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Cytoreduction and hyoerthermic intraperitoneal chemotherapy in peritoneal
carcinomastosis of colorectal origin
Verwaal, V.J.
Publication date
2004
Link to publication
Citation for published version (APA):
Verwaal, V. J. (2004). Cytoreduction and hyoerthermic intraperitoneal chemotherapy in
peritoneal carcinomastosis of colorectal origin.
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Chapterr seven
Recurrencess after peritoneal carcinomatosis of
colorectall origin treated by cytoreduction and
hyperthermicc intraperitoneal chemotherapy:
location,, treatment and outcome
Vicc J. Verwaal
1, Henk Boot
2, Berthe M.R Aleman
3,
Harmm van Tinteren
4and Frans A.N. Zoetmulder
1d e p a r t m e n tt of Surgery, d e p a r t m e n t s of Gastroenterology,
3
Departmentt of Radiotherapy and
4Department of Biometrics
Thee Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam,, the Netherlands
Background:Background: After treatment of peritoneal carcinomatosis of colorectal origin by cytoreduction and hyper-thermicc intraperitoneal chemotherapy (HIPEC), recurrences develop in approximately 80% of patients. This
studyy evaluates the outcome of such recurrences after initial treatment by cytoreduction and HIPEC.
Methods:Methods: Between November 1995 and May 2003, 106 patients underwent cytoreduction and HIPEC. The progression-freee interval, the location of the recurrence, and its treatment were recorded. Factors potentially relatedd to survival after recurrences were studied.
Results:Results: Sixty-nine patients had a recurrence within the study period. For patients who had undergone a grosss incomplete initial cytoreduction, the median duration of survival after recurrence was 3.7 months (SE. 0.3).. If a complete cytoreduction had been accomplished initially, the median duration of survival after the recurrencee was 11.1 months (SE 0.9). A shorter interval between HIPEC and recurrence was associated withh shorter survival after treatment of recurrence (Hazard ratio 0.94; SE 0.02). After effective initial treat-ment,, a second surgical debulking for recurrent disease resulted in a median survival duration of 10.3 monthss (SE 1.9), and after treatment with chemotherapy it was 8.5 months (SE 1.6). The survival was 11.2 monthss (SE 0.5) for patients who received radiotherapy for recurrent disease. Patients who did not receive furtherr treatment survived 1.9 months (SE 0.3).
Conclusions:Conclusions: Treatment of recurrence after cytoreduction and HIPEC is often feasible and seems worth-whilee in selected patients. Selection should be based mainly on the completeness of initial cytoreduction and thee interval between HIPEC and recurrence.
Recurrence e
I n t r o d u c t i o n n
Peritoneall carcinomatosis is a manifestation of colorectal cancer in which intraperitoneal seeding off tumor cells occurs. After implantation on the peritoneal surfaces, the malignant cells may form tumorr nodules throughout the abdominal cavity, which can cause bowel obstructions. Cytoreduc-tivee surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a novel treat-mentt for this disease. In recent years, several phase II studies and one phase III study have shown thatt this merapy improves survival to a median of two years and mat up to 20% of patients live longerr than five years and are probably cured.1-6 A common feature of all these studies is that the outcomee was determined mainly by the completeness of the cytoreduction.7^9 After a macroscopi-callyy complete debulking, patients have a reasonable chance of surviving.
Recurrentt disease after cytoreduction and HIPEC develops in approximately 80% of patients. Thesee recurrences can occur within the abdomen as well as at distant sites. A local recurrence is likelyy to cause bowel obstruction, which needs surgical treatment. Radiotherapy may be indicated if thee local recurrence cannot be removed surgically with free margins. Systemic chemotherapy is the treatmentt of choice for patients who have distant metastases. Systemic therapy is also given in casess of multiple intra-abdominal recurrences.
Althoughh the above-mentioned general guidelines are common policy,1011 there is no good docu-mentationn on the effects of third-line treatment of recurrent peritoneal carcinomatosis after cytore-ductionn followed by HIPEC. Most patients have a strong desire to be treated for recurrence. Pa-tientss who survive the "HIPEC struggle" tend to agree to any possible means of increase their life span,, no matter what the associated morbidity and mortality might be.
Thee objectives of the study were to determine the patterns of recurrence and the survival after third-linee and even fourth-line treatment of patients with peritoneal carcinomatosis of colorectal originn managed by cytoreduction and HIPEC.
Patientss and methods
Betweenn November 1995 and May 2003, 106 patients were treated for peritoneal carcinomatosis off colorectal origin at The Netherlands Cancer Institute. The first 35 patients were enrolled in phasee I and II studies. The next 49 patients were enrolled in a randomized phase HI study, and the remainingg 22 patients were treated afterward. The protocols were approved by the local ethics committee.. The protocols were open for patients with proven peritoneal metastases of colorectal originn or cytologically positive ascites. Patients with radiological evidence of distant metastases weree excluded. Patients had to be younger than 71 years and fit to undergo major surgery (with normall bone marrow indices and normal renal and liver function). All patients were treated in ac-cordancee to the phase III study protocol,5 and their data were prospectively collected.
Thee treatment is described in detail elsewhere.12 In brief, it consisted of two elements: aggressive surgicall cytoreduction and HIPEC. Mitomycin C was used as intraperitoneal chemotherapy at a temperaturee of 40°C to 41 °C for 90 minutes.
Chapterr 7
Duringg laparotomy, we collected data on the tumor distribution. Before cytoreduction, we re-cordedd the presence of macroscopic tumor deposits in seven abdominal regions: pelvis and sig-moid;; right lower abdomen; small bowel and mesentery; omentum and transverse colon; sub-hepaticc space and stomach; right subphrenic space; and left subphrenic space. After completion of cytoreduction,, the absence of residual tumor was recorded as R-l. If the largest residual tumor was smallerr than 2.5 mm, it was regarded as an R-2a resection; if it was larger than 2.5 mm, the cytore-ductivee surgery was scored as R-2b.
Afterr discharge and recovery, 5-fluorouracil/leucovorin was given as adjuvant therapy in a weekly,, slightly modified Laufman regimen for 26 weeks13. Irinotecan was used in 3-week intervals iff 5-fluorouracil/leucovorin had been given within one year before the HIPEC treatment.
Thee protocol required patients to visit the outpatient clinic every three months for two years and att 6-month intervals thereafter. The follow-up visit included a recording of history, physical exami-nation,, and determination of serum CEA and CA 19.9 values, with the addition of computed to-mographyy (CT) scanning of the abdomen every other visit. If symptoms arose, CT-scan or endo-scopyy was performed as required to determine their cause. Positron emission tomography (PET) wass performed in cases involving a tumor marker rise or inconclusive CT-scan findings.
AA local recurrence was defined as any new lesion revealed by physical examination or CT in com-parisonn with the first examination findings after the HIPEC procedure. When a lesion was found onn endoscopy, a recurrence was diagnosed only if histological proof was obtained. If a tumor markerr value doubled, attempts were made to confirm the presence of a recurrence. If the tumor markerr value kept rising, the patient was considered to have recurrent disease even if this could not bee demonstrated with an extensive search. Systemic metastases were defined as any lesion evident onn a CT-scan or chest radiograph that was not seen at a previous examination. The location of a recurrencee was classified in one of five groups: intra-abdominal, liver, lung, both systemic and in-tra-abdominall and unknown.
Recurrencess were treated according to the following general guidelines. Surgical treatment was alwayss considered as the first option. Surgery with curative intent was performed in cases involving onee intra-abdominal lesion if this lesion could be removed with a free margin. After operative treat-ment,, patients did not receive systemic chemotherapy as adjuvant therapy. In cases involving pre-dictablyy questionable margins, radiotherapy with curative intent was given. The radiation schedule wass determined on the basis of the patient's general condition and the extent of the recurrence. In thee patient's condition was reasonably good and the tumor was of limited size, a total of 39 Gy was givenn in 13 fractions. If resection or radiotherapy could not possibly be curative for all recurred le-sions,, systemic chemotherapy was given. Typically, patients who underwent systemic chemother-apyy had multiple intra-abdominal locations of metastasis. Second- or third-line chemotherapy was alsoo offered for distant metastases, with or without local recurrence.
Whenn an abdominal emergency occurred, mostly due to bowel obstruction, the first objective wass to restore bowel function conservatively. Laparotomy was performed if this approach failed. Thee aims were then to relieve the obstruction and to make a second attempt to debulk. No second hyperthermicc intraperitoneal chemotherapy procedures were done.
Recurrence e
Thee patients were grouped in the original category of completeness of cytoreduction after the HIPECC procedure: no macroscopic residual tumor (R-l), minimal residual disease (maximum thicknesss of 2.5 mm, R-2a), or gross residual disease (R-2b).
Thee Kaplan-Meier method was used to determine overall survival, progression-free interval, and survivall after recurrence. The progression-free interval was calculated from the moment of the HIPECC procedure to the date of proven recurrence. Survival after recurrence was determined from thee date this recurrence was diagnosed.
Thee log rank test was used for univariate analysis and the Cox proportional hazard method was usedd for multivariate analysis.
Results s
Cytoreductionn as initial treatment for peritoneal carcinomatosis was macroscopkally complete l)) in 54 patients (51%), nearly complete 2a) in 37 patients (35%), and grossly incomplete (R-2b)) in 15 patients (14%). Tumor characteristics of the primary colorectal cancer and the extent of thee peritoneal carcinomatosis are given in table 1. After a median follow-up of 47.5 months (range 1.33 to 88.3 months), 69 of the 106 patients had had a recurrence. The time to recurrence was re-latedd mainly to the completeness of the cytoreduction in the initial treatment for carcinomatosis (tablee 2).
Mostt of the recurrences after an R-l or R-2a resection occurred in the abdominal cavity. Distant metastasess as first recurrences were predominandy located in the liver (table 3). In one patient the tumorr marker value rose but the location of the recurrence was unknown. The time to liver metas-tasess and recurrence at unknown locations was shorter than for other sites.
Patientss who had undergone R-l and R-2a resections had a median survival of 11.1 months (SE 0.9)) and 5.9 months (SE 0.8) after recurrence, respectively. When there was gross residual tumor (R-2bb resection) at the initial cytoreduction site, median survival was a mere 3.7 months (SE 0.3). A shorterr interval between the initial treatment of carcinomatosis and recurrence was related to shorterr survival after recurrence (Hazard ratio 0.94; 95% confidence interval [CI] 0.91-0.98). Signet celll carcinoma and older age were also significant risk factors for a shorter survival (Hazard ratios, 3.55 and 1.0; SE's 1.6 and 0.02, respectively). Gender, location of the primary tumor, synchronic or metachronicc carcinomatosis, and malignancy grade had no prognostic value.
Twelvee patients did not receive any treatment for their recurrence, mosdy because of a poor per-formancee state. They survived for a median period of 1.9 months (SE 0.3). Twenty-eight patients underwentt surgery, which for six patients consisted of an explorative laparotomy only. Twenty pa-tientstients received systemic chemotherapy, and nine patients, radiotherapy. Only six of 11 patients with ann initial R-2b resection underwent further treatment.
Fifty-eightt patients who had an effective initial cytoreduction (R-l and R-2a) were further ana-lyzed.. Seven of them received no treatment at all, whereas five patients underwent an explorative laparotomyy only. Among six patients who underwent bypass surgery for recurrence, the median
Chapterr 7
Tablee 1. Characteristics of 106 tionn and H I P E C divided
Alll patients Mediann age Femalee / Male Locationn CRC Appendix x Colon n Rectum m NS S Differentiationn CRC' Good d Moderate e Poor r Histology2 2 Adenocarcinoma a Mucinouss carcinoma Signett cell carcinoma
Numberr regions PC 0 - 5 5
6 - 7 7
patients s with h byy results of initial
R-l l 54 4 55.5 5 2 4 / 3 0 0 7 7 44 4 3 3 --8 --8 30 0 11 1 41 1 7 7 4 4 51 1 3 3 peritoneall carcinomatosis cytoreduction n R-2a a 37 7 52.0 0 1 7 / 2 0 0 6 6 29 9 --2 --2 3 3 24 4 9 9 25 5 5 5 7 7 24 4 13 3 R-2b b 15 5 48.0 0 5 / 1 0 0 2 2 9 9 2 2 2 2 1 1 5 5 9 9 9 9 2 2 4 4 5 5 10 0 treatedd by cytoreduc-All l 106 6 53.4 4 4 6 / 6 0 0 15 5 82 2 5 5 4 4 12 2 59 9 29 9 75 5 14 4 15 5 80 0 26 6 R-l:: no residual tumor, R-2a: residual tumor < 2.5 mm, R-2b: residual tumor > 2.5 mm CRC:: colorectal cancer, NS: not specified, PC: peritoneal carcinomatosis
'dataa of 6 patients missing, 2data of 2 patients missing
Tablee 2. Time to recurrence in 69 patients with recurrence after cytoreduction and H I P E CC by initial cytoreduction result
Numberr of Number Median time to SE patientss at risk recurrences recurrence
(months) ) R-l l R-2a a R-2b b 54 4 37 7 15 5 25 5 33 3 11 1 13.7 7 10.8 8 4.8 8 1.0 0 1.7 7 0.4 4 R-l:: no residual tumor, R-2a: residual tumor < 2.5 mm, R-2b: residual tumor > 2.5 mm
Recurrence e
survivall was 4.5 months (SE 0.5). The median survival of the 15 patients who underwent a second surgicall debulking was 10.3 months (SE 1.9). The 16 patients who received systemic chemotherapy forfor recurrence survived a median of 8.5 months (SE 1.6). Most of those patients were treated with irinotecan;; three patients one patient received radiotherapy for a metastasis in an abdominal wound.. Five patients received radiotherapy for which the intent was a long-term palliative effect, andd their survival was 11.2 months (SE 0.5). Survival was 8.7 months (SE 1.1) among the four pa-tientss who underwent short-term palliative radiotherapy.
Tablee 3. Location of recurrences after treatment by cytoreduction and HIPEC Initiall cytoreduction R-l l N=54 4 Intra-abdominal l Liver r Lung g Intra-abdominall and systemic c Unknownn location All l 13 3 8 8
--3 --3 1 1 25 5 R-2a a nn = 37 26 6 2 2 1 1 4 4 --33 3Disease-freee interval (SE) (months) ) 12.7(1.6) ) 9.00 (0.6) 14.7 7 13.7(1.1) ) 3.9 9 12.3(2.1) )
R-l:: no residual tumor, R-2a: max residual tumor 2.5 mm
Discussion n
Theree is growing evidence that patients affected by peritoneal carcinomatosis of colorectal origin benefitt from cytoreduction and some form of intraperitoneal chemotherapy. Although this treat-mentt may improve survival, the majority of patients will have recurrent disease within the first threee years. These recurrences most often occur intra-abdominally, even if the abdomen is assumed too be free of tumor nodules after the initial cytoreduction and HIPEC (R-l and R-2a). This con-trastss with the natural history of colon cancer; in one-half of patients with colon cancer, the first sitesite of recurrence is the liver.14"16 The pattern corresponds more to findings in rectal cancer, where locall recurrence occurs more often.17
Thee tendency for intra-abdominal recurrences instead of hematogenic metastases can be ex-plainedd in two ways: either a biological mechanism makes cancer cells more adherent to the perito-neumm and encourages local seeding rather than hematogenic spread or else intraabdominal recur-rencee occurs long before systemic metastases develop. The latter argument is unlikely because the mediann time for the development of liver metastases in this study was less than for intra-abdominal
Chapterr 7
r e c u r r e n c e s . .
T h ee survival time after recurrence in our series depended o n the interval between the initial treat-m e n tt of carcinotreat-matosis and the appearance of recurrent disease. This kind of relationship is also seenn in o t h e r forms o f recurrence in colon cancer. G o l d b e r g et al.18 concluded mat the treatment o ff a r e c u r r e n c e within the first year after the initial treatment for colon cancer resulted in a limited 5-yearr survival rate, in contrast with recurrences treated after three years. It seems likely that this reflectss slow growth characteristics of the tumor involved. This feature o f the t u m o r determines thee o d d s o f survival after second-line and third-line treatment.
Patientss in w h o m initial treatment of peritoneal carcinomatosis failed (R-2b resections) not only hadd early progression of disease b u t often failed third-line treatment as well. This seems logical, be-causee a less aggressive treatment is unlikely to benefit these patients w h e n a more aggressive treat-m e n t ,, e.g., cytoreduction followed by H I P E C , fails to cure the initial carcinotreat-matosis. These patients s h o u l dd therefore be spared the morbidity risk of a third-line treatment.
T h e r ee h a v e been only a few reports on the results of treatment of recurrence after cytoreduction a n dd H I P E C . Portilla et al.8 noted long-term survival after cytoreduction was repeated. T h e value of t h e s ee third-line treatments, however, is difficult to assess in terms of morbidity and mortality.
I nn the presented analysis patients were treated with one of the three treatment options. T h e analysiss s h o w s that systemic chemotherapy has its value as a single-treatment modality. This sug-gestss diat systemic c h e m o t h e r a p y should be considered in addition to a secondary cytoreduction, b e c a u s ee this p r o c e d u r e will probably leave macroscopic or microscopic disease behind.
T h ee c u r r e n t evaluation of various treatments for recurrences pertains to a subgroup analysis and givess only level III evidence. F r o m these data it is not possible to determine which treatment m o -dalityy is optimal, because surgery, chemotherapy, and radiotherapy were given for different vol-u m e ss of recvol-urrent disease. A randomized trial on third-line treatments in this patient g r o vol-u p is not feasiblee because patterns of recurrent disease vary and the n u m b e r of patients is limited.
I nn conclusion, m o s t recurrences after cytoreduction and H I P E C are intraabdominal. T h e m e -diann survival of patients w h o underwent effective treatment of their initial peritoneal carcinomato-siss w a s approximately o n e year. T r e a t m e n t o f recurrence of peritoneal carcinomatosis of colorectal originn is feasible and seems worthwhile for selected patients. Selection should be based mainly on thee success of cytoreduction and H I P E C and on a long interval between this treatment and the oc-c u r r e n oc-c ee of reoc-current disease. In addition, younger age and the absenoc-ce of pathologioc-c signet oc-cells favorr o u t c o m e .
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Recurrence e
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