Ann Surg Oncol DOI 10.1245/s10434-014-3647-0

ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY

Pathological Response to Neoadjuvant Chemotherapy: A New Prognosis Tool for the Curative Management of Peritoneal Colorectal Carcinomatosis Guillaume Passot1,2, Benoıˆt You2,3, Gilles Boschetti4, Juliette Fontaine5, Sylvie Isaac5, Evelyne Decullier6,7, Christele Maurice6,7, Delphine Vaudoyer1,2, Franc¸ois-Noe¨l Gilly1,2, Eddy Cotte1,2, and Olivier Glehen1,2,8 1

Department of Oncologic and General Surgery, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud Pierre Be´nite, Lyon, France; 2EMR 37-38 Universite´ Lyon 1, Lyon, France; 3Department of Oncology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud Pierre Be´nite, Lyon, France; 4Department of Gastroenterology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud Pierre Be´nite, Lyon, France; 5Department of Pathology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud Pierre Be´nite, Lyon, France; 6Hospices Civils de Lyon Pole IMER, Lyon, France; 7Universite´ de Lyon, Lyon, France; 8Department of General Surgery, Centre Hospitalier Lyon Sud, Pierre Be´nite, France

ABSTRACT Purpose. The primary objective of this study was to determine the incidence rate of pathological complete responses (pCRs) following neoadjuvant systemic chemotherapy for the treatment of peritoneal carcinomatosis (PC) of colorectal origin. The secondary objective was to evaluate whether pathological response assessments predict survival of patients treated with curative intent by complete cytoreductive surgery (CRS). Methods. A retrospective review was performed of 115 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by 124 procedures of complete CRS alone or combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The pathological response was defined as the mean percentage of cancer cells remaining within all specimens. Univariate and multivariate analyses were performed to identify predictors of survival and pathological response outcome. Results. Twelve procedures (9.7 %) resulted in pCRs, defined as no residual cancer cells in all specimens, 25 (20.2 %) resulted in major responses (1 to 49 % residual cancer cells), and 87 (70.1 %) resulted in minor or no responses ([50 % residual cancer cells). The cumulative 5-year survival rates were 75 and 57 % for patients with

Ó Society of Surgical Oncology 2014 First Received: 25 October 2013 G. Passot e-mail: [email protected]

pCR and major responses, respectively. Using multivariate analysis, pathological response was the only independent predictor of survival (P = 0.01; major response: hazard ratio [HR] = 4.91; minor response: HR = 13.46). No significant predictor of pathological response was identified. Conclusions. Pathological complete response can be achieved with preoperative systemic chemotherapy for patients with PC of colorectal origin. The degree of pathological response can be assessed and represented as a new outcome for prognosis following treatment with curative intent.

Cytoreductive surgery (CRS) alone or combined with hyperthermic intraperitoneal chemotherapy (HIPEC) as therapeutic management may offer patients with peritoneal carcinomatosis (PC) from colorectal cancer a chance for long-term survival and even for cure, as recently reported by Goere et al.1–4 For patients who can be treated with complete CRS, median survivals range from 22 to 60 months, and the 5-year survival rate may reach more than 50%.5 These survival results are close to those observed after liver resection for colorectal liver metastasis (CLM).6,7 Improvements in the outcomes of patients with PC may be attributed not only to advances in surgical or HIPEC techniques, but also to the emergence of more effective systemic chemotherapy.8 As in CLM management, perioperative or neoadjuvant systemic chemotherapy is increasingly used for different reasons. First, it can identify nonresponders who may not benefit from a CRS. Second, chemotherapy may avoid or limit extraperitoneal

G. Passot et al.

spread of the malignancy. Third, it could reduce the amount of disease, increasing the possibility of a complete CRS, which represents the most important prognostic factor.9 Pathological tumor response to chemotherapy has been identified and recognized as an important prognostic factor in patients treated with preoperative chemotherapy for colorectal cancer metastasis.10,11 PC represents a metastatic evolution of colorectal cancers, but its development, natural history, and response to systemic chemotherapy differs from that of liver or lung metastases, as demonstrated in several studies.12,13 A report from the Eindhoven Cancer Registry showed that despite increasing use of palliative chemotherapy and the availability of new agents, population-based survival of patients with PC did not improve until very recently and that the response to palliative chemotherapy in patients with PC should be evaluated separately from hematogenous metastases.14 Therefore, we conducted this retrospective study on a specific group of patients with PC of colorectal origin (PCCR) treated with curative intent to determine if pathological complete response (pCR) is achievable after neoadjuvant systemic chemotherapy, which has never been reported, and whether pathological response would predict survival as it does for CLM. PATIENTS AND METHODS Patient Selection Between January 2005 and July 2012, a total of 144 consecutive procedures for curative treatment of PC of colorectal origin performed at Lyon Sud Hospital were considered in the present analysis. All surgical data were prospectively collected. Eligibility criteria were neoadjuvant systemic chemotherapy, pathologically proven PC from colorectal cancer before CRS, World Health Organization (WHO) performance status of 0–1, and life expectancy of more than 12 weeks. Patients with carcinomatosis of appendiceal origin were excluded. The patient treatment strategies were defined and then regularly reassessed for all patients during multidisciplinary meetings according to international guidelines before curative surgery, based on imaging assessments. Selection of chemotherapy regimen was based on standard criteria among drugs approved by French national health authorities. Morphological response was evaluated in multidisciplinary meetings. Patients with progression were considered nonresponders and switched to a new chemotherapy regimen. Patients with extraperitoneal disease of small size potentially accessible to a curative resection (one

or two liver or lung metastases, lymphadenopathy localized) were considered for the study if extraperitoneal disease was treated during study period. For all other patients, exploratory laparotomy was performed to assess the chance of achieving a complete CRS. Patients eligible for curative treatment were treated with CRS and HIPEC or included into the ACCORD 15 PRODIGE 7 French, randomized, controlled trial comparing CRS alone with CRS with HIPEC (NCT00769405 clinicaltrial.org). All patients provided informed consent before surgery. Inclusion criteria were pathological confirmation of PCCR prior to CRS, use of neoadjuvant chemotherapy, and a complete resection of the PC with pathological analysis of all samples. Patients with nonresectable disease or with macroscopic residual disease (CC 2 or 3: residual nodules [2.5 mm) were excluded from the present study. Surgery For all patients, chemotherapy was discontinued at least 4 weeks before CRS. Under general anesthesia, all patients underwent a median laparotomy. After a comprehensive exploration of the abdominal cavity, complete CRS was performed if possible. The goal of the surgical procedure was a complete resection of disease considered as CC 0 (no residual node) or CC 1 (residual nodules \2.5 mm),15 combining peritonectomies and organ resections as described by Sugarbaker.16 The HIPEC procedure was done after complete CRS with a closed abdomen technique according to randomization in a French randomized trial for included patients (PRODIGE 7/ACCORD 15). The cytotoxic agent used was oxaliplatin at 360 mg/m2 for 30 min. Evaluation of Morphological Response The response to neoadjuvant systemic chemotherapy was judged during a multidisciplinary meeting using: 1.

2.

3.

A comparison between data from the previous exploratory surgery and data from the procedure combining CRS and HIPEC when the PC was not detectable on radiological imaging. However, because most patients underwent the first exploratory surgery at another center, an objective comparison using the peritoneal cancer index (PCI) or Gilly score was not possible;15,17 A comparison of radiological imaging performed before and after neoadjuvant chemotherapy when PC was measurable; Changes in tumor markers before and after neoadjuvant chemotherapy assessed by CEA (carcinoembryonic antigen) and Ca19.9.

Pathological Response of Carcinomatosis

Evaluation of Pathological Response All surgical specimens were sent to the pathology department and fixed in 10% buffered formalin. Because of the retrospective nature of this study, the macroscopic examination was not standardized and pathologic sampling was variable depending on the case. Sampling was usually focused on the largest nodules. At least one sample was taken for each resection and was selected by the surgeon. In case of ‘‘en bloc’’ resection, pathologists tried to sample each different anatomical structure. Pathological response was based on the determination of the percentage of viable tumor cells with respect to the area of each nodule, independent of the presence of chemotherapy-related tissue injury, fibrosis, or necrosis. Three groups were created for statistical analysis; no residual cancer cells in all specimens (complete response), 1 to 49 % residual cancer cells (major response), and [50 % residual cancer cells (minor or no response; Fig. 1). This classification was proposed by extrapolation of pathological response proposed in CLM.10,11 For patients with multiple specimens, a mean of values was used to define pathological response. Follow-Up Patients were reviewed in the outpatient clinic every 3 months for the first 2 years after surgery, every 6 months for the next 3 years, and annually thereafter. Abdominal and pelvic computed tomography (CT) scans was performed at 6-month intervals for the first 2 years and then annually. Postoperatively, all patients’ cases were evaluated by multidisciplinary meetings, and postoperative chemotherapy could be proposed according to international guidelines and patient recovery. For patients presenting with a recurrence during the follow-up, a new treatment was proposed according to the tumor location and size and the patient’s performance status. Statistical Analysis

FIG. 1 Pathological samples of peritoneal carcinomatosis representative of a complete response (no residual tumor cells), b major response (1–49 % residual tumor cells), and c minor response ([50 % residual tumor cells)

Morphological response was determined after analysis of these three criteria and considered as present when lesions decreased, absent if tumor growth was observed, and stable if no change was observed on two exams before and after chemotherapy.

Descriptive data were expressed as means (standard deviation [SD]) and medians (range) for quantitative variables, and as number (percentage) for qualitative data. Overall survival time was defined as the time from the first HIPEC to the date of death or the date of last follow-up. Prognostic factors of survival evaluated were pathological response, morphological response, tumor stage according to the TNM classification, neoadjuvant chemotherapy, PCI, peritoneal cytology, and the HIPEC procedure. The prognostic factor of pathological response evaluated was neoadjuvant chemotherapy. PCI and tumor stage according to TNM criteria were not available before neoadjuvant

G. Passot et al. TABLE 1 Regimen used for the last line of neoadjuvant chemotherapy Number of patients

Number of cycles (median)

TABLE 2 Patient characteristics and clinical data according pathological response group Pathological response Complete (n = 12)

Major (n = 25)

Minor (n = 79)

None (n = 8)

FOLFIRI

20

4.0

FOLFIRI?beva

27

5.0

FOLFIRI?cetux

7

5.0

FOLFOX

33

4.0

Female

5 (42)

12 (48)

29 (37)

6 (75)

FOLFOX?beva

16

6.0

Male

7 (58)

13 (52)

50 (63)

2 (25)

FOLFOX?cetux

5

4.0

Others regimens Total

7 115

6.0 –

T3

1 (8)

12 (48)

44 (56)

1 (12)

T4

8 (67)

10 (40)

30 (38)

7 (88)

Overall median

–

5.0

Unreported

3 (25)

3 (12)

5 (6)

0 (0)

FOLFIRI leucovorin?fluorouracil?irinotecan, FOLFOX leucovorin?fluorouracil?oxaliplatin, beva bevacizumab, cetux cetuximab

Gender: n (%)

T status: n (%)

PCI: Median (min-max) 3 (0-10)

8 (3–24)

9.5 (2–25) 16 (5–26)

Mean (± SD)

10 (± 6)

11 (± 6)

4 (± 3)

16 (± 9)

HIPEC: n (%)

chemotherapy for all patients and could not be evaluated. Median survival times and survival rates were computed using the Kaplan-Meier method. Hazard ratios and P values were obtained using the Cox proportional hazards model. The influence of baseline risk factors on survival was assessed using univariate and multivariate Cox proportional hazards model. Factors with a significance degree \0.2 were introduced in the multivariate model, and those with P \ 0.15 were retained in the final model. The influence of baseline risk factors on pathological response was assessed using Chi-square test (if the application conditions were met; otherwise, Fisher’s exact test was used) for categorical data or using a nonparametric Mann– Whitney for quantitative variables. Logistic regression was used for multivariate analysis. Fisher’s exact test was used to evaluate correlations between morphological and pathological responses. P \ 0.05 was considered statistically significant. Statistical analysis was performed using the SASÒ software (SAS Institute Inc., Cary, NC). RESULTS Descriptive Data Between January 2005 and July 2012, 115 patients with PCCR received neoadjuvant chemotherapy and 124 CRS, with or without HIPEC, were performed. Nine patients underwent two surgical procedures after neoadjuvant chemotherapy, with HIPEC given after the second procedure. The median age of patients was 59 (range, 37–72) years, and the patient population included 50 females and 65 males. According to TNM classification, the primary lesions were 54 T3, 50 T4, 11 T unknown, 22 N0, 87N?(N1 and N2), and 6N unknown. At the time of CRS, the primary tumor was in place for 20 patients (17 %). Sixty-seven patients (58 %) presented with synchronous

Yes

9 (75)

14 (56)

61 (77)

7 (88)

No

3 (25)

11 (44)

18 (23)

1 (12)

14 (18)

3 (38)

65 (82)

5 (62)

Positive peritoneal cytology: n (%) Yes 1 (8) 3 (12) No

11 (92)

22 (88)

HIPEC hyperthermic intraperitoneal chemotherapy, PCI peritoneal carcinoma index, SD standard deviation

PC. All patients received at least one line of neoadjuvant systemic chemotherapy. The median number of cycles of neoadjuvant administrated was five. The regimens are described in Table 1. A second, third, and fourth line of neoadjuvant chemotherapy was given to 14, 8, and 1 patients, respectively. The median PCI at the time of CRS was 9 (range, 0–26). Before surgery, morphological response was considered as present, absent, or stable in 51, 44, and 20 patients respectively. All patients included in the analysis had a complete resection, CC 0 or CC 1. Among the 124 procedures, 33 were performed with CRS alone, and 91 were combined with HIPEC. Twenty-one patients (18 %) had a positive peritoneal liquid cytology. The median follow-up time was 560 (range, 10–2,403) days. Five patients (4 %) died postoperatively within 90 days of surgery. Seventynine patients (69 %) presented with a recurrence during the study period. The overall median survival was 36 months. Pathological Response and Survival Based on the 124 specimens taken during the procedures, 12 patients (9.7 %) achieved a pCR, 25 (20.2 %) a major response, 79 (63.7 %) a minor response, and 8 (6.4 %) had no response (Table 2). There was no correlation between the morphological and pathological responses (P = 0.51), and the morphological response had no impact on survival.

Pathological Response of Carcinomatosis 1.00

Survival probability

0.75

0.50

0.25 Complete response Major response Minor or no response

0.00 0

1

2

P = .0019 3

4

5

Time (in years) Patients at risk Complete response Major response Minor or no response

0 12 23 80

1 10 16 54

2 7 11 21

3 5 5 9

4 2 3 4

5 2 2 1

FIG. 2 Overall survival according to pathological response

Survival curves for the 115 patients are presented according to pathological response group in Fig. 2. Cumulative 1-, 3-, and 5-year OS rates were 100, 100 and 75 %, respectively, for complete responses; 100, 77, and 57 %, respectively, for major responses; and 85, 41, and 13 %, respectively, for minor or no responses. Table 3 reports factors influencing survival. Using Cox multivariate analysis, pCR and major pathological responses remained the only significant prognostic factors of OS against the common prognostic factors in PCCR. The combination of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) with bevacizumab was the regimen that achieved the longest survival rates. We did not identify any prognostic factors that significantly influenced pathological response using univariate and multivariate analysis. DISCUSSION This is the first study to report pCR in patients with PCCR after neoadjuvant systemic chemotherapy. Moreover, it confirms the strong prognostic impact of this parameter on the survival of patients, as previously reported for CLM.10,11 For PCCR, the complete response rate was 9.7 %, close to the 10 % reported for CLM.11 However, the major response rate was lower (20 vs. 36 %) than for CLM, illustrating the lower response of peritoneal lesions to systemic chemotherapy compared with extraperitoneal metastases from colorectal cancers.12,13 In their pooled analysis of 2,095

patients with metastatic disease of colorectal origin, Franko et al. recently reported that the presence of PC had an unfavorable prognostic influence and underlined the magnitude of this impact (HR = 1.3) and its clinical relevance.18 This difference could be due to the lower penetration of systemic chemotherapy into PC nodules.19,20 This study is the first to show the strong impact of pCR on survival in PC. The classification of pCR was established according to the experience obtained in CLM, allowing for an approach less subject to variability and more reproducible.10,11 Of course, this classification should be evaluated in other prospective and multicentric trials before being validated and used in practice. As was demonstrated for CLM, achieving a pCR after systemic neoadjuvant chemotherapy occurs at a low rate but allows for better survival.21 Unfortunately, we failed to identify any prognostic factors of pCR, probably because of the limited statistical power related to the small number of patients and also certainly because of the great heterogeneity of systemic chemotherapy regimens. As suggested for liver metastasis, neoadjuvant chemotherapy for PC might enable the selection of patients sensitive to chemotherapy and increase survival.22–24 Franko et al. observed no differential impact of systemic chemotherapy on the basis of the presence or absence of PC.18 Their study also suggested the superiority of FOLFOX versus FOLFIRI (irinotecan, leucovorin, and fluorouracil) and FOLFIRINOX (irinotecan, oxaliplatin) in the first-line setting after initial FU (fluorouracil) treatment. In our study, the univariate analysis of survival suggested that the FOLFOX plus bevacizumab leads to better survival. This also was suggested by Chua et al. in one trial evaluating the impact of new modern systemic chemotherapy.25 This regimen was an independent predictor of pathological response in the MD Anderson experience with CLM.11 More studies are needed to determine the best neoadjuvant chemotherapy regimen and, of course, no conclusions can be made regarding our practice until such results have been confirmed in larger studies. We previously reported that progression after morphological evaluation was not a contraindication to a curative approach for PCCR, and patients with morphologic progression amenable to complete CRS still had an interesting long-term survival.26 The present study reports the absence of a correlation between morphological and pathological responses and did not identify any preoperative assessments of morphological response as a prognostic factor of survival. Once more, radiologic response to chemotherapy appeared to be an unsatisfactory predictor of survival. CT scan remains the standard for evaluating PC, despite the recent development and evaluation of diffusion magnetic resonance imaging or positron emission tomography–CT scans. New criteria for radiologic responses should be

G. Passot et al. TABLE 3 Univariate and multivariate analysis of prognostic factors of survival Nb

Primary tumor size T Primary tumor nodal status Extraperitoneal disease Last line of preoperative chemotherapy regimen

Anti EGFR Bevacizumab Peritoneal cytology

Median overall survival (mo)

Univariate analysis

Multivariate analysis

P

HR

P

0.33

1.00

–

1.40

0.71–2.74

0.45

1.00

–

1.40

0.58–3.38

0.70

1.00

–

0.83

0.32–2.15

1.00 0.39

0.16–0.99

95 % CI

T3

54

40.3

50

35.1

Negative

22

43.6

Positive

87

36.3

No

94

36

Yes

20

40.3

FOLFOX FOLFIRI

33 20

26.2 –

FOLFIRI?beva

27

36

0.44

0.14–1.31

0.46

0.15–1.41

FOLFIRI?cetux

7

–

0.18

0.02–1.34

0.18

0.02–1.37

FOLFOX?beva

16

–

0.21

0.05–0.89

0.20

0.04–0.85

FOLFOX?cetux

5

11.9

3.23

0.90–11.6

1.62

0.40–6.49

Other

7

–

0.36

0.08–1.53

0.32

0.07–1.38

No

103

36.3

Yes

12

40.3

No

66

32.3

Yes

49

–

Negative

62

43.6

21

22.1

0–14

85

40.3

15–39

27

22.1

HIPEC

No Yes

33 82

– 36

Morphological response

Absent

44

43.6

Stable

20

Present

51

Complete

12

NA

Major

23

Minor or absent

80

Pathologic response

HR

T4

Positive PCI

95 % CI

0.01

0.88 0.02 0.04 0.05

0.06

1.00

–

1.08

0.38–3.07

1.00

–

0.36

0.15–0.86

1.00

–

2.55

1.05–6.15

1.00

1.00 0.36

0.13–0.98

-

2.07

1–4.26

0.076

1.00 2.94

– 0.89–9.65

0.13

1.00

–

30.3

2.01

0.89–4.54

40.3

0.85

0.4–1.83

1.00

–

NA

2.93

0.33–26.24

4.91

0.53–45.28

31.3

10.03

1.36–73.9

13.46

1.79–101.1

0.008

0.010

1.00

Bold values are statistically significant HR hazard ratio, CI confidence interval, NA not available, FOLFIRI leucovorin?fluorouracil?irinotecan, FOLFOX leucovorin?fluorouracil?oxaliplatin, beva bevacizumab, cetux cetuximab, EGFR epidermal growth factor receptor, PCI peritoneal cancer index, HIPEC hyperthermic intraperitoneal chemotherapy

developed in order to better select patients for curative surgery. The results of the present study should be considered with caution. Indeed, the pathological classification of response was extrapolated from the experience obtained in CLM.10,11 Of course, this classification should be evaluated in other prospective and multicentric trials before being validated and used in practice. Moreover, this is a retrospective study with a limited number of patients in unbalanced subgroups, thereby limiting the statistical power of the analyses. We acknowledge the limited value of the indirect comparisons between chemotherapy regimens. Well-designed, prospective studies specifically dedicated to PCCR are needed.

CONCLUSIONS Neoadjuvant chemotherapy may allow pCR in patients with PCCR, and the rate is similar to that reported for CLM and with the same strong prognostic impact. A similar pathological response evaluation as those reported for CLM may be applied to PC and should be validated at other centers and in additional studies. It could become a new outcome end point after curative treatment for PC. The impact of each regimen of neoadjuvant systemic chemotherapy on pathological response and survival remains unclear and merits further evaluation. Pathological classification and pathological response will be evaluated in a prospective national multicenter study.

Pathological Response of Carcinomatosis ACKNOWLEDGMENT FRENCH (Fe´de´ration de Recherche EN Chirurgie) for study design. CONFLICT OF INTEREST Data collection creation used in the study was supported by Roche.

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