Annals of Surgical Oncology

, Volume 18, Issue 6, pp 1540–1546

Surgical Cytoreduction and Survival in Appendiceal Cancer Peritoneal Carcinomatosis: An Evaluation of 46 Consecutive Patients

Authors

  • Terence C. Chua
    • Hepatobiliary and Surgical Oncology UnitUNSW Department of Surgery, St George Hospital
  • Ihssan Al-Alem
    • Hepatobiliary and Surgical Oncology UnitUNSW Department of Surgery, St George Hospital
  • Akshat Saxena
    • Hepatobiliary and Surgical Oncology UnitUNSW Department of Surgery, St George Hospital
  • Winston Liauw
    • Department of Medical OncologyCancer Care Centre, St George Hospital
    • Hepatobiliary and Surgical Oncology UnitUNSW Department of Surgery, St George Hospital
Colorectal Cancer

DOI: 10.1245/s10434-011-1714-3

Cite this article as:
Chua, T.C., Al-Alem, I., Saxena, A. et al. Ann Surg Oncol (2011) 18: 1540. doi:10.1245/s10434-011-1714-3

Abstract

Background

Surgical cytoreduction and intraperitoneal chemotherapy is increasingly accepted as an effective treatment modality for mucinous appendiceal neoplasm. For the majority of patients with low-grade histology, outcomes have been encouraging. The survival of patients with neoplasms of malignant character is protracted and this study was designed to evaluate the effectiveness of this surgical strategy on outcomes.

Methods

Forty-six consecutive patients with mucinous and nonmucinous appendiceal cancer with peritoneal dissemination were studied. Clinicopathological and treatment related factors were obtained from a prospective database. The study’s end points of disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method.

Results

The median DFS and OS after cytoreduction were 20.5 and 56.4 months respectively. Five-year overall survival rate was 45%. Five independent factors associated with DFS and OS were identified through a multivariate analysis: age (DFS p = 0.001, OS p = 0.002), completeness of cytoreduction (DFS p = 0.001, OS p = 0.003), previous chemotherapy treatment (DFS p = 0.021), CA 199 levels (DFS p = 0.013), and tumor grade (OS p = 0.005).

Conclusions

Cytoreductive surgery and intraperitoneal chemotherapy may achieve long-term survival in appendiceal malignancies with peritoneal dissemination for which the predictors of outcomes identified through this study may tailor the disease management to commit patients early toward this successful surgical strategy.

Malignancies arising from the appendix include tumors of neuroendocrine lineage known otherwise as carcinoid tumors and of epithelial origin that include mucinous adenocarcinoma and nonmucinous adenocarcinoma. Carcinoid tumors of the appendix are small, slow growing, and rarely metastasize. It is sufficiently treated by appendectomy alone or a right hemicolectomy in the instance of a larger tumor or presence of nodal metastasis without compromising the overall long-term survival outcome.1 On the contrary, appendiceal malignancies of epithelial origins, due to their pattern of growth, have a propensity to exhibit direct growth and a propensity to rupture leading to peritoneal dissemination.2 Peritoneal dissemination results in carcinomatosis and this has been considered a terminal disease with a median survival time rarely exceeding 12 months.3,4 Intra-abdominal carcinomatosis is a morbid condition that results in subacute intestinal obstruction, abdominal pain that progressively lead to cachexia and eventual demise.

Distinction of the tumor type in this instance of peritoneal dissemination from an appendiceal malignancy is paramount to the surgical management of this condition. Mucinous tumors that usually arise within a mucocele may be minimally aggressive or have an invasive character. They often result in pseudomyxoma peritonei. Histologically, they are classified as low- and high-grade, depending on the features of invasiveness present.5 Non-pseudomyxoma appendiceal adenocarcinoma is less common. In a French registry study, of 353 patients with appendiceal neoplasm that were accrued, only 50 patients (14%) had appendiceal adenocarcinoma.6 The biologic behavior of this tumor type tends to develop non-pseudomyxoma carcinomatosis but its propensity for developing distant metastatic disease is less known.

A comprehensive treatment approach involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) has evolved as a novel approach for peritoneal carcinomatosis. It offers disease control within the peritoneum. This study was designed to analyze critically the outcomes of malignancy of the appendix (both mucinous and nonmucinous adenocarcinoma) that lead to carcinomatosis after cytoreductive surgery, reporting disease-free and overall survival outcomes, and to describe clinicopathological parameters that would influence survival.

Patients and Methods

Between January 1997 and June 2010, 46 consecutive patients with mucinous and nonmucinous adenocarcinoma of the appendix were treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy at the program in peritoneal surface malignancy at the St George Hospital (Sydney, Australia). Mucinous adenocarcinoma were diagnosed as high-grade tumor based on Bradley’s classification, and nonmucinous adenocarcinoma were tumors without macroscopic and microscopic mucin (no extracellular mucin) after histological examination of tissue biopsy or surgical specimens.5 All patients were discussed at a weekly multidisciplinary team meeting, which comprised a surgical oncologist, medical oncologists, radiologist, oncology nurses, and research staff. The suitability to undergo cytoreduction was based on a patient’s performance status and intercurrent comorbidities. Informed consent was obtained from all patients.

Perioperative and Operative Treatment

The detailed description of the preoperative, operative, and postoperative management may be obtained from previous reports from our institution where they were previously described.7 Before treatment, routine serological tests and computed tomography (CT) imaging was performed. The surgical procedure was performed via a midline laparotomy where an exploration was performed to quantify the intraabdominal tumor burden and scored using the Peritoneal Cancer Index (PCI).8 Cytoreductive surgery was performed with limited peritonectomy procedures as described by Sugarbaker in diseased regions of the abdomen and pelvis.9 The volume of residual disease after cytoreduction were recorded prospectively using the Completeness of Cytoreduction (CC) score.8 CC0 indicates that no macroscopic residual cancer remained, CC1 that no nodule >2.5 mm in diameter remained, CC2 that nodules between 2.5 mm and 2.5 cm in diameter remained, and CC3 that nodules >2.5 cm in diameter remained. The intraperitoneal chemotherapy regimen comprised either or both of 90 min of intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (10–12.5 mg/m2) in 3 liters of 1.5% dextrose peritoneal dialysis solution at 42°C and/or early postoperative intraperitoneal chemotherapy (EPIC) during the immediate postoperative period with 5-flurouracil (650 mg/m2) in 1 liter of 1.5% dextrose peritoneal dialysis solution administered intraperitoneally. All patients were planned for HIPEC and EPIC as an intention to treat. However, eight patients were treated in the private hospital where HIPEC was not available and EPIC was delivered instead. Inability to deliver EPIC was a result of postoperative complications. Postoperative complications were classified as major (grade III/IV) or minor (grade I/II) according to the National Cancer Institute Common Toxicity Criteria.

Data Collection and Statistical Analysis

Clinical data of patients who met the inclusion criteria for this study was extracted from a computerized, prospective database. A retrospective chart review was performed to determine the primary treatment and to confirm the histopathology of the tumor. Surgical treatment before cytoreduction was classified as local surgical excision (i.e., appendectomy or right hemicolectomy) or debulking surgery (bowel resection, omentectomy, resection, or other major organs). Patients who receive chemotherapy as an adjuvant or stand-alone treatment before cytoreduction were dichotomized as having received chemotherapy. Pre-cytoreduction tumor markers, including CEA, CA 125, and CA199, were retrieved. The time from initial diagnosis to date of cytoreduction was calculated as the time to cytoreduction. Standardized cytoreductive parameters, including the PCI, CC score, use of HIPEC, use of EPIC, and use of PIC (having both HIPEC and EPIC), were retrieved. Pathological characteristics, including the tumor grade, presence of lymph node involvement, presence of signet ring morphology, and the tumor type (mucinous or nonmucinous), were identified. Follow-up data extracted include the time of recurrence diagnosed radiologically by the presence of demonstrable disease on CT scan and the type of treatment for recurrence. Statistical analysis was performed using SPSS® for Windows version 15.0 (SPSS, Munich, Germany). The Kaplan-Meier method was used to analyze survival. Clinical, treatment, and pathological characteristics were entered into univariate analysis using the log-rank test and multivariate analysis using the Cox-regression model. p < 0.05 was considered statistically significant.

Results

Of 46 patients treated, 21 were men (46%) and 25 were women (54%). The median age of the entire cohort was 52.5 (range, 32.2–79.4) years. The median time from diagnosis to referral for cytoreductive surgery was 8.5 (range, 0–153.8) months. At the time of diagnosis, 20 patients (44%) had no oncological treatment (laparoscopy, open and close or biopsy only, or none), 6 patients (13%) had a limited resectional operation (appendectomy, salpingo-oophorectomy or right hemicolectomy), and 20 patients (44%) were subjected to tumor debulking surgery. Twenty-four patients (52%) received prior chemotherapy. Amongst these 24 patients, 13 patients receive single line 5FU-based chemotherapy and 11 received modern chemotherapy (oxaliplatin-based combination). Of the 11 patients who received modern chemotherapy, one patient received bevacizumab in combination with oxaliplatin-based chemotherapy and one patient received second-line irinotecan-based combination chemotherapy.

The median PCI was 20.5 (range, 3–39). Thirty-three patients (72%) had a CC0, ten patients (22%) had CC1, and three patients (7%) had CC2 cytoreduction. To achieve cytoreduction required a right hemicolectomy/partial colectomy in 16 patients (35%), anterior resection/Hartmann’s resection in 10 patients (21%), and a subtotal colectomy in 13 patients (28%). An ostomy was constructed in 17 patients (37%). Thirty-eight patients (83%) received HIPEC and 40 patients (87%) received EPIC. Thirty-four patients (74%) received both HIPEC and EPIC (PIC).

There were two mortalities (4%). Three patients (7%) had no complications, three patients (7%) had grade 1 complications, 15 patients (32%) had grade 2 complications, nine patients (20%) had grade 3 complications, and 14 patients (30%) had grade 4 complications. The most common complications include infection in 26 patients (57%), abdominal collection in 26 patients (57%), pleural effusion in 16 patients (35%), pneumothorax in 8 patients (17%), and fistula in 8 patients (17%). Ten patients (22%) required a return to the operating room for management of complication.

Survival Outcomes

After a follow-up of 22.5 (range, 4.6–117) months, the median overall survival was 56.4 months, with a 3-, 5-, and 7-year survival of 59, 45, and 34% respectively. Twenty-eight of 46 patients (39%) developed disease recurrences. The median disease-free survival was 20.5 months, with a 1- and 3-year disease-free survival of 61 and 30% respectively (Fig. 1). The site of treatment failure include the abdomen alone in 22 patients (48%), the abdomen and a distant metastatic site in 4 patients (9%), and a distant metastatic site alone in 2 patients (4%).
https://static-content.springer.com/image/art%3A10.1245%2Fs10434-011-1714-3/MediaObjects/10434_2011_1714_Fig1_HTML.gif
Fig. 1

Kaplan–Meier survival analysis of overall survival (bold line) and disease-free survival (dotted line)

Treatment of Recurrent Disease

Eleven of 22 patients with isolated recurrence in the abdomen underwent secondary cytoreduction. The mean time from first to second cytoreductive surgery was 20.5 (14.5) months. At the secondary cytoreduction, eight patients (73%) had CC0, two patients (18%) had CC1, and one patient (9%) had CC2 cytoreduction. Three patients underwent a third cytoreduction. The detailed clinical and treatment characteristics are shown in Table 1.
Table 1

Clinical and treatment characteristics of patients undergoing cytoreductive surgery for high grade appendiceal neoplasm

Variable

First cytoreductive surgery (n = 46)

Second cytoreductive surgery (n = 11)

Third cytoreductive surgery (n = 3)

Mean time from prior operation (mo ± SD)

20.5 ± 14.5

27.2 ± 9.1

Peritoneal cancer index (mean ± SD)

21.4 ± 10.6

13.1 ± 7.1

18 ± 4.6

Completeness of cytoreduction

   

 CC0

33

8

2

 CC1

10

2

1

 CC2

3

1

 

No. of patients receiving HIPEC (%)

38 (83)

9 (82)

2 (67)

No. of patients receiving EPIC (%)

40 (87)

7 (50%)

0

No. of patients completing PIC (%)

34 (74)

5 (36%)

0

Mean overall survival (months)

61.0

80.7

79.1

Factors Influencing Survival

Seventeen variables were analyzed as factors that influence disease-free and overall survival. From univariate analysis, age (p = 0.003), previous chemotherapy use (p = 0.04), type of prior surgery (p = 0.019), completeness of cytoreduction (p = 0.002), EPIC (p = 0.011), PIC (p = 0.045), tumor grade (p < 0.001) and signet ring morphology (p = 0.04) were factors influencing overall survival. Age (p < 0.001), previous chemotherapy use (p = 0.001), type of previous surgery (p = 0.014), CA 199 (p = 0.016), completeness of cytoreduction (p = 0.007), and tumor grade (p = 0.024) were factors that influenced disease-free survival (Table 2). From multivariate analysis, independent factors associated with a longer disease-free survival include no previous chemotherapy treatment before cytoreduction (hazard ratio (HR) (95% confidence interval (CI)); 5.5 (1.3–23.4), p = 0.021), nonelevated CA199 tumor marker (HR (95% CI); 4.0 (1.3–12), p = 0.013), younger age (HR (95% CI); 6.0 (2–17.6), p = 0.001), and complete cytoreduction (HR (95% CI); 4.8 (1.9–12.2), p = 0.001). Independent factors associated with a longer overall survival include younger age (HR (95% CI); 8.4 (2.1–33.2), p = 0.002), favorable tumor grade (HR (95% CI); 6.2 (1.8–22.1), p = 0.005), and complete cytoreduction (HR (95% CI); 4.3 (1.6–11.4), p = 0.003; Table 2).
Table 2

Univariate and multivariate analysis of clinical, treatment and pathological factors influencing disease-free and overall survival

 

n

Median disease-free survival (months)

p

Median survival (months)

p

Univariate

Multivariate

Univariate

Multivariate

Total

46

20.5

  

56.4

  

Age (year)

  

<0.001

0.001

 

0.003

0.002

 <60

31

30.3

  

65.4

  

 ≥60

15

8.9

  

19.8

  

Sex

  

0.258

  

0.515

 

 Male

25

25.4

  

65.4

  

 Female

21

10.7

  

34.9

  

Time to cytoreduction (mo)

  

0.233

  

0.128

 

 <12

25

20.5

  

65.4

  

 ≥12

21

14.2

  

33.5

  

Prior chemotherapy

  

0.001

0.021

 

0.040

0.683

 No

22

38

  

NR

  

 Yes

24

11

  

33.5

  

Prior surgery

  

0.014

0.589

 

0.019

0.64

 None

20

46

  

NR

  

 Limited

6

11

  

19.8

  

 Debulking

20

10.7

  

33.5

  

CEA

  

0.122

  

0.129

 

 ≤5

10

46

  

NR

  

 >5

29

14.2

  

44.3

  

 Unknown

7

      

CA 125

  

0.332

  

0.696

 

 ≤35

10

25.6

  

56.4

  

 >35

21

20.5

  

65.4

  

 Unknown

15

      

CA 199

  

0.016

0.013

 

0.394

 

 ≤40

15

46

  

56.4

  

 >40

25

10.4

  

34.9

  

 Unknown

6

      

Peritoneal Cancer Index

  

0.655

  

0.753

 

 0–10

8

25.6

  

56.4

  

 11–20

15

16

  

NR

  

 21–39

23

16.8

  

NR

  

Completeness of cytoreduction

  

0.007

0.001

 

0.002

0.003

 CC0

33

25.4

  

56.4

  

 CC1

10

6.5

  

NR

  

 CC2

3

6.5

  

8.4

  

HIPEC

  

0.293

  

0.108

 

 No

8

10.4

  

20.7

  

 Yes

38

25.4

  

65.4

  

EPIC

  

0.081

0.811

 

0.011

0.14

 No

6

6.4

  

8.4

  

 Yes

40

23.4

  

56.4

  

PIC

  

0.167

  

0.045

0.309

 No

12

10.4

  

20.7

  

 Yes

34

25.6

  

65.4

  

Tumor grade

  

0.024

0.073

 

<0.001

0.005

 Well

21

30.3

  

NR

  

 Mod

19

16.8

  

56.4

  

 Poor

6

1.7

  

3.1

  

Positive lymph node

  

0.436

  

0.547

 

 No

36

23.4

  

56.4

  

 Yes

10

16

  

44.3

  

Signet ring morphology

  

0.3

  

0.04

0.205

 No

38

20.5

  

NR

  

 Yes

8

10.4

  

33.5

  

Mucinous pseudomyxoma

  

0.456

  

0.124

 

 No

9

14.2

  

33.5

  

 Yes

37

20.5

  

65.4

  

Discussion

There has been progress in the understanding of mucinous appendiceal malignancies. In 1995, Ronnett described the distinctive features amongst mucinous appendiceal neoplasm, classifying them based on pathological features into two groups: disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). Age-adjusted 5-year survival rates were 84% for patients with DPAM, 37.6% for patients with PMCA with intermediate or discordant features, and 6.7% for patients with PMCA.10 This led to a universal classification system of appendiceal mucinous neoplasm that results in pseudomyxoma peritonei. Whilst this histological division based on cellular features accurately stratifies patients, appendiceal malignancies may involve heterogeneous cellular morphology, including signet-ring and goblet-cell type pattern. Hence, more recently, Bradley et al. categorized mucinous tumors into low- and high-grade for which low-grade tumors included DPAM and PMCA-intermediate and high-grade tumors included PMCA subtype and tumors with signet-ring morphology.5 Furthermore, nonmucinous appendiceal tumors that do not manifest any extracellular mucin are regarded as appendiceal adenocarcinoma without pseudomyxoma. Together, high-grade appendiceal mucinous adenocarcinoma and appendiceal adenocarcinoma are regarded as true appendiceal cancer for which their outcomes are evaluated in this study.

Retrospective analysis of a prospectively collected database of 46 consecutive patients with appendiceal adenocarcinoma treated with cytoreductive surgery and PIC demonstrated a median survival of 56.4 months and 3- and 5-year survival of 59 and 45% respectively. There was no difference in outcomes between patients with high-grade mucinous adenocarcinoma (pseudomyxoma type) and tumors that were non-pseudomyxoma adenocarcinoma. This survival result is superior to the outcomes of patients with peritoneal carcinomatosis from colorectal cancer who were treated with cytoreductive surgery and PIC from our institution with a median and 3-year survival of 36 months and 60% previously reported.11 This was despite the patient cohort with appendiceal adenocarcinoma having a mean PCI of 21 compared with 11 for colorectal adenocarcinoma. This demonstrates that in peritoneal carcinomatosis from appendiceal adenocarcinoma (mucinous and nonmucinous), the extent of carcinomatosis does not bear important prognostic effect if a complete cytoreduction is achieved. As with a recently published article in the Annals of Surgery, where we demonstrated that upfront cytoreduction achieves superior recurrence-free and a trend toward superior overall survival over delayed cytoreduction after prior debulking surgeries in low-grade appendiceal mucinous neoplasm,12 we also show in this cohort that prior chemotherapy treatment was associated with poorer disease-free survival after cytoreduction. In patients who had no oncological surgical treatment compared with limited resection and debulking surgery, disease-free were 46, 11, and 10.7 months. Overall survival was superior in patients who had no oncological surgical treatment (median survival not reached, 5-year survival 75%) compared with a median survival of 19.8 months and 5-year survival of 20% for patients who underwent limited resection and a median survival of 33.5 months and 5-year survival of 35% for patients who underwent debulking surgery. These findings continue to suggest that early treatment of peritoneal carcinomatosis from intestinal malignancies with cytoreductive surgery and intraperitoneal chemotherapy will achieve better oncologic outcomes.

The pattern of recurrence strongly suggest that despite its invasive nature, appendiceal adenocarcinoma has a strong propensity of remaining within the peritoneal cavity with only 6 of 28 recurrences (21%) presenting in distant metastatic site for which 2 patients had pleural metastasis and 4 patients had pulmonary metastasis. Of 22 patients with abdomen-only recurrence, 11 underwent secondary cytoreductive surgery at an average of 20.5 months from the previous cytoreduction and a further 3 patients underwent tertiary cytoreductive surgery 27.2 months from the second cytoreduction. In this highly selected subgroup of patients who were subjected to aggressive treatment of recurrent disease, the mean overall survival of the 11 patients who underwent secondary cytoreductive surgery was 80.7 months and the mean overall survival of the 3 patients who underwent tertiary cytoreductive surgery was 79.1 months. Such encouraging survival data from repeated cytoreductions in peritoneal carcinomatosis from appendix cancer has not been previously reported and this practice is not widely practiced. Repeat cytoreductions if performed are only offered to patients with low-grade appendiceal mucinous neoplasm with pseudomyxoma peritonei. Elias et al. in the French multi-institutional study demonstrated that treatment results for appendix adenocarcinoma were better than colon, rectum, and small bowel adenocarcinomas.6 Furthermore, Omohwo et al. showed that there was no statistically significant difference in survival between the low-grade and high-grade mucinous appendiceal tumors when a complete cytoreduction was performed with 5-year overall survival of 80 vs. 68% (p = 0.69).13 Together, this body of evidence suggests that peritoneal carcinomatosis from appendix cancer must be viewed as a separate entity of other intestinal malignancies because of its superior survival posttreatment. It may be appropriate to adopt a similar treatment strategy of aggressive cytoreduction as with low-grade mucinous pseudomyxoma given its potential for long-term survival.

From a histopathological perspective, the tumor grade that represents the differentiation or architectural atypia of the malignant cells predicted for disease-free and overall survival. Lymph node metastasis did not influence disease-free and overall survival. Signet ring morphology often an indicator of an aggressive tumor for intestinal pathology resulted in an overall poorer survival. Whether the presence of signet ring morphology alone or the tumor grade together influences survival is unknown. It is observed that signet rings cells may be present even in well-differentiated appendiceal tumors compared with its predilection to occur in poorly differentiated adenocarcinoma of the stomach,14 small bowel,15 and colon,16 which have more aggressive biological behavior.

In conclusion, the treatment of peritoneal carcinomatosis arising from appendiceal mucinous and nonmucinous adenocarcinoma with a comprehensive strategy combining cytoreductive surgery and perioperative intraperitoneal chemotherapy achieves favorable survival results and repeat cytoreduction for the treatment of recurrence may contribute to long-term survival. The factors that influence survival identified through this analysis support an early treatment and a complete cytoreduction as strategies of a management plan to achieve the best possible outcome.

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© Society of Surgical Oncology 2011