded because of systemic metastases. Based on the tumour markers, only two showed some response to chemotherapy and in four of the nine patients the imaging data suggested there might be a response. Nevertheless, surgical exploration showed that of the nine patients who proceeded within the trial protocol, two developed early progressive disease, two had macroscopically stable disease, four had progressive disease at laparoscopy and one had proven progressive disease at laparotomy after palliative chemotherapy outside the protocol. In other words, 78% of patients had progressive disease while under chemotherapy and 22% had stable disease. No clear macroscopic response to chemotherapy could be demonstrated (Table 2). When compared with the data of Passot et al. [26] our findings indeed suggest that disease assessment based on imaging and tumour markers alone might provide an optimistic interpretation of the response of PC to systemic chemotherapy. Because no response to chemotherapy could be demonstrated in any of the included patients, further inclusion of more patients into the trial seemed unethical. As a result, only a very small number of patients were included, which is a serious limitation to this trial. In addition, half the patients had a tumour of unfavourable histological type (mucinous or signet cell type), which makes the interpretation of results even more difficult. On the other hand, the current literature offers no clear
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prospective data on the results of chemotherapy in unresectable PC from CRC. Therefore, despite these important limitations, we feel the results of this trial could still be of value. Furthermore, despite the good performance status of all patients at the start of chemotherapy, the majority completed their systemic chemotherapy with reduced dose, which indicates that PC has a substantial influence on the patient’s functional status. Assessment of the extent of PC was often incomplete as all seven abdominal regions were not always fully accessible for macroscopic assessment. Nevertheless the criteria for unresectability were met in all cases, so this fact does not affect outcome. It was often not possible to obtain peritoneal biopsies, and biopsies before and after chemotherapy could only be compared in patients A and C. In conclusion, the trial has demonstrated that PC does not respond well to systemically administered chemotherapy. None of the patients showed a macroscopic response to preoperative chemotherapy and in none was the PC rendered resectable by chemotherapy.
Author contributions Concept & statistics: D. Hompes, V. Verwaal, H. van Tinteren. Data acquisition: D. Hompes, A. Aalbers, H. Boot, V. Verwaal. Pathology data: M.-L. van Velthuysen. Imaging data: W. Vogel, W. Prevoo. Data analysis, interpretation & writing manuscript: D. Hompes, V. Verwaal.
Conflict of interest None of the authors have any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.
Funding No funding sources to be disclosed.
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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Inclusion and exclusion criteria.
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Original article
A prospective pilot study to assess neoadjuvant chemotherapy for unresectable peritoneal carcinomatosis from colorectal cancer D. Hompes*, A. Aalbers*, H. Boot†, M.-L. van Velthuysen‡, W. Vogel§, W. Prevoo¶, H. van Tinteren** and V. Verwaal* *Department of Surgical Oncology, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, †Department of Digestive Oncology, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, ‡Department of Pathology, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, §Department of Nuclear Medicine, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands, ¶Department of Radiology, Antoni van Leeuwenhoek-Hospital/ the Netherlands Cancer Institute, Amsterdam, the Netherlands and **Department of Statistics, Antoni van Leeuwenhoek-Hospital/the Netherlands Cancer Institute, Amsterdam, the Netherlands Received 2 September 2013; accepted 13 December 2013; Accepted Article online 16 January 2014
Abstract Aim Twelve to 13% of patients with colorectal cancer (CRC) develop peritoneal carcinomatosis (PC), the majority of whom present with unresectable disease. This study aimed to document the actual response rate to and response characteristics of preoperative modern systemic chemotherapy in this patient group. Method Patients underwent a positron emission tomography (PET)/CT scan, laparoscopy and peritoneal biopsy to document unresectable PC. After four courses of preoperative chemotherapy (capecitabine/ oxaliplatin bevacizumab), the extent of PC was re-evaluated by PET/CT(or CT), laparoscopy and peritoneal biopsy (if considered safe). Results Ten patients (seven men, three women) with good performance status of median age 60.3 (45.6– 72.8) years were studied. The first laparoscopy documented unresectable PC. One patient was excluded because of systemic metastases on PET/CT. Nine proceeded to follow the trial protocol. Of these, one developed early progressive disease, two had macroscopically
Introduction Peritoneal carcinomatosis (PC) occurs in 12–13% of patients with colorectal cancer (CRC) [1–3]. The majority present with unresectable PC, unfit for complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Unresectable Correspondence to: D. Hompes, MD, PhD, Department of Surgical Oncology, University Hospitals Gasthuisberg Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected]
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stable disease and five had progressive disease at second laparoscopy. One patient developed a small bowel perforation at first laparoscopy and received palliative chemotherapy outside the protocol, after which progressive disease was found at an explorative laparotomy. Thus, 7 (78%) patients with unresectable PC from CRC developed progressive disease under neoadjuvant chemotherapy and 2 (22%) patients remained stable. No clear macroscopic response to chemotherapy could be demonstrated. Conclusion Unresectable PC from CRC does not respond well to systemic chemotherapy. Keywords Peritoneal carcinomatosis, colorectal cancer, unresectable, neoadjuvant chemotherapy, response What does this paper add to literature? To our knowledge, this is the first trial that has prospectively assessed and documented the response of unresectable peritoneal carcinomatosis from colorectal cancer to systemic chemotherapy.
PC from CRC has a prognosis with a median overall survival (OS) of 5–6 months [4–9]. Currently these patients are treated with systemic chemotherapy. For unresectable metastatic CRC a median OS of almost 2 years has been reported in patients being treated with modern chemotherapy regimens, with a 5-year OS of about 13% [10], but without any chance of cure [11,12]. There is little information on systemic therapy for PC from CRC [1,4,5,13–15]. After 5-fluorouracil (5-FU)/leucovorin-based chemotherapy median OS of 5.2–12.6 months have been reported [13–15]. It is
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suggested that patients with PC have a longer survival with systemic treatment, but the available data are difficult to interpret because studies often include patients with resectable as well as unresectable PC [1,4,5,13– 15] and PC often accompanies other metastatic sites in liver or lung [1,4,5,16]. The patient’s performance status and comorbidity at diagnosis probably influence the treatment and outcome [2,9,16]. This prospective observational pilot study aimed to document the actual response rate and response characteristics of preoperative modern systemic chemotherapy in patients with initially unresectable PC from CRC, by laparoscopy before and after chemotherapy.
Method
Neoadjuvant chemotherapy for peritoneal carcinomatosis from CRC
erations applied to the biopsy procedure. Before the start of the systemic chemotherapy a positron emission tomography (PET)/CT scan was performed to search for systemic metastases.
Trial step II: preoperative chemotherapy In step II patients received four cycles of systemic chemotherapy.
Trial step III: chemotherapy
re-evaluation
after
neoadjuvant
In step III a re-evaluation of the extent of PC was performed by PET/CT or CT and there was a second laparoscopy, for which the same safety considerations applied as for step I.
Assessment of the extent of PC
Chemotherapeutic agents
The trial aimed to evaluate the efficacy of preoperative chemotherapy with capecitabine, oxaliplatin and bevacizumab in patients with unresectable PC from CRC. Response was assessed by laparoscopic evaluation of the intra-abdominal extent of disease using the seven-region count described by Verwaal et al. [17] and, when a peritoneal biopsy was considered safe, by histopathological examination of a PC-affected region of peritoneum. Unresectable PC is defined as a tumour load of more than five of the seven regions [17,18] and/or extensive involvement of the small bowel by PC.
Every 3 weeks patients received capecitabine (1000 mg/ m² twice daily on days 1–14) and oxaliplatin (130 mg/ m2 on day 1) with or without bevacizumab (7.5 mg/kg on day 1). In patients for whom oral intake was difficult 5-FU (400 mg/m2 in bolus form + 600 mg/m2 as a infusion over 22 h on days 1 and 2) and oxaliplatin (85 mg/m2 on day 1) with or without bevacizumab (5 mg/kg on day 1) were administered every 2 weeks.
Inclusion and exclusion criteria
Patients who had initially been excluded from CCRS + HIPEC due to the extent of their disease were eligible for this trial. Patients had to be fit enough to undergo the entire course of treatment. Patients with systemic metastasis (lung, liver, bone or other extraabdominal sites) were excluded. See Table S1 for more details. Trial schedule
Trial step I: diagnostics At step I of the trial a blood sample was taken, and carcinoembryonic antigen (CEA) and cancer antigen 19–9 (CA19-9) determined. Then the first laparoscopy was performed, with documentation of all seven abdominal regions with digital photographs. A biopsy of a PCaffected peritoneum (1.5 9 1.5 cm) was taken and a similar area of peritoneum was marked with clips. For safety reasons, regions that were inaccessible due to tumour or extensive adhesions were not documented but registered as inaccessible. These same safety consid-
Medical ethics committee
The trial protocol was revised and approved by the local medical ethics committee of the Netherlands Cancer Institute/Antoni van Leeuwenhoek-Hospital and by the National Research Authorities. All patients gave written informed consent. Statistical analysis
The primary objective was to assess the efficacy of preoperative chemotherapy in reducing the number of regions affected from more than five to less than or equal to five. Because experience with the proposed chemotherapeutic regimen already existed and this regimen was given to patients with inoperable PC, a onetailed (rather than a two-tailed) design was considered to be more efficient and practical. The highest response rate, which if true would imply that the treatment did not warrant further investigation, was set at 20%. The smallest rate that would imply that the treatment had potential and would be investigated further was set at 40%. The hypothesis was tested at a = 0.05 and a 90% power. Applying the method of A’Hern, a sample size of 47 (evaluable) patients was
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needed with 15 being the minimum number of responses required for the conclusion of ‘efficacy’ [19].
Results Patient and tumour characteristics
Ten patients were included into the trial. Table 1 summarizes patient characteristics, the Eastern Cooperative Oncology Group (ECOG) performance status (PS) [20] and the tumour characteristics (localization, pGTNM data). PC was already present at diagnosis of
the primary tumour in all patients. One patient in whom the primary tumour and the PC had both been resected 28 months previously presented with recurrent PC. The median interval between the diagnosis of the primary tumour and inclusion into this trial was 2.1 (0.0–28.0) months. In half of the patients the primary tumour was still in situ at inclusion in the trial. Intra-operative findings before and after neoadjuvant chemotherapy
All patients included had histopathological proof of PC from CRC. The median CEA value at inclusion was 11.5 lg/l (range 1.0–256.0 lg/l1). See Table 2.
Table 1 Patient and tumour characteristics. Patient or tumour characteristic Male/female Median age at inclusion (years) Patient’s general condition ASA score
ECOG performance status Primary tumour Localization
G stage T stage
N stage Cell type In situ at inclusion Peritoneal carcinomatosis (PC) Synchronous Previous PC?* Interval between diagnosis of PC and inclusion (months)
No. of patients (n = 10) 7/3 60.3 (range 45.6–72.8)
1 2 3 0 1
4 3 3 7 3
Appendix Right colon Left colon Rectosigmoid Rectum G2 Gx T3 T4 Tx N1 Nx Mucinous type Signet cells
4 1 1 3 1 2 8 1 4 5 3 7 4 1 5
10 1 2.1 (range 0–28.0)
*One patient had a medical history of primary CRC and PC, which was resected earlier: that patient was included in this trial with recurrent PC.
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Trial step I In nine patients PET/CT showed PC without systemic metastases. In seven of them laparoscopy showed six or seven abdominal regions and the small bowel to be affected by PC. In two patients the pelvis was inaccessible for assessment and in two others extensive invasion of the small bowel was the main reason for unresectability. One of these patients had an inaccessible right hemiabdomen. A peritoneal biopsy could be taken in eight patients, showing adenocarcinoma in seven and mucin without cells in one; in this patient, the primary tumour was found to be a moderately differentiated adenocarcinoma of the transverse colon. For logistical reasons, PET/CT could only be performed after laparoscopy in patient G (see Table 2 for patient designations). Unfortunately, liver metastases were found. Hence, this patient was excluded from the trial and started on palliative chemotherapy. Patient I developed a small bowel perforation during laparoscopy, resulting in a postoperative enterocutaneous fistula. She was also excluded from the protocol and, after recovery from this complication, she was started on palliative chemotherapy (5-FU/leucovorin/oxaliplatin).
Trial step II Of the eight patients who went on to have preoperative chemotherapy, four received capecitabine/oxaliplatin with bevacizumab and four received capecitabine/oxaliplatin only. Seven patients received four cycles of chemotherapy, with dose reduction due to chemotoxicity in six. In patient H the systemic therapy was stopped after two cycles, owing to clinical disease progression with bowel obstruction. An early CT scan showed liver metastasis, enlarged mediastinal lymph nodes and progression of PC, and the patient died shortly after discontinuing treatment.
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68.7 52.9 45.6 62.5 58.2 72.8 63.5 52.7 49.8 65.2
Patient
A B C D E F G H I J
M M M F M M F M F M
Gender a, a, a, a, b a, a, b a, a, b b
b b
b b b b
Reason for unresectability* Capox/BV Capox Capox/BV Capox/BV Capox/BV Capox Palliative chemo Capox Folfox Capox
Preop. chemotherapy 20.0 23.0 2.0 20.0 3.0 121.0 3.0 256.0 1.0 3.0
Preop.
CEA (lg/l)
2.0 69.0 6.0 13.0 13.5 156.0 – – – 5.0
Postop. 1† 0 1 0 1 0 NA 0 NA 1
Response on PET/ CT or CT? 0 NA‡ 0 0 0 0 NA NA‡ NA 0
Response at laparoscopy? PD PD SD SD PD PD NA PD PD PD
Stable or progressive disease
No No No No No No Yes§ No Yes– No
Trial stopped
1 1 0 0 1 1 0 1 0 0
Cancerrelated death
M, male; F, female; CEA, carcinoembryonic antigen; SD, stable disease; PD, progressive disease; Capox, capecitabine/oxaliplatin; Fofox, 5-fluorouracil/leucovorin/oxaliplatin; BV, bevacizumab; NA, not applicable; 0, no; 1, yes. *a, PC in 6–7/7 abdominal regions; b, extensive small bowel invasion. †Slight response on positron emission tomography (PET) but slight progression CT. ‡Laparoscopy not performed because of clinical progressive disease (ileus) and systemic metastases/progressive disease on CT. §PET/CT was performed after laparoscopy: trial was stopped because of liver metastases. ¶Trial stopped because of small bowel perforation at laparoscopy: extensive PC.
Age (years)
Table 2 Intra-operative findings before and after preoperative chemotherapy.
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Trial step III After the end of preoperative chemotherapy the median CEA value was 13.0 (2.0–156) lg/l. For patient B the second CT scan showed evident progression of the PC, and for this reason no second laparoscopy was performed. In the other six patients, who all completed the preoperative chemotherapy, the second PET/CT or CT showed stable disease in three and suggested slight regression of PC in the other three. At second laparoscopy all six patients had PC in six or seven abdominal regions and extensive small bowel involvement. PC had remained stable in two patients and progressed in four. The subhepatic space was inaccessible in two patients and the pelvis in one. Due to safety considerations peritoneal biopsies were only taken in three patients: two showed adenocarcinoma and one showed mucin only. Patient I was found to have progressive PC disease during laparotomy performed outside the protocol, despite the palliative chemotherapy she had received. As an example, Fig. 1 shows intra-operative laparoscopic views of the seven abdominal regions in two patients before and after chemotherapy. The histopathological images of the peritoneal biopsies taken in Patient A show a mucinous tumour in which cellularity almost disappeared after chemotherapy, whereas in patient C, chemotherapy barely changed the cellularity of the tumour (Fig. 2).
Trial closure No response to chemotherapy could be demonstrated in any of the included patients. For this reason, is would have been unethical to include further patients in the trial. The median OS for the included patients was 8.3 (range 1.4–16.8) months.
Discussion The majority of patients with PC from CRC present with unresectable disease [4,16] and have a very poor prognosis [4–9]. Currently, systemic chemotherapy is the only available treatment option for these patients. Under modern chemotherapy regimens, there are reports of a median OS of of 23.9 months and a 5-year OS of 13% for metastatic CRC [11,12]. It is difficult to determine whether this finding for metastatic CRC in general also applies to PC. Preoperative chemotherapy is accepted as a down-sizing technique for initially unresectable systemic metastases from CRC, especially liver metastases, with response rates as high as 50% [21–25]. Conversion to resectability occurs in 10–20% [21–24], which results in 5-year OS rates of 30–40% [21]. At present, reported data on the efficacy of systemic chemotherapy for PC are scarce and difficult to interpret.
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Three important observations should, however, be made. First there are few data on the effect of chemotherapy for PC, although there is some information in the literature on the difference between chemotherapy and CCRS + HIPEC. Thus, in a multicentre study, Elias et al. compared the outcome of patients with resectable PC from CRC treated by palliative chemotherapy with that of patients with a comparable extent of PC undergoing CCRS + HIPEC. In these highly selected patients with limited PC, the median survival was 23.9 months in the chemotherapy group compared with 62.7 months in the HIPEC group [10]. In a retrospective study by Passot et al., 90 patients received preoperative chemotherapy before undergoing CCRS + HIPEC. The authors found a response in 36% of patients, stable disease in 21% and progressive disease in 21%, but it should be noted that response was assessed on data from previous explorative surgery and/or radiological imaging [26]. The literature on systemic chemotherapy is far less optimistic when patients with resectable and unresectable PC are combined in one trial [13,14,27,28]. The randomized controlled trial by Verwaal et al. [14] reports a disease-specific survival of 12.6 months. A retrospective trial by Zani et al. [28] reports a median OS of 16.3 months under modern chemotherapy and Klaver et al. [27] reported a median OS of 18.2 months after adding a biological agent to the chemotherapy, but no clear data on the extent of PC are given and this retrospective study included patients who were rejected for CCRS + HIPEC based on the presence of systemic metastases or advanced age. For unresectable PC, results are even worse. A retrospective analysis by Hompes et al. [9] showed a median OS of 6.3 months, with a median OS of 9.3 months after chemotherapy vs 3.1 months without chemotherapy. Pelz et al. [15] reported comparable findings, with 12.0 months under modern chemotherapy regimens vs a median OS of 5.0 months without chemotherapy. Thus, with a median OS of 8.3 months (range 1.4–16.8 months) the results of this trial concur with the literature data on patients with unresectable PC undergoing systemic chemotherapy. It is important to note that, because the few published data on systemic therapy for PC from CRC are heterogeneous and because there are no clear data available on the ‘natural history’ of PC from CRC (i.e. the outcome without chemotherapy), no clear conclusions can be drawn on the potential benefit to OS of systemic chemotherapy for PC from CRC. In the present trial, systemic chemotherapy does not convert unresectable PC into resectable PC, thus turning these patients into candidates for cure by CCRS + HIPEC. Nevertheless, systemic chemotherapy might still result in a benefit to OS for some.
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Abdominal region
Before Chemotherapy
After Chemotherapy
Right subprenic space [Patient J]
Left subphrenic space [Patient J]
Subhepatic space [Patient A]
Omentum / Transverse colon [Patient A]
Right lower abdomen [Patient A]
Small bowel / Mesentery [Patient A]
Pelvis
[Patient J]
Figure 1 Digital photographs of peritoneal carcinomatosis in the seven abdominal regions before and after preoperative chemotherapy. The figure shows laparoscopic views from different abdominal regions in patients A and J before and after systemic chemotherapy in order to document the response to chemotherapy.
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Patient A
Patient C
Before Chemotherapy
After Chemotherapy
Figure 2 Histopathology of peritoneal carcinomatosis from colorectal cancer before and after preoperative chemotherapy in patients A and C to document the response to chemotherapy.
Secondly, performance status (PS) is an important clinical predictive factor for survival in patients with Stage IV disease [16,17]. PS, age and American Society of Anesthesiologists (ASA) score, and postoperative morbidity and mortality after palliative surgery are important prognostic factors for OS in patients with unresectable CRC metastases [9,29]. Furthermore, treatment differed significantly for different extents of PC in Pelz’s study [15]. Patients who did not receive chemotherapy more frequently had a high tumour load. Also, low tumour load initially showed a tendency toward benefit from chemotherapy, but after 3 years survival was similar for different extents of disease. The best results with chemotherapy were reached in patients with low tumour load and in patients with PC only (i.e. without systemic metastases) [15]. There are several Indications that PC as a local phenomenon has a higher influence on OS than systemic dissemination [5,9,15]. PC is a major cause of disease-specific mortality in patients with metastatic CRC [5]. According to Pelz et al. [15] the biologically aggressive nature of PC impairs the functional status of patients to an extent that they are only eligible for best supportive care. Thirdly the difficulty of assessment of PC lies in the inability to image lesions < 1 cm in diameter and to assess tumour response on the RECIST criteria. Thus the extent of PC and the treatment response cannot be accurately documented or monitored [15]. This makes retrospective evaluation of PCI (the peritoneal carcinomatosis index according to Sugarbaker) very difficult. For this reason Pelz et al. [15,30] used the terms ‘low’, ‘moderate’ and ‘extensive’ to describe the tumour burden, analogous to the PCI. Still, this remains only an estimate of the extent of PC. Laparoscopy is the only reliable tool that is currently available to assess the extent of PC.
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This observational pilot study provides the first prospective assessment of unresectable PC from CRC under modern systemic chemotherapy. Laparoscopy was performed to assess the extent of PC before and after combined chemotherapy with capecitabine/oxaliplatin with or without bevacizumab. All included patients had a good PS and ASA score at PC diagnosis. One patient had to be excluded because of systemic metastases. Based on the tumour markers, only two showed some response to chemotherapy and in four of the nine patients the imaging data suggested there might be a response. Nevertheless, surgical exploration showed that of the nine patients who proceeded within the trial protocol, two developed early progressive disease, two had macroscopically stable disease, four had progressive disease at laparoscopy and one had proven progressive disease at laparotomy after palliative chemotherapy outside the protocol. In other words, 78% of patients had progressive disease while under chemotherapy and 22% had stable disease. No clear macroscopic response to chemotherapy could be demonstrated (Table 2). When compared with the data of Passot et al. [26] our findings indeed suggest that disease assessment based on imaging and tumour markers alone might provide an optimistic interpretation of the response of PC to systemic chemotherapy. Because no response to chemotherapy could be demonstrated in any of the included patients, further inclusion of more patients into the trial seemed unethical. As a result, only a very small number of patients were included, which is a serious limitation to this trial. In addition, half the patients had a tumour of unfavourable histological type (mucinous or signet cell type), which makes the interpretation of results even more difficult. On the other hand, the current literature offers no clear
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prospective data on the results of chemotherapy in unresectable PC from CRC. Therefore, despite these important limitations, we feel the results of this trial could still be of value. Furthermore, despite the good performance status of all patients at the start of chemotherapy, the majority completed their systemic chemotherapy with reduced dose, which indicates that PC has a substantial influence on the patient’s functional status. Assessment of the extent of PC was often incomplete as all seven abdominal regions were not always fully accessible for macroscopic assessment. Nevertheless the criteria for unresectability were met in all cases, so this fact does not affect outcome. It was often not possible to obtain peritoneal biopsies, and biopsies before and after chemotherapy could only be compared in patients A and C. In conclusion, the trial has demonstrated that PC does not respond well to systemically administered chemotherapy. None of the patients showed a macroscopic response to preoperative chemotherapy and in none was the PC rendered resectable by chemotherapy.
Author contributions Concept & statistics: D. Hompes, V. Verwaal, H. van Tinteren. Data acquisition: D. Hompes, A. Aalbers, H. Boot, V. Verwaal. Pathology data: M.-L. van Velthuysen. Imaging data: W. Vogel, W. Prevoo. Data analysis, interpretation & writing manuscript: D. Hompes, V. Verwaal.
Conflict of interest None of the authors have any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.
Funding No funding sources to be disclosed.
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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Inclusion and exclusion criteria.
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