The Role of Surgery in Abdominal Non-Hodgkin’s Lymphoma: Experience From the Childrens Cancer Study Group ByMichael

P. LaQuaglia,

Charles

J.H. Stolar,

Mark Krailo,

and Denman

Philip Exelby,

Stuart

Siegel,

Anna

Meadows,

Hammond

Arcadia, California l To determine the appropriate role of surgical intervention in non-Hodgkin’s lymphoma primary to the abdomen, we analyzed the effect of multiple prognostic determinants on event-free survival for patients entered into the CCG-551 study. Eighty-four patients were identified with abdominal lymphoma and of these adequate data for analysis was available on 66 (61%). Variables of interest included: extent of disease at diagnosis, completeness of resection, use of bowel resection, radiation to the primary site, and sex/age/ race. The median age on study was 6 years; 79% of patients were white and 85% were male. Thirty-three patients (49%) presented with localized disease. Laparotomy was performed in 67 children (gg%) with complete gross resection in 28 (42%). of the 10 reported surgical complications, 8 occurred in those with extensive disease who were incompletely resected. Radiation to the primary site was given in 60% of patients with median dose of 2,000 cGy. Analysis was performed both for the overall group and for the subgroup receiving optimal chemotherapy for histopathology. Variables with significant predictive effect on event-free survival in univariate analysis included extent of disease (P I .OOl), complete resection (P < .002), and use of bowel resection (P I .004). However, in multivariate analysis, only extent of disease was an independent predictor of outcome. The data support a role for complete operative excision of localized lymphomas especially when accomplished with bowel resection. Aggressive attempts at debulking extensive retroperitoneal or mesenteric lymphomas are contraindicated. Copyright o 1992 by W.B. Saunders Company INDEX WORDS:

Non-Hodgkin’s

lymphoma,

abdominal

sur-

gery.

T

HE PROGNOSIS for childhood non-Hodgkin’s lymphoma improved significantly with the realization that virtually all cases were disseminated at diagnosis and systemic therapy was necessary for long-term disease-free survival. In 1975, Wollner et al’ established the lo-drug LSA,-L, protocol while Meadows et al successfully used the 4-drug COMP regimen to treat childhood non-Hodgkin’s lymphomas.2*3The CCG-551 study, which compared these two regimens, showed that LSA,-L, was more effec-

From the Lymphoma Strategy Group of the Childrens Cancer Study Group, Arcadia, CA. Presented at the 22nd Annual Meeting of the American Pediatric SurgicalAssociation, Lake Buena Vi&a, Florida, May 15-18, 1991. Address reprint requests to Michael P. LaQuaglia, MD, Department of Surgery (Pediatric Surgery), Memorial Sloan-Kettering Cancer Center, 1275 YorkAve, New York, NYlOO21. Copyright o 1992 by EB. Saunders Company 0022-3468/92/2702-0018$03.00/0

230

tive for disseminated lymphoblastic tumors, whereas COMP had a therapeutic advantage in treatment of undifferentiated lesions.4 Survival increased from 10% to 15% to 75% to 80% during this period. In patients with primary presentation in the abdomen the role of surgery remained controversial. Magrath et al supported aggressive operative debulking, defined as >90% tumor removal, prior to chemotherapy after analysis of a large single institutional series of patients with Burkitt’s lymphoma from Uganda.5,6 Kemeny et al7 also suggested a survival advantage in patients undergoing complete resection but noted that extent of disease was not evaluated. Others cautioned against extensive initial surgery, which might delay institution of systemic therapy.8.9 The question as to whether tumor bulk determined resectability and ultimate prognosis, or surgical resection alone had a primary effect on outcome remained unanswered. In this study we analyzed data on the subgroup of patients with abdominal non-Hodgkin’s lymphoma in the CCG-551 study to ascertain variables, including extent of disease and surgical resectability, which significantly affect disease-free survival. Multivariate analysis was used to determine independent outcome predictors. The results of this analysis were used to develop a rational surgical approach to non-Hodgkin’s lymphomas presenting in the abdomen. MATERIALS Patient

AND

METHODS

Selection

Data on the CCG-551 study were obtained from the CCSG operations office. All untreated patients less than 18 years of age and with biopsy-confirmed non-Hodgkin’s lymphoma of any pathological type but with primary anatomic presentation in the abdomen were eligible to enter the study if they had less than 25% blasts in a bone marrow aspirate and none in the peripheral blood. Five months after initiation (30 patients enrolled) the eligibility criteria were expanded to include all patients with “undifferentiated” lymphomas regardless of extent of bone marrow involvement or blasts in the peripheral blood.

Clinical and Pathological Extent mined by aspiration, white-cell gram, and

Evaluation

of disease, based on protocol specifications, was deterhistory, physical examination, hemogram, bone marrow a spinal fluid cell count and cytocentrifugation for morphology, chest x-ray, bone survey, intravenous uroradionuclide or computed axial tomography scans of the

Journalof Pediatric Surgery, Vol27, No 2 (February), 1992: pp 230-235

SURGERY OF NON-HODGKIN’S

231

LYMPHOMA

liver, spleen, and bone. Routine lymphangiography and staging laparotomy were not performed. Data concerning surgical variables were entered onto a surgical check-list completed by the institutional operating surgeon. Of particular interest was the extent of intraabdominal disease, anatomic location of the primary tumor, resectability (complete gross removal versus incomplete resection), and the incidence and type of surgical complications. Localized disease was defined as isolated mural involvement of the bowel with or without positive mesenteric nodes in adjacent echelons, localized involvement of mesenteric nodes but without fixation to retroperitoneal structures or major mesenteric arteries, or localized solid organ involvement. Tissue suitable for histological examination was obtained from all patients and reviewed by the study pathologist who confirmed the diagnosis of non-Hodgkin’s lymphoma. Histopathologic subtype was determined according to the Rappaport system’” by institutional pathologists and the study pathologist.

Patients with localized abdominal disease underwent exploratory laparotomy and complete gross excision if feasible. Children with widespread abdominal disease also underwent exploratory laparotomy with tissue biopsy. In some patients with extensive intraabdominal disease a “debulking” procedure was also performed.

Statistical Analysis Variables analyzed for their effect on disease-free survival included: age at diagnosis, sex, race, extent of intraabdominal disease, surgical resectability, use of bowel resection, and use of abdominal radiation therapy. Complete resection was defined as complete gross excision. The product-limit method (KaplanMeier) was used to estimate the distribution of event-free survival and the statistical significance of observed differences was assessed using the log-rank test.“.” Covariates with significant predictive effect on outcome (P I .l) were then considered for entry into a Cox proportional hazards model.”

RESULTS

Patient Characteristics In the CCG-5.51 study 84 patients with nonHodgkin’s lymphoma primary in the abdomen were identified. Sufficient information was available on 68 (81%) for univariate and multivariate analysis. All subsequent findings refer to this group. The median age at diagnosis was 8 years (range, 1 month to 16 years). There were 58 males (85%) and 54 children were white (79%). Non-Hodgkin’s lymphoma was preoperatively diagnosed in 10 (15%). Localized (intraabdominal) disease was encountered in 33 children (49%) and extensive in 35 (51%). Surgery Laparotomy was performed in 67 patients (99%) and one child had an endoscopic transrectal biopsy of a large pelvic tumor. Operation was elective in 31 patients (46%) and urgent in 37 (54%). Preoperative diagnoses are listed in Table 1 and broken down as to whether exploration was elective or urgent. The most

Table 1. Preoperative Diagnoses Preoperative

Urgent

Elective

Diagnosis

29

3

lntussusception

0

17

Appendicitis

0

8

Perforation

0

4

Intestinal obstruction

0

3

Abdominal pain

1

1

Not stated

1

1

31

37

Abdominal mass

Tota I

frequent preoperative diagnosis was an abdominal mass (31), which was associated with tenderness or other symptoms in 5 cases. This was followed by intussusception (17) and then appendicitis (8). Anatomically the main tumor mass involved the bowel in 58 patients (85%). The small bowel was involved in 28 children, the large bowel in 14, and both the small and large bowel in 17. In addition, the liver was involved in 8 patients with simultaneous bowel lymphoma in 5, whereas the kidney was also a primary site in 8 and 7 of these also had tumor infiltrating the bowel. Six patients had ovarian tumors with 5 of these also suffering bowel involvement. All of the 5 patients with splenic lymphoma also had bowel infiltration. The relationship among tumor burden, urgency of surgery, and resectability is listed in Table 2. It can be noted that complete gross resection of abdominal lymphoma was never accomplished when disease was extensive despite 35 operative procedures. In contradistinction, 28 of 33 patients (85%) with localized disease underwent complete resection and the majority (24/28) of these were urgently explored. Of particular note is that 91% of patients undergoing complete resection with localized disease had a bowel resection. There were 10 reported surgical complications in the entire series (15%). Eight of these occurred in incompletely excised patients who also had extensive disease and the remaining 2 developed in children with localized, completely resected disease. Complications are listed in Table 3 and related to disease

Table 2. Extent of Disease Correlated With Resectability, Urgency of Operation, and Bowel Resection Complete

Incomplete

Complete

Incomplete

Resection

Resection

Resection

Resection

4

3

0

24

Emergency

24

2

0

11

Total

28

5

0

35

26 (91%)

3 (60%)

0

8 (23%)

Elective

No. with rasection involving bowel (%)

232

LAQUAGLIA ET AL

Table 3. Complications of Operation Extent of Complication

Disease

urgency

Resection

Infected ascites

Localized

Urgent

Complete

No

Wound infection

Localized

Urgent

Complete

Yes

Persistent ileus

Extensive

Urgent

Incomplete

Yes

Wound infection

Extensive

Elective

Incomplete

Yes

Extensive

Urgent

Incomplete

Yes

Reexploration for bleeding (omenturn)

Extensive

Elective

Incomplete

Yes

Pleural effusion, chest tube needed

Extensive

Elective

Incomplete

Yes

Renal failure

Extensive

Elective

Incomplete

No

Subhepatic abscess (operative drainage re-

Extensive

Urgent

Incomplete

No

Extensive

Urgent

incomplete

No

Blood loss

(> 250

ml)

Alive

quired) Wound dehiscence

extent, resectability, urgency of operation, and survival. Finally, there were 4 reported second-look laparotomies (6%) all done in patients with extensive, incompletely excised disease. Residual tumor that remained unresectable was found in 3 and the status of the fourth could not be determined. Chemotherapy and Radiation

Of the 68 patients in this study 38 (56%) received the LSA,-L, regimen and 30 (44%) received COMP. Five of the patients receiving LSA,-L, had the lymphoblastic subtype and, therefore, received histopathologically appropriate chemotherapy. All 30 patients who got COMP had undifferentiated histology and received appropriate chemotherapy; thus, a total of 35 patients in this study received histologically appropriate chemotherapy. External beam, supervoltage abdominal radiation therapy was given to 41 patients (60%) and median dose was 2,000 cGy (range, 200 to 3,038 cGy). Outcome and Univariate Analysis

Outcome data are summarized in Table 4, which shows that the 46 survivors had a higher rate of complete resection, urgent exploration, and localized disease. Also, the complication rate was lower in this group. The Kaplan-Meier curves for overall and event-free survival (Fig 1) show that actuarial survival in the overall group was approximately 65%. There was no difference between overall and event-free

survival, implying that deaths were related to uncontrolled disease and salvage after relapse was minimal. In univariate analysis age at diagnosis, sex, race, and radiation therapy to the abdomen were not significant predictors of outcome while extent of disease at diagnosis, complete resection of the primary, and excision achieved with bowel resection were significant. Data are summarized in Table 5 and show the results of log-rank analysis performed on the entire group in the study (n = 68) and a parallel analysis on the subgroup who received histologically appropriate chemotherapy (n = 35). Results are basically the same except for the loss of statistical power occasioned by smaller numbers in the subgroup. The survival in patients with extensive versus localized disease is compared in Fig 2. Figure 3 shows the effect of complete gross resection on outcome, whereas Fig 4 demonstrates the impact of bowel resection. Reference to Table 2 again underscores the fact that complete removal usually involved bowel resection. Multivariate Analysis

Variables with significant effect on outcome in univariate analysis were compared and the only independent predictor of event-free survival was extent of abdominal disease at diagnosis (P 2 .OOOOl). A parallel analysis that looked at the subgroup receiving optimal chemotherapy based on histopathologic subtype gave similar results.

Table 4. Patient Outcome Patient Group Complete

Urgently

vbnge)

NO.

Resection

Explored

Localized

Survivors 2,650 days (766-3.168)

46

25 (54%)

27 (59%)

29 (63%)

Deaths 174 days (30-491)

22

3 (14%)

10 (45%)

4 (18%)

4 (18%)

Total 2,360 days (30-3,168)

68

28 (41%)

37 (54%)

33 (49%)

10 (15%)

Median Follow-up

Complications

6 (13%)

233

SURGERY OF NON-HODGKIN’S LYMPHOMA

I?

Event-tree survival 0 Overall survival n

.2

(68 Rs., 43 Censored) (68 Pk. 46 Censored)

.2 -

I

I

I

I

528

1056

1584

2112

J

I

2640

3168

I 528

0

I 1056

Fig 1. These Kaplan-Meier curves show the overall survival and disease-free survival for the 66 patients included in this study.

DISCUSSION

The results of this study support several conclusions useful in determining the appropriate role of surgical intervention in abdominal non-Hodgkin’s lymphoma in childhood. The strongest predictor of event-free survival is tumor burden at diagnosis, as measured, in this analysis, by extent of abdominal disease. This is consistent with observations clearly showing that outcome is most dependent on the number of malignant cells present at initiation of therapy and can be predicted by measurement of serum lactic dehydrogenase, interleukin II receptor, and P,-microglobulin levels.‘4-‘” The data from the present analysis indicate that the amount of bulk disease in the abdomen is also a reliable predictor. To determine whether surgical removal of the abdominal tumor alters the clinical course or, conversely, whether the presenting mass primarily determines the feasibility of surgical resection, we examined the effect of complete surgical excision on event-free survival. In univariate analysis complete excision does favorably affect outcome but none of the patients with extensive abdominal disease underwent complete excision. Indeed, most complete resections were performed during emergency laparotomies for symptomatic, localized bowel involvement in pa-

Fig 2.

disease

I 2640

I 3168

All Patients (n = 68)

Optimal Therapy Patients (n = 35)

Negative

P 5 ,001

P 2 ,069

Complete resection

Positive

P 5 ,002

P 2 ,071

Use of bowel resection

Positive

P 5 ,004

P 5 ,070

Survival in the extensive versus localized disease groups.

1

.a

.6

Complete resection

(28 Rs.. 24 Censored)

0 Incomplete resection

(40 Rs., 19 Censored)

n

.2

Predictive Effect on Event-Free Survival

Extensive

I 2112

tients explored for intussusception or to rule out appendicitis (Tables 1 and 2). The fact that bowel resection was associated with better prognosis suggests that intestinal involvement is associated with an increased frequency of abdominal symptoms resulting in earlier laparotomies. Alternatively, a mesenteric or retroperitoneal mass that does not involve bowel wall remains clinically silent until a relatively larger tumor burden is reached as is the case with neuroblastoma or Wilms’ tumor. Complete resection is most readily accomplished in patients who have localized bowel involvement and early development of abdominal symptoms. When tumor burden was compared with resectability in multivariate analysis only the extent of disease remained an independent predictor of event-free survival. In essence, extent of disease is the ultimate

Table 5. Log-Rank Comparisons of Variables With Significant

Effect on Outcome

I

i 584 Time (days)

Time (days)

Variable

(35 Pts., 15 Censored) (33 Pts., 26 Censored)

P _

The role of surgery in abdominal non-Hodgkin's lymphoma: experience from the Childrens Cancer Study Group.

To determine the appropriate role of surgical intervention in non-Hodgkin's lymphoma primary to the abdomen, we analyzed the effect of multiple progno...
737KB Sizes 0 Downloads 0 Views