Natural history of peritoneal carcinomatosis from nongynecologic malignancies

Surg Oncol Clin N Am 12 (2003) 729–739

Natural history of peritoneal carcinomatosis from nongynecologic malignancies Olivier Glehen, MDa, Dimitri Osinsky, MDa, Annie Claude Beaujard, MDb, Franc¸ois Noe¨l Gilly, PhD, MDc,* a

Centre Hospitalo-Universitaire Lyon Sud, Surgical Department, 69495 Pierre Be´nite Cedex, France b Centre Hospitalo-Universitaire Lyon Sud, Intensive Care Department, 69495 Pierre Be´nite Cedex, France c Lyon University of Sciences, Surgical Department, Centre Hopitalo-Universitaire Lyon Sud, 69495, Pierre Be´nite Cedex, France

The primary peritoneal malignancies such as malignant mesothelioma and papillary serous carcinoma are rare. In contrast, peritoneal dissemination from digestive cancers is common. In the past, carcinomatosis has been regarded as a terminal disease, and most oncologists would regard it as a condition only to be palliated. However, recent reports suggest curative treatment options for selected patients with carcinomatosis from nongynecologic cancer. Since the early 1980s, there has been a renewed interest in carcinomatosis and an attempt to formulate new multimodal therapeutic approaches. Descriptions of previously unexplored treatment options such as peritonectomy procedures [1], intraperitoneal chemohyperthermia [2,3], and early postoperative intraperitoneal chemotherapy [4], have appeared. However, prospective studies to document the etiology, clinical features, and natural history of carcinomatosis from nongynecologic malignancies remains limited. The clinical features and natural history of surgically treated disseminated intraperitoneal cancer comes from two prominent studies in the literature: the first study by Chu et al. (1989) [5], included 100 patients; the second effort was the French multicentric prospective

* Corresponding author. E-mail address: [email protected] (F.N. Gilly). 1055-3207/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1055-3207(03)00044-9

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study called EVOCAPE 1. It included 370 patients, and was reported a decade later [6]. Pathophysiology of carcinomatosis The pathophysiology of carcinomatosis is well studied in gastrointestinal cancer by in vitro and in vivo experiments. In the progression of a digestive cancer the first malignant cells appear in the intestinal mucosa. Invasion moves to the submucosa, the muscular layers, and finally, the serosal surface. During this time, three patterns of dissemination may occur. Malignant cells may invade into the venules of the bowel wall and thereby disseminate via the hematogenous route through the portal vein. If these cells implant within the liver vasculature. the result is liver metastases. A second route of dissemination can occur during the invasion of malignant cells from the mucosa to the serosal surface. Microscopic lymphatic channels within the bowel wall convey cancer cells to lymph nodes nearby and then progress to distant lymph nodes. A third route of cancer dissemination occurs from invasion of the bowel wall through to the serosal surfaces. A cancer nodule penetrating the mesothelium may result in seeding of malignant cells from the primary tumor to adjacent and distant peritoneal surfaces. A vehicle for cancer cell distribution such as mucin or ascites will expand the spread of new peritoneal implants [7]. The exfoliation of cancer cells from established implants may result in a rapid progression to the spread. Not only primary cancer-induced but also iatrogenic surgically induced mechanisms for carcinomatosis exist. Narrow margins of resection, leakage of tumor cells from lymphatic channels that have been surgically divided during the resection, venous blood loss from the tumor at the time of resection, and trauma to the primary malignancy may result in cancer seeding onto abdominal and pelvic surfaces. The implants that arise from the primary tumor and those that arise from the surgical manipulation together cause peritoneal carcinomatosis. Free nodules of cancer on peritoneal surfaces and cancer progressing within the resection site of the primary cancer may have a similar source but a different gross appearance. Cancer cells that become individually implanted on peritoneal surfaces will proliferate and become visible as cancer nodules. Other malignant cells, free inside the peritoneal cavity, become trapped at sites of trauma; they will become recognized within the abdominal incision, at ligatures around blood vessels or lymphatic chains, and within suture lines. Entrapped cancer cells will progress where fibrin accumulations and blood clots will secure them and enhance their growth [7]. High-density cancer seeding at the resection site with progression will appear as a confluence of disease. It has been shown that peritoneal damage responsible for promotion of tumor cell adherence and growth has been clearly demonstrated in animal

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models. There is a significant correlation between the amount of peritoneal trauma, the proportion of cancer cells implanting at damaged peritoneal surfaces, and the progression of carcinomatosis [8]. The same experiments showed that the enhancing effect of trauma was not only restricted to the wounded site but also had a generalized effect. Other laboratory studies have confirmed that the conditions that accompany major abdominal surgery provide an optimal milieu for efficient seeding of tumor cells [9].

Clinical features of carcinomatosis from nongynecologic malignancies The clinical features of peritoneal carcinomatosis have been reported from the prospective study conducted by Chu et al. on 100 patients. There were 45 colorectal, 20 pancreas, 6 gastric, 4 small bowel, 2 appendix, 2 unknown primaries, and 21 miscellaneous malignancies [5]. Also, the French prospective multicentric study EVOCAPE 1 reported on 370 patients. There were 125 gastric, 118 colorectal, 58 pancreas, 4 small bowel, 3 liver, 12 pseudomyxoma peritonei, 7 mesothelioma, and 43 unknown malignancies [6]. The following information is restricted to the 370 patients included in the French EVOCAPE 1 study.

Clinical presentation of carcinomatosis Synchronous carcinomatosis occurring with primary cancer was found in 55% of patients (257 of 470); carcinomatosis documented in follow-up occurred in the other 45%. Ascites (164 of 470) and bowel obstructions (114 of 470) were the main clinical symptoms in both groups. Resection of the primary tumor was performed for 42.0% of the patients, while only bypass surgery was performed to reestablish gastrointestinal continuity in 34.2% of the patients. Explorative laparotomy and biopsies were reported for 23.8% of the patients. The previously described carcinomatosis staging system of Gilly was used to assess the extent of carcinomatosis (Table 1). Gastric carcinoma The mean age of these 125 patients (76 males) was 60.5 years (range 21-96 years). Seventy-three patients had synchronous carcinomatosis (58.4%), and the most frequent symptom in this group was ascites (35 of 125) (Table 2). Bowel obstruction occurred in nine patients (0.07%). The stage of the disease was advanced as evidenced by the pTNM classification. Fifty patients were pT3, and 62 patients were pT4. Positive lymph nodes were recorded in 117. Of considerable interest are two patients who had a pT1 and six patients who had a pT2 gastric cancer (Table 3). By the Gilly peritoneal carcinomatosis staging 72 of 125 were stages 3 and 4, according to the previously described PC staging (Table 4).

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Table 1 Gilly peritoneal carcinomatosis staging (from reference) Stage

Peritoneal carcinomatosis description

Stage 0 Stage 1

No macroscopic disease Malignant implants less than 5 mm in diameter Localized in one part of the abdomen Malignant implants less than 5 mm in diameter Diffuse to the whole abdomen Malignant implants 5 mm to 2 cm in diameter Large malignant masses (more than 2 cm in diameter)

Stage 2 Stage 3 Stage 4

Data from Gilly FN, Carry PY, Sayag AC, et al. Regional chemotherapy and intraoperative hyperthermia for digestive cancers with peritoneal carcinomatosis. Hepatogastroenterology 1994;41:124–9.

Colorectal carcinoma The mean age of these 118 patients (62 males) was 62.3 years (range 20–92 years). Sixty-nine patients had synchronous carcinomatosis (58.5%). The most frequent symptom was ascites (35 of 118), while bowel obstruction occurred in 23 patients (19.5%) (Table 2). The stage of the disease was advanced (Table 3), as evidenced by the pTNM classification. Seventy-six were pT3, 38 were pT4. Only 27 patients (39%) were lymph node positive. Four patients had a pT2 colorectal cancer. Peritoneal carcinomatosis staging revealed 78 of 118 were stages 3 and 4 (Table 4). Pancreatic cancer The mean age of these 58 patients (27 males) was 65.5 years (range 26–89 years). Forty patients had synchronous peritoneal carcinomatosis (68.9%), and the most frequent presenting symptom (Table 2) was ascites (25 of 58). Bowel obstruction occurred for six patients (10.3%). The stage of the disease was advanced, as evidenced by the presence of ascites (43.1%). The Gilly carcinomatosis staging showed 32 of 58 patients stages 3 and 4. Carcinoma of unknown primary The mean age of these 43 patients (15 males) was 67.5 years (range 24–83 years). Twenty-eight patients (65.1%) had carcinomatosis diagnosed at the time of entrance into the study. The most frequent symptom was ascites (21 of 43), while bowel obstruction occurred in 14 patients (32.5%) (Table 2). Peritoneal carcinomatosis stages were advanced with 38 of 43 patients stage 3 and 4 (Table 4). Clinical information on EVOCAPE 1 patients The purpose of the EVOCAPE 1 study initiated in 1997 was to gather more precise information on the evolution of nongynecologic carcinomatosis treated with palliative intent and the survival of patients with this

212

Total

59

9 23 6 14 3 0 2 2 127

35 35 25 21 1 0 8 2

Abbreviations: PC, peritoneal carcinomatosis; US, ultrasonography.

73 69 40 28 0 2 / /

Gastric Colorectal Pancreas Unknown Small bowel Liver Pseudomyxoma Mesothelioma 58

13 11 5 20 0 0 4 5 144

1 1 / /

63 75 4

Resection of primary tumor

Ascites

Surgical procedures Positive US or CT scan

Synchronous CP

Intestinal obstruction

Clinical features

Table 2 Clinical features and surgical procedures

125

35 26 30 20 3 0 10 1

By-pass

101

27 17 24 23 0 2 2 6

Biopsy

Chemotherapy

97

17 46 11 10 1 1 6 5

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Table 3 PTNM and differentiation of primary tumors Differentiation

PTNM

WD MD PD UD Unknown PT1 PT2 PT3 PT4 PN0 PNþ M1 Total Gastric 22 Colorectal 41 Pancreas 13 Unknown 3 Small bowel 1 Liver 0 Pseudomyxoma Mesothelioma

31 22 15 5 0 2

16 14 5 10 1 0

9 1 1 1 0 0

47 40 24 24 2 1

2 0 0

6 4 2

Total

75

46

12

138

2

12

80

55 76 30

62 8 38 14 26 5

117 104 53

19 27 6

125 118 58 43 4 3 12 7

161 126 27

274

52

370

Abbreviations: WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated; UD, undifferentiated.

disease [6]. To fulfill these requirements, patients diagnosed by laparoscopy need to be excluded as well as the patients treated by new aggressive approaches such as intraperitoneal chemohyperthermia with or without peritonectomy procedures. Of these 370 patients, 212 (57%) were identified at the time the primary tumors were diagnosed (synchronous carcinomatosis) and 158 found during the follow-up of known malignancies (metachronous PC). All 370 patients underwent surgery. The Gilly staging of peritoneal carcinomatosis was as follows: stage 0 (n ¼ 13), stage 1 (n ¼ 47), stage 2 (n ¼ 71), stage 3 (n ¼ 84), and stage 4 (n ¼ 155), as described in Table 4. The procedures performed (Table 2) were resection of primary tumors in 144 patients, by-pass to reestablish gastrointestinal continuity in 125 and only laparotomy with biopsies in 101 patients. The overall operative mortality and morbidity rates were 21% (77 of 370) and 16% (60 of 370), respectively. Ninety-seven patients underwent postoperative palliative systemic chemotherapy (one to eight courses, 5-fluorouracil combined with folinate for 64 patients and 5-fluorouracil combined with oxaliplatin for 33 patients). Table 4 Peritoneal carcinomatosis staging PC staging Gastric Colorectal Pancreas Unknown Small bowel Liver Pseudomyxoma Mesothelioma Total

Stage 0

Stage 1

Stage 2

Stage 3

9 2 2 0 0 0 0 0

22 11 11 1 1 1 0 0

22 27 13 4 1 2 2 0

27 33 12 7 0 0 3 2

45 45 20 31 2 0 7 5

125 118 58 43 4 3 12 7

13

47

71

84

155

370

Abbreviation: PC, peritoneal carcinomatosis.

Stage 4

Total

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Survival of patients in EVOCAPE 1 The mean and the median overall survival were 6.0 months (0.1 to 48.0 months) and 3.1 months respectively (Fig. 1). Mean and median survival according to the peritoneal carcinomatosis staging are shown in Table 5. For gastric carcinoma patients, overall mean and median survival were 6.5 months (range 0.1–48.0) and 3.1 months, respectively. Several potential prognostic factors were analyzed for survival differences: synchronous or metachronous peritoneal carcinomatosis, initial pTNM classification, lymph node involvement, peritoneal carcinomatosis staging, presence of ascites and presence of liver metastases (Table 6). The Gilly carcinomatosis stage 3 and 4, ascites and liver metastasis were significantly correlated with reduced survival. For colorectal cancer patients, overall mean and median survival times were 6.9 months (range 0.6–44.9) and 5.2 months, respectively. Potential prognostic factors were analyzed for survival differences as shown in Table 7. Only the carcinomatosis staging of Gilly showed a significant impact on survival. For pancreatic carcinoma patients, overall mean and median survival times were 2.9 months (range 0.3–13.6) and 2.1 months, respectively. Four potential prognostic factors were analyzed for survival differences as shown in Table 8. The presence of ascites was associated with reduced survival. For patients diagnosed with primary unknown cancer, overall mean and median survival times were 2.9 months (range 0.2–12) and 1.5 months, respectively.

Fig. 1. Survival rates of 370 patients with peritoneal carcinomatosis according to carcinomatosis staging system by Gilly. Stages 0, 1, and 2 (diamond), stages 3 and 4 (triangle).

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Table 5 Survival of peritoneal carcinomatosis according to pc staging PC stages

Mean (months)

Range (months)

Median (months)

Stage Stage Stage Stage Stage

0 1 2 3 4

19.9 9.8 6.8 5.6 3.7

0.1–24.1 1.6–48.0 0.2–40.0 0.1–24.1 0.1–36.0

10.0 7.0 5.0 3.9 2.0

Overall

6.0

0.1–48.0

3.1

Postoperative deaths are included, ddl ¼ 4, P\0.0001.

Symptoms of carcinomatosis patients The major symptoms indicative of carcinomatosis are bowel obstruction and ascites [10–13]. Bowel obstructions were most frequently reported for colorectal cancers (20% in the present study), while ascites was more often reported for pancreatic cancer (43%). The clinical presentations of carcinomatosis are not specific except when the abdominal examination Table 6 Potential prognostic factors for survival in gastric cancer with peritoneal carcinomatosis. Median (months) Peritoneal carcinomatosis Synchronous Not synchronous Initial pTNM staging T1T2 (n ¼ 8) T3 (n ¼ 55) T4 (n ¼ 62) Lymph node involvement N0 Nþ PC staging Stage 1 Stage 2 Stage 3 Stage 4 Differentiation WD and MD PD and UD Ascites Yes No Liver metastases Yes No

Mean (months)

P value

2.8 3.1

4.8 5.1

P ¼ 0.6 NS

9.0 4.0 2.5

20.4 9.7 4.2

P ¼ 0.06

8.8 8.5

7.0 7.8

P ¼ 0.52 NS

7.9 6.2 5.8 1.9

11.2 4.5 3.5 2.6

P ¼ 0.001

4.2 2.4

5.2 4.7

P ¼ 0.4 NS

1.4 3.8

3.6 5.4

P ¼ 0.05

1.0 3.3

2.6 5.3

P ¼ 0.0009

Abbreviations: PC, peritoneal carcinomatosis; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated; UD, undifferentiated.

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Table 7 Potential prognostic factors for survival in colorectalcancer with peritoneal carcinomatosis Median (months) Peritoneal carcinomatosis Synchronous Not synchronous Initial pTNM staging T1T2 (n ¼ 4) T3 (n ¼ 76) T4 (n ¼ 38) Lymph node involvement N0 Nþ PC staging Stage 1 Stage 2 Stage 3 Stage 4 Differentiation WD and MD PD and UD Ascites Yes No Liver metastases Yes No

Mean (months)

P value

4.1 5.3

6.0 6.2

P ¼ 0.78 NS

7.3 5.3 3.4

9.3 7.2 4.7

P ¼ 0.5 NS

8.7 7

10.2 6.8

P ¼ 0.13 NS

12.5 8.3 4.4 2.7

14.3 8.4 6.0 4.4

P ¼ 0.001

3.2 5.5

5.3 5.3

P ¼ 0.9 NS

3.7 5.1

5.1 6.5

P ¼ 0.6 NS

4.4 5.9

6.1 6.1

P ¼ 0.4 NS

Abbreviations: PC, peritoneal carcinomatosis; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated; UD, undifferentiated.

Table 8 Potential prognostic factors for survival in pancreatic cancer with peritoneal carcinomatosis

PC staging Stage 1 and 2 Stage 3 and 4 Differentiation WD and MD PD and UD Ascites Yes No Liver metastases Yes No

Median (months)

Mean (months)

P value

3.1 2.3

3.2 2.4

P ¼ 0.45 NS

2.1 2.5

3.5 3.2

P ¼ 0.85 NS

1.4 3.8

3.4 5.8

P ¼ 0.05

2.8 1.8

4.2 3.1

P ¼ 0.36 NS

Abbreviations: PC, peritoneal carcinomatosis; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated; UD, undifferentiated.

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revealed malignant masses palpable through the anterior abdominal wall. Other symptoms that exist may be related to the primary tumor as well as nonspecific cancer symptoms such as weight loss, anorexia, anemia, and abdominal pain. It can be concluded that carcinomatosis can remain asymptomatic for a period of time. As noted above, the progression of carcinomatosis may be exponential. Delay in the diagnosis and a failure to rapidly initiate definitive treatment would be expected to have an adverse effect on survival. The extent of the disease at the initiation of treatment may have a significant impact on the benefits achieved. Asymptomatic patients with localized or small volume peritoneal surface malignancies should be selected for comprehensive multimodal treatments. The challenge remains to identify these asymptomatic or early carcinomatosis patients during follow-up. This concept emphasizes the need for advancement in imaging of the peritoneal cavity.

Comparison of site-specific survival The French EVOCAPE 1 study confirms the very poor prognosis (median 3.1 months) for all carcinomatosis patients. The length of survival seemed to be greatly influenced by the stage of the peritoneal carcinomatosis. It was 5 to 10 months for stages 0, 1 and 2 versus 2.0 to 3.9 for stages 3 and 4 (Fig. 1). Survival times do differ according to the location of the primary tumor. A pancreatic origin has the shortest survival (2.1 months), gastric origin 3.1 months, and colorectal location 5.2 months. Some unexpected long-term survival times were observed [10]. The range of survival of the French series was 0.1 to 48.0 months in gastric cancer, 0.6 to 44.9 months in colorectal cancer, and 0.3 to 13.6 months in pancreatic cancer.

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