Download Secondary cytoreductive surgery followed by

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Management of peritoneal surface component of ovarian cancer
Deraco Marcello, MD,a, Raspagliesi Francesco MD,b, and Kusamura Shigeki MD,c
a Attending
Surgeon Department of Surgery at the Istituto Nazionale per lo Studio e la Cura dei Tumori, Italy
Coordinator of SITILO-ONLUS (Italian society of integrated locoregional therapy)/Peritoneal Neoplastic Study
Group
bChief
of Gynecologic Oncology division of Istituto Nazionale per lo Studio e la Cura dei Tumori
cClinical
researcher at Gynecologic Oncology division of Istituto Nazionale per lo Studio e la Cura dei Tumori
This work was partially supported by AIRC and CNR-mior
aCorresponding
author for proof and reprints:
Department
of
gynecologic
oncology
Istituto
Deraco Marcello, MD
Nazionale per lo Studio e la Cura dei Tumori, via
Department of surgery, Istituto Nazionale per lo
Venezian 1, 20133 Milano-Italy. Phone number: *
Studio e la Cura dei Tumori, via Venezian 1, 20133
39 2 2390 362; Fax number: * 39 2 2390 349.
Milano-Italy. Phone number: * 39 02 2390 2362;
Email: [email protected]
Fax number: * 39 02 2390 .2404;
E-mail: [email protected]
Web page: www.marcelloderaco.com
bCoauthor
address:
Raspagliesi Francesco, MD
Department
of
gynecologic
oncology
Istituto
Nazionale per lo Studio e la Cura dei Tumori, via
Venezian 1, 20133 Milano-Italy. Phone number: *
39 2 2390 362; Fax number: * 39 2 2390 349.
E-mail: [email protected]
cCoauthor
address:
Shigeki Kusamura
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1.
Introduction
Ovarian cancer is the sixth most common cancer of women world-wide and is responsible for the
greatest number of deaths from gynecological malignancy in Europe and North America [1]. About 165,000
women are diagnosed each year [2]. In spite of improvements in survival using platinum alone or platinum and
paclitaxel in combination, the long-term survival rates remain disappointing and median survival is of the order
of 36 months for advanced cases [3].
The conventional clinical approach for advanced (stage III/IV) ovarian cancer is based on debulking
surgery followed by systemic chemotherapy. Clinical studies have shown that cisplatin and/or taxol-based firstline chemotherapy achieves the highest response rates (around 70-80%), with a high proportion of complete
responses, in patients with epithelial ovarian cancers [3]. However, negative second-look laparotomy, which is
attainable in only 20-40% of cases, does not necessarily mean the patient is cured. Up to 47% of these
patients relapse within 5 years; disease-free survival does not generally exceed 18 months, and 5-year
survival ranges from 48 to 85% [4,5].
2.
Primary cytoreductive surgery: the limits of radicality and biological aggressiveness
Over the past 25 years it has become largely established, through retrospective analysis, that optimal
resection of metastatic epithelial ovarian cancer has a favorable impact on survival of patients with advanced
staged disease [6,7]. The most recent report supporting the importance of cytoreductive surgery in the
treatment of ovarian cancer was published by Bristow et al [8]. They evaluated retrospectively the relative
effect of percent maximal cytoreductive surgery and other prognostic variables on survival among 81 cohorts
of patients (total of 6,885) with stage III/IV ovarian carcinoma, treated with cisplatin based chemotherapy. A
statistical significant correlation between percent of maximal cytoreduction and log median survival time
emerged and this link remained significant after controlling for other variables (p<.001). The conclusion was
that maximal cytoreduction was one of the most powerful determinants of cohort survival among patients with
advanced ovarian cancer.
It is unclear whether the survival advantage after the procedure results from a inherent diminished
biological aggressiveness of the tumor which allows an optimal cytoreduction or it derives directly from
maximal surgical effort. Results of a retrospective analysis of 349 patients with postoperative residual masses
less than or equal to 1 centimeter suggested that patients who present with large-volume disease and achieve
small-volume disease by surgical debulking have poorer outcomes than similar patients who present with
small-volume disease [6].
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On the other hand, Le et al examining the role of cytoreductive surgery (CRS) in the management of
stage II and III epithelial ovarian cancer patients reported a 5 year survival rates for patients with initial
microscopic disease (group 1) and patients with large volume of disease at the time of exploration and tumor
reduced to microscopic residuals (group 2), of 62% and 56%, respectively (p-value not significant). In addition,
the groups were equivalents regarding known prognostic factors [9].
Critics of cytoreduction in ovarian cancer claim that tumor debulking can only benefit a small proportion
of patients, since the majority of them are rendered with sub optimal residual disease. In fact, the rate of
optimal cytoreduction has ranged from 25% to 40% [10]. Thus, ultra radical procedure has been proposed by
some surgeons as a method to increase the rate of optimal cytoreduction, in order to enhance the survival
benefit resultant from surgery. With technological advances such as the ultrasonic surgical aspirator and argon
beam coagulator, and methods such as peritoneal stripping, splenectomy, and en bloc resections of the
ovaries, and sigmoid colon, optimal cytoreduction rates have been reported as high as 91%
[11,12,13,14,15,16,17,18]. There is no consensus whether the level of intervention can be translated to
survival benefit, nor that it necessarily results in increased risk of morbidity. Potter et al retrospectively
analyzed 302 patients with epithelial ovarian malignancies submitted to extensive debulkings. It was shown
that patients who underwent extensive procedure including bowel resection and peritoneal stripping did not
fare as well as those who did not undergo these procedures and yet had residual disease remaining [18].
In contrast, Eisenkop et al evaluated 213 stage III ovarian cancer patients submitted to cytoreduction
using procedures such as extrapelvic bowel resection, diaphragm stripping, full-thickness diaphragm resection,
modified posterior pelvic exenteration, peritoneal implant ablation and/or aspiration, and excision of grossly
involved retroperitoneal lymph nodes [19]. They evaluated if the necessity to employ those procedures to attain
complete cytoreduction correlates with biologic aggressiveness of tumor and independently influences survival.
They verified that survival was independently influenced only by the extent of peritoneal carcinomatosis that
required removal and that other procedures as well as type of adjuvant chemotherapy did not impact the final
outcome. The authors concluded that the need to resect a widespread peritoneal carcinomatosis correlates
with biological aggressiveness and diminished survival, but not significantly enough to justify abbreviation of
the operative effort.
In summary, the controversies surrounding the advisable limits of surgical radicality, and relative
importance of maximal surgical effort and biological behavior of the tumor in the final outcome of patients are
supposed to persist unless more prospective randomized data can be accumulated. Nevertheless it could be
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stated that the standard of care of patient with stage III ovarian cancer should include an attempt at the optimal
cytoreduction of disease based on prospective data reported by van der Burg regarding interval debulking [43].
3.
First line chemotherapy
Following the surgical staging systemic chemotherapy with paclitaxel (Taxol) plus cisplatin or
carboplatin is commonly used for advanced cases [3,20]. Platinum based chemotherapy regimens have been
shown to produce higher response rates and, in some studies, have produced a statistically significant survival
advantage compared to drug regimens without platinum.
The Gynecologic Oncology Group (GOG) has carried out a randomized, phase III clinical trial
comparing paclitaxel and cisplatin (TP) with cyclophosphamide and cisplatin (CP) in sub-optimally debulked
(>1 cm residual mass) stage III/IV patients who had no prior chemotherapy [3]. There was a statistically
significant higher clinical response rate in the TP arm as compared to CP arm (73% vs 60%). Median survival
was also significantly better in the TP arm (24 months vs 38 months; P=0.001). Differences in surgically
documented complete response were not statistically significant (20% for CP and 26% for TP). Further, in a
European-Canadian trial carried out in patients with both optimally and sub-optimally debulked tumors the
relapse-free and overall survival advantages of TP over CP were confirmed [21] and were seen in both groups
of patients (i.e., those with large-bulk and low-bulk disease).
Another randomized trial that compared paclitaxel (135 mg/m2) combined with cisplatin (75 mg/m2)
with paclitaxel monotherapy (200 mg/m2) given over 24 hours or cisplatin monotherapy (100 mg/m2) found
equivalent survival for all 3 regimens. Paclitaxel monotherapy was inferior in response rate and progressionfree interval while cisplatin monotherapy was associated with significant neurotoxicity [22].
In the European-Canadian study, paclitaxel was administered over a more convenient 3 hours at a
dose of 175 mg/m2. Because the 3-hour regimen of paclitaxel is associated with substantial neurotoxicity when
given with cisplatin [21], carboplatin has frequently been substituted for cisplatin in this regimen. Clinical trials
assessing the efficacy of this substitution are in progress. Initial reports indicate no loss of efficacy [23], and in
a meta-analysis, carboplatin was found to be as effective as cisplatin alone and in combination. Thus, many
investigators consider the 3-hour regimen of paclitaxel plus carboplatin (AUC 5-7) to be an acceptable
alternative to the GOG regimen of paclitaxel and cisplatin as the preferred initial chemotherapy for patients
with stage III/IV ovarian cancer.
In an international phase III study, 1,077 chemotherapy-naive patients with stage Ic-IV ovarian cancer
were randomized to receive carboplatin (AUC=5) plus either docetaxel 75 mg/m 2 or paclitaxel 75 mg/m 2 for six
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cycles. Patients treated with paclitaxel plus carboplatin presented a higher neurotoxicity events as compared to
those treated with docetaxel plus carboplatin. Docetaxel/carboplatin and paclitaxel/carboplatin produced
similar response rates (66% and 62%, respectively), and a preliminary data show an equivalence in terms of
progression-free survival between two treatments. Thus, docetaxel may be considered an emerging valid
alternative to paclitaxel as part of first-line therapy in ovarian cancer [24].
4.
Second line therapies
In contrast to the primary setting, no standard treatment strategy for patients with relapsing or
persistent ovarian cancer after completion of upfront chemotherapy has been defined. When previous effective
drug combinations fail, there is virtually no chance of inducing a significant response with second-line
treatment. A partial response and control of malignant effusions can be achieved occasionally and are usually
associated with a short survival.
Several groups of investigators have studied alternative forms of second-line or salvage therapy, such
as new drugs or high-dose chemotherapy with autologous bone marrow support or intraperitoneal
chemotherapy. Available data (Table 1) shows a somewhat higher response rate to carboplatin+ifosfamide in
platinum-sensitive patients compared to platinum-resistant ones. According to different studies
[20,25,26,27,28,29,30,31,32,33,34,35,36,37], the response rate to salvage systemic chemotherapies in the
latter subgroup never exceeds 26.8%, and median survival ranges from 8.8 months to 15 months.
Following high-dose chemotherapy, a fairly high response rate has been observed that, however, did
not reflect in a higher median survival, at least in the one study performed on an adequate series of patients
[27]. Conversely, in platinum-resistant patients treated by intraperitoneal chemotherapy, a low response rate
was observed, whereas the median survival was about two-three times longer than that observed following any
other treatment.
5.
Secondary CRS
Besides the second line antiblastic therapies presented above, another treatment option for
chemoresistant or recurrent disease is the secondary CRS. Unfortunately, the benefits of this alternative have
not been clearly established by randomized data. To separate patients based on differences in biologic tumor
behavior, secondary operations for ovarian cancer can be offered in 5 clinical settings [38].
a)
Progressive disease: those patients with evidence of clinical disease progression while receiving first
line therapy;
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b)
After neoadjuvant chemotherapy: those patients with a bulky unresectable tumor or clinically not
suitable for a radical operation, undergo a primary chemical cytoreduction followed by a surgical
procedure, instead of being submitted to a major upfront surgical effort.
c)
Interval debulking: those patients with bulky, suboptimally cytoreduced tumor by initial surgery, are
submitted to 3 cycles of induction chemotherapy before the secondary cytoreduction;
d)
Second-look operation: those patients who are clinically and radiologically free of disease after primary
surgery and first-line chemotherapy, who are found to have macroscopic disease at second-look
operation (SLO);
e)
Recurrent disease: those patients who enjoy a clinical disease free interval after completing primary
therapy, and then develop recurrent disease;
There is limited data on secondary CRS in patients with progressive disease. Morris et al performed
secondary CRS prior to completion of first line chemotherapy on 31 patients with tumor progression and 2
patients with stable disease [39]. Optimal debulking (<2cm) was accomplished in 55%. Median survival for
<1cm residual disease patients was 12 months, compared with 7.8 months for patients with larger RD
(p<0.03). This apparent survival advantage disappeared after 2 years of follow-up. Operative morbidity
occurred in 24% of patients, with 22 of 31 patients requiring a small or large bowel resection. The authors
concluded that in patients with stable disease unresponsive to first line therapy, secondary CRS is associated
with unacceptable surgical morbidity considering the limited survival benefit. Another report described similar
outcomes for 77 patients submitted to surgery for progressive ovarian cancer prior to completing first-line
chemotherapy [40]. Not statistically significant difference in terms of median survival emerged between the 32
optimally resected (<2cm) patients and those left with larger residual tumor (12 moths each). Thus, there is
little evidence to support a role for secondary CRS in the setting of progressive disease resistant to primary
chemotherapy.
Despite advances in intraoperative and postoperative care, with development of specific surgical
procedures to maximize the optimal cytoreduction rate and indirectly pursue a survival advantage, a
substantial proportion of patients do not present enough clinical condition to undergo a radical surgery. A
neoadjuvant chemotherapy can be a reasonable alternative for this subset of patients, instead of offering them
an extensive surgery with a potential serious morbidity, which occasionally precludes or significantly delays the
initiation of postoperative chemotherapy. Moreover, neoadjuvant chemotherapy for primary unresectable cases
can lead to the selection of a subset of patients sensitive to chemotherapy in whom optimal cytoreduction can
be achieved in a high proportion of the cases. Probably the best candidates for neoadjuvant chemotherapy
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seem to be those with stage IV disease, total metastatic tumor load greater than 1000 g, uncountable plaque
shaped peritoneal metastases (i.e., >100), and/or poor performance status (World Health Organization
performance status of either 2 or 3) [41]. Whether this optional approach leads to an equivalent or favorable
impact on survival is still unclear since the accumulated level of evidence is scarce. The only prospective trial
addressing this issue is ongoing [42].
Regarding the secondary surgery performed in a interval setting, the EORTC conducted a prospective
trial and reported a 33% reduction in mortality in patients submitted to cytoreduction, even though they were
considered unresectable prior to chemotherapy. Patients were randomized after undergoing sub optimal
debulking surgery and 3 courses of chemotherapy, to interval debulking followed by further 3 courses of
chemotherapy versus 3 cycles of chemotherapy only. The results demonstrated a prolongation in both
progression free survival and the median survival in the interval-debulking arm (5 and 6 months respectively).
Multivariate analysis revealed interval debulking as independent prognostic factor [43].
Second look operation was originally defined as a systematic surgical reexploration of patients with
ovarian cancer who are clinically free of disease after completing a planned treatment program of primary CRS
and chemotherapy. Despite the clinical and radiological absence of disease, approximately 40% of patients
reaching SLO will have macroscopic disease detected at the time of surgery [44]. There are no clear cut data
showing that therapeutic decisions based upon results of this procedure alter (or does not) outcomes for the
patient. In a large non-randomized trial, there was no survival advantage in patients who received a SLO as
compared to those who did not [44] and the only randomized trial albeit statistically underpowered, was
negative [45]. Approximately 40% of patients with macroscopic disease are able to undergo complete
resection to be left with only microscopic RD, 30% are able to be partially debulked and left with minimal RD
(<2cm), and 30% are left with bulky RD. The majority of studies [38,46,47,48,49,50,51,52,53] demonstrate
some survival advantage for patients who can be debulked to microscopic or small macroscopic RD. When
second look operation is performed and residual tumor is detected, it seems advisable to remove all
macroscopic disease if technically feasible.
Concerning the secondary cytoreduction performed in recurrent disease all retrospective studies and
one prospective study report a statistically significant increase in disease-free survival of 1 or 2 years in
patients who are able to achieve optimal redebulking [54]. A prospective randomized clinical trial evaluating the
impact of secondary CRS in advanced ovarian cancer is ongoing [55]. The subset of better suited for repeat
cytoreduction are those with initial disease-free interval of more than 12 months, platinum sensitive tumors,
isolated resectable nodules (no more than 3), and no ascites [56].
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6.
Locoregional approach
6.1.
Intraperitoneal chemotherapy under normothermia
Because ovarian cancer is often asymptomatic in its early stages, more than 75% of patients have
advanced stage disease (FIGO stage III or IV) at diagnosis. Ovarian cancer usually spreads via local shedding
into the peritoneal cavity followed by implantation on the peritoneum, and via local invasion of bowel and
bladder. Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatics
drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. The disease
remains in the cavity for most of its natural history, and this biological behavior provides the opportunity for
increasing drug concentration selectively in the tumor area by direct intraperitoneal instillation in order to
overcome intrinsic or acquired drug resistance and simultaneously reduce systemic side-effects.
A large intergroup trial randomized 654 stage III ovarian cancer patients optimally cytoreduced (largest
nodule<2 cm) to intraperitoneal cisplatin plus intravenous cyclophosphamide or intravenous cisplatin plus
intravenous cyclophosphamide [57]. Intraperitoneal therapy was associated with a significantly improved
median survival (49 versus 41 months) and fewer toxic side effects. Although the favorable results of this trial
the procedure have not become part of clinical practice. First, the onset of the study was in 1986, before the
advent of paclitaxel. Second, somewhat counter intuitively, survival was not dependent on the extent of tumor
residual mass. Third, problems with catheters emerged due to postoperative adhesions rendering the
procedure not suitable for clinical practice. In a subsequent Gynecologic Oncology Group trial, 523 patients
were randomized to intravenous cisplatin/paclitaxel of high-dose carboplatin followed by intraperitoneal
cisplatin plus intravenous paclitaxel. The preliminary results demonstrated a significant increase in recurrencefree interval (28 versus 22 months), without the same favorable impact on overall survival.
However, the intraperitoneal chemotherapy carries some problems such as limited drug absorption
into the tumor tissue in normothermic conditions and incomplete drug distribution due to the abdominal
postoperative adhesion [58]. In order to circumvent these drawbacks some investigators have conceived a
combined approach of cytoreduction followed by intraperitoneal hyperthermic perfusion. This new treatment
strategy was initially employed in advanced gastrointestinal cancer, and a slight increase in morbidity in
patients treated by this aggressive loco regional approach has been reported [59,60] with respect to major
conventional surgical procedures. Recently, it has also been considered as second-line and salvage therapy in
Phase I/II clinical studies in the management of advanced ovarian cancer with some promising results
[61,62,63].
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6.2.
Cytoreduction
For the CRS the peritonectomy technique is performed. Firstly described by Sugarbaker [64], the
procedure encompasses a maximum of 6 different visceral and/or parietal peritoneum resections, depending
on the intracavitary disease extension and on previous surgery and it constitutes a useful resource for the
achievement of minimal residual disease. After the cytoreduction the patient is submitted to the second phase
of procedure, i.e. intraperitoneal hyperthermic perfusion (IPHP).
6.2.1.
Preparation
In the operating room, the patient is put in a supine position with gluteal folds advanced to the break on
the operating table to allow full access to the perineum during the surgical procedure. This position is essential
to avoid intraoperative skin or muscle necrosis. The weight of the legs must be directed to bottom of the feet by
positioning the footrests so that minimal weight is borne by the calf muscle. Myonecrosis within the posterior
compartment of the leg may occur unless the legs are protected properly. A 3-way bladder catheter and a
large-bore silastic nasogastric tube are positioned.
Abdominal skin preparation is from mid chest to mid thigh as well as the external genitalia, including
vagina. The abdomen is opened from xyphoid to pubis. Generous abdominal exposure is achieved through the
use of a Thompson Self-Retaining Retractor. A 2 mm ball-tip electrosurgical handpiece, on pure cut at high
voltage, is used to dissect the tumor on peritoneal surfaces from normal tissue. The ball-tip electrode is used
for dissecting on visceral surfaces, including stomach, small bowel, and colon.
6.2.2. Surgical Steps
Each procedure that composes the peritonectomy technique must be performed in an orderly
sequence of surgical maneuvers to create an optimum cytoreduction. One or more of following steps can be
performed and the detailed description of the technique can be found elsewhere [64,65]:
1) greater omentectomy, right parietal peritonectomy  right colon resection;
2) pelvic peritonectomy  retosigmoid colon resection  total hystererectomy bilateral salpingooophorectomy with an immediate low rectal anastomosis with a circular stapler;
3) lesser omentectomy and dissection of the duodenal-hepatic ligament  antrectomy 
colecystectomy;
4) right upper quadrant peritonectomy with Glissonian’s capsule;
5) left upper quadrant peritonectomy  splenectomy;
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6) other intestinal resection and adominopelvic mass resection.
6.3.
Intraperitoneal hyperthermic perfusion (IPHP)
6.3.1.
The rationale
The performance of regional drug delivery under supra-normal temperature is known as IPHP and it
has become an area of growing interest supported by experimental observations. The biophysical effects of
hyperthermia are incompletely understood, but probably include: membrane protein denaturation, increased
vascular permeability, alterations of multimolecular complexes such as the insulin receptor, cytoskeleton,
changes in enzyme complexes for DNA synthesis and repair. Moreover, the architecture of the vasculature in
solid tumors is chaotic, resulting in regions with low pH, hypoxia and low glucose level. This susceptible
microenvironment renders solid tumors more sensible to hyperthermia [66,67].
Cisplatin has been shown to penetrate much deeper in the tumor tissue under hyperthermic conditions
[68]. Moreover, at 40-42C, neoplastic cells become more chemosensitive due to an increase in the
intracellular concentration of drugs and in their activation process, especially for alkylating agents, and to
alterations in the DNA repair process [69,70]. In addition, it has been shown that these events have a greater
intensity in cisplatin-resistant rather than cisplatin-sensitive ovarian cancer cell lines. Formation of platinumDNA adducts after cisplatin exposure is enhanced and/or adduct removal is increased in heated cells, resulting
in a relatively higher DNA damage [71]. Finally, IPHP favors the drug diffusion into the peritoneal cavity and
the elimination of microscopic cancer residues by circuit filters [72].
6.3.2.
The device, priming, and drug schedules
The IPHP requires the employment of heart-lung machine, comprised by a roller pump, a thermostat, a
heat exchanger and an extra corporeal circuit. The perfusate flow is controlled as well as the heat exchanger
adjusts the temperature of perfusate, by circulating perfusate at a desired temperature in the inflow phase of
circuit. The extra corporeal circuit consists of interconnected tubes which has: a) an input section (inflow); b)
an output section (outflow); c) an axis of rapid filling up; d) a central body connected with a filter; e) a deflow
section; f) a series of multiperforated catheters in their extremities.
The priming, defined as the liquid filling the circuit could be of various type: i) peritoneal dialysis
solution, ii) physiologic solution, or iii) a composition of Normosol solution R pH 7.4 associated with Haemagel
(in the proportion 2:1). The priming volume ought to be abundant enough to achieve homogeneity and
constancy of heating, but not excessive, in order to avoid abdominal distension and bodily thermo-dilution. For
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an optimal working of circuit 3-4 l of perfusate for opened technique and 6 l for closed technique is usually
sufficient.
Various drug combinations for ovarian cancer have been tested by experimental and phase I/II clinical
studies: cisplatin alone [61,73], carboplatin alone [74], mitoxantrone alone [75], cisplatin+doxorubicin [62]. The
criteria for choosing the ideal combination should be based on the pharmacokinetic profile of drugs, tumor
chemo sensibility and toxicity. Ideally the drug must be water-soluble and of high molecular weight in order to
guarantee a low peritoneal clearance. This, combined with a high systemic clearance, will result in
pharmacological advantage expressed by a higher exposure of tumor to the agent (high AUCpe/AUCpl ratio).
For intraperitoneal therapy to be effective against intraperitoneal tumors, the drug must also diffuse inward
from the periphery of the tumor mass. The penetration ability of drug in the tumor is a function of passive
diffusion, removal from by the capillary blood flow and temperature modulation. Penetration by passive
diffusion is related to the AUCpe/AUCpl ratio, although this may not hold true for all drugs. Finally, the
influence of temperature in the cytotoxicity should also be of concern, so that higher the cell killing capacity of
the drug due to the hyperthermia the better.
Cisplatin has become the most widely used agent in the systemic treatment of ovarian cancer with the
response rate of 50%. Combination chemotherapy with cisplatin and other cytotoxic drugs, most commonly
doxorubicin and cyclophosphamide with or without hexamethymelanine, became standard systemic treatment,
before the advent of paclitaxel, with response rate of 70-80%. Cisplatin systemic combinations were found to
be more effective than alkylating agents as a single agent of combinations, when measured by clinical
response rates and progression free intervals [76].
When cisplatin was employed in a loco regional setting, in the treatment of epithelial ovarian cancer, a
comparable distinctive antiblastic effect was shown. Cisplatin has a high AUCpe/AUCpl ratio, as compared to
other cytostatic drugs, a deep tumor penetration ability (table 2) [68,77,78,79,80] and partial response rate of
up to 65% in normothermic condition [81] (table 3).
Another eligible agent for IPHP is carboplatin. Despite a better therapeutic index than cisplatin, with
substantially less renal toxicity, less nausea and less neurotoxicity, carboplatin has not a favorable
pharmacokinetic profile as cisplatin (table 2) [68,74,82]. In fact, the AUCpe/AUCpl ratio, tumor penetration
capacity and response rate are markedly lower [83,84,85].
Doxorubicin has one of the highest AUCpe/AUCpl ratio of about 80 (table 2) [86,87]. Irrespective of
limited tumor diffusion ability, not more than several cell layers, a response rate of 30% was reported when
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doxorubicin was administered intraperitoneally, under normothermic condition [88]. The dose limiting toxicity,
chemical induced peritonitis, makes doxorubicin feasible for loco regional employment only at very low dose.
Oxaliplatin, gemcitabine, and paclitaxel are also promising for IPHP [58,75,89,90,91]. However, since
they are still under experimental and/or phase I clinical investigations, they should be further investigated
before been evaluated in a prospective phase III trial.
In summary, the best chemotherapy combination for IPHP for patients with ovarian cancer is still to be
defined. However, experimental and phase I/II clinical studies suggests the combination of cisplatin (43.0 mg/l
of perfusate) and adriamycin (Dx) (15.25 mg/l of perfusate) the most advisable regimen for epithelial ovarian
cancer [92]. A complete response rate of up to 59% has been reported with the employment of this
combination in IPHP for advanced and recurrent epithelial ovarian cancer in a phase II clinical trial [62].
6.3.3.
Modalities of execution: open and closed abdominal techniques
After secondary CRS, 4 Tenckhoff catheters are placed in the abdominal cavity. Two inflow catheters
are placed in the right subphrenic cavity and at deep pelvic level, respectively; and two further catheters in the
left subphrenic cavity and in the superficial pelvic site.
In the closed technique the skin of abdominal wall is temporary closed with a running suture and the
Tenckhoff catheters connected to the circuit, in order to initiate the IPHP [93]. In the open modality, also known
as Coliseum technique [59], the abdomen is covered with a plastic sheet and drug vapor is evacuated to
protect the operating room personnel.
The catheters are connected to the extra-corporeal circuit and the preheated polysaline perfusate
containing cisplatin and adriamycin is instilled in the peritoneal cavity using the heart-lung pump at a mean flow
of 600 - 1000 ml/min for 60 minutes. In order to achieve intrabdominal temperature of 42.5C, the inflow
temperature is kept at approximately 44C. Throughout the perfusion, if the opened technique is adopted, the
surgeon should continuously manipulate the viscera to distribute both heat and chemotherapy. Following
perfusion, the perfusate is quickly drained and the abdomen closed after careful intraperitoneal inspection.
One of major issue for debate has been the modality of IPHP execution. Investigators have not
achieved a consensus about opened or closed abdomen techniques. Proponents of Coliseum technique [59]
claim better drug and heat distribution by continuous manipulation of the abdominal organs. Deficiencies were
noted in the distribution of methylene blue dye with the closed technique, which, in its turn, was blamed for
higher rate of complications [94].
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On the other hand, the closed technique permits an increase in the intrabdominal pressure that might
lead to increased convection driven drug penetration of macromolecular agents such as TNF  inside the
tumor [95,96]. Moreover, a series of 94 patients with abdominal sarcomatosis, pseudomyxoma peritonei,
peritoneal mesothelioma from four Italian oncological institutes (Milan, Rome, Padua, Turin) treated by CRS
and intraperitoneal hyperthermic perfusion had recently been analyzed. One of the endpoint of the
investigation was rates of morbidity/mortality related to the procedure. Seventy-three patients were submitted
to the closed procedure and it was verified that there was no statistically significant link between the modality
of IPHP (closed versus open) with morbidity grades III/IV (p=0.6) [Deraco M. personal communication]. Since
up to date no prospective controlled clinical trial has been conducted addressing specifically the superiority of
one technique over the other, the issue remains unclear. The accumulated data suggests that there is no
striking difference between both in terms of operative morbidity.
6.3.4.
Precautions and monitoring of cardiovascular, temperature and laboratory parameters
The main intraoperatory potential complication is the generalized hyperthermia that can be avoided
submitting the patient to hypothermia. This can be obtained by the application of cooling packages in the
flexing faces of joints and in the head. The bladder is instilled with cooling physiologic solution during
hyperthermia to avoid mucosal damage. The optimal temperature expected for the patient before the
beginning of IPHP is 32-330C; and this can be achieved passively just maintaining the abdomen opened during
the surgery, without any heating. During IPHP, continuous peritoneal temperature monitoring is performed by 6
thermocouples placed in the abdominal cavity, peritoneal site and rhino pharynx for core temperature. The
cardiovascular parameters such as central venous pressure mean arterial pressure should also be
continuously monitored. In the same way, the hemoglobin level, coagulation system parameters and arterial
partial oxygen and carbonic gases pressures as well as arterial pH are determined every 30 minutes.
6.4.
Secondary cytoreduction and intraperitoneal hyperthermic perfusion for ovarian cancer
Investigators from Netherlands Cancer Institute have published a study [74] where 5 heavily pre-
treated patients with extensive abdominal ovarian bulky tumor were submitted to aggressive cytoreduction
followed by perfusion of the abdominal cavity with hyperthermic cisplatin 50-70 mg/m2 for 90 min. During
perfusion the intra-abdominal temperature was maintained at 400 C. No major intra- or post-operative
complications emerged. Median post-operative ileus (resuming of soft diet) was 11 days (9-13 days). Toxicity
due to intraperitoneal cisplatin was mainly metabolic and of grade 1-2, while no nephrotoxicity was observed.
They concluded that aggressive cytoreduction combined with hyperthermic intra-operative intraperitoneal
cisplatin was feasible in a small group of heavily pre-treated ovarian cancer patients with extensive tumor bulk
13
14
with acceptable morbidity and toxicity. They stated that further studies should be carried out in larger groups of
patients to further establish the feasibility of this intensified treatment strategy. The effectiveness of this
combined treatment is likely to be dependent on the effectiveness of post-operative adjuvant chemotherapeutic
regimens.
Hager et al. in 2001 [97] conducted a prospective clinical trial evaluating the feasibility, efficacy and
impact of IPHP chemotherapy on survival and quality of life of patients with advanced, peritoneal disseminated
ovarian cancer. Thirty-six patients with ovarian cancer were accrued for the study, their selection being based
on their progression following different systemic chemotherapies. The intraperitoneal temperature was 42-430
C. Median overall survival time from the first IPHP chemotherapy treatment 19 +/- 4 months. The observed 1year overall survival rate of all patients from the start of the first IPHP was 65 +/- 8% and the 5-year overall
survival was 16 +/- 7%. Malignant ascites vanished within less than 3-5 procedures. The adverse effects were
mild especially compared to systemic chemotherapy. In 3 out of 162 treatments, peritoneal disturbances with
symptoms of subileus were observed. The authors concluded that IPHP is technically feasible, safe, and may
improve the treatment outcome of patients with advanced ovarian cancer as salvage therapy, in second-line
treatment or even as consolidation or maintenance therapy following induction chemotherapy.
At the National Cancer Institute of Milan the currently discussed treatment was evaluated in 27
patients with advanced recurrent ovarian carcinoma [62]. Median times to overall progression and local
progression were 21.8 months and 16 months, respectively. Variables that affected the overall survival or time
to progression were as follows: residual disease (p=.00025), patient age (p=.04), and lag time between
diagnosis and CRS+IPHP (p=.04). Treatment-related morbidity, mortality and toxicity were 11%, 4% and 27%,
respectively. Eight (89%) of 9 patients had ascites resolution.
It is hard to ascertain in which extent the apparent survival advantage reported by these uncontrolled
clinical studies resulted from selection bias. Moreover, the investigations involved heterogeneous patient
population, at different stages of disease evolution, usually heavily pre-treated, and therefore, with different
tumor chemo resistances.
Anyway, the SITILO (Italian society of integrated locoregional therapy) will carry out a prospective
multicentric randomized trial to test the effectiveness of secondary cytoreductive surgery associated with
intraperitoneal hyperthermic perfusion in patients with cisplatin resistant advanced epithelial ovarian cancer.
Patients with epithelial ovarian cancer stage III/IV, submitted to surgical staging and 6 courses of first line
platinum based chemotherapy, and with persistent but clinically resectable disease, or early relapsing tumors
(< 6months after the completion of first line chemotherapy) will be randomly allocated to one of treatment
14
15
groups: 1) Study group: secondary cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP)
followed by second line chemotherapy; 2) Control group: second line chemotherapy (Figure )1. The primary
endpoint is overall and progression free survivals. Some secondary endpoints will be the analysis of morbidity,
mortality and toxicity related to the procedure. The expected absolute improvement in survival is 20% (40%
expected survival at 5 year in the study group vs 20% in the control group). Sample size for each group is 100
patients. Calculations were performed assuming 0.05 significance level (one-tailed test), a 90% power, 3 years
for patients accrual followed by 2 additional years period of follow-up [98].
7.
Summary
Primary surgery followed by systemic platinum based chemotherapy is the cornerstone in the
management of ovarian cancer patients. However the majority of them has an advanced disease (stage III/IV)
at the time of diagnosis rendering the optimal primary cytoreduction feasible in only small percentage of the
cases. This a hampering factor for the success of subsequent antiblastic therapy. There are 2 alternatives to
overcome this unfavorable situation: 1) employment of ultraradical interventions such as peritonectomy
procedures, in order to increase the optimal cytoreduction rate, or; 2) neoadjuvant chemotherapy. Whether
such strategies would have an influence on the final outcome of patients is an issue to be defined in further
prospective randomized studies.
For a second line therapies no definite treatment has already been defined. When previous effective
drug combinations fail, there is virtually no chance of inducing a significant response with second-line
treatment. The combination of secondary cytoreductive surgery and intraperitoneal hyperthermic perfusion
constitutes an feasible and potential option for this subset of patients based on phase II studies. A randomized
trial will be conducted to test the effectiveness of such procedure in patients cisplatin resistant disease
(macroscopic residual or relapse within 6 months after the completion of first line chemotherapy).
15
16
Tables
Table 1: Effect of salvage therapies as a function of first-line platinum response
Median survival
No. of
Therapy
Reference
Response rate (%)
(months)
Patients
Resistant
Sensitive
Paclitaxel
Trimble et al. [20]
1000
22
-
8.8
Carboplatin+
ifosfamide
Lorusso et al.[26]
35
0
56
-
Ifosfamide
Sutton et al. [30]
41
Markman et al. [31]
41
12
Hexamethylmelamine
Vergote et al.[29]
61
14
-
9*
Tamoxifen
Hatch et al. [32]
105
5-FU + leucovorin
Look et al. [25]
49
6.6
17.2
-
Etoposide
Rose et al. [33]
41
26.8
20
18
10.8
41
34.1
Lipossomal
Doxorubicin
Muggia et al. [34]
35
Gemcitabine
Friedlander et al.
[35]
38
Lund et al. [36]
42
19
Huinink et al.[28]
112
13.3
28.8
15
Bookman et al. [37]
139
12.4
19.2
11
Stiff et al. [27]
100
81
94
13
Topotecan
High-dose
Chemotherapy
25.7
16.5
11
13.9
6.7
6.2
*Median survival for responders to Hexamethylmelamine
16
17
Table 2: Pharmacokinetic profile of some chemotherapies when delivered intraperitoneally associated with
hyperthermia
Drug
AUCpe/AUC Molecular
pl
weight
Doxorubicin
87.9
Mitoxantrone
5.6 - 15.2
Cisplatin
Carboplatin
14
1.9 - 5.2
544
300
Tumor
penetration
Mechanism of hyperthermic
modulation
4-6 cell layers
Enhanced tissue absorption;
increased Dx aglycon
concentration
5-6 cell layers
yes
References
86,87,88
75,58
2-2.5 mm
Enhanced tissue absorption;
increased DNA adduct formation;
increased activity at low pH;
Increased production of O2
radicals; reduction of cisplatin
resistance
68,77,78,79,80
0.2-0.5 mm
Enhanced tissue absorption;
increased DNA adduct formation;
74,68,82
Dx: Doxorubicin; AUC, area under the concentration-time curve in peritoneal cavity (AUCpe) and plasma (AUCpl).
The AUC is calculated integrating the concentration curve over time and reflects the total amount of drug present in
peritoneal cavity of plasma.
17
18
Table 3: Response rate of intraperitoneal chemotherapy in ovarian cancer according to the drug
Drug
Dose (mg/m2)
Number of
patients
Response (%)
CR
PR
Reference
Doxorubicin
10 - 50
10
0
30
87
Mitoxantrone
14*
8
0
50
75
90 - 270
18
0
55
99
60 - 150
27
33
50
23
120 - 180
4
25
200 - 650
27
15
200 - 500
22
18
36
82
150 - 350
22
14
9
84
60**
76
24
Cisplatin
Carboplatin
Paclitaxel
100
65
81
50
101
83
102
* under hyperthermic condition; **weekly for 16 weeks
18
19
Figure 1: Stage III / IV epithelial ovarian cancer with macroscopic residual disease after 1 st line chemotherapy:
a multicentric prospective randomized study comparing loco regional approach + systemic chemotherapy vs
systemic chemotherapy alone. Protocol outline
Stage III/IV epithelial ovarian cancer
Primary surgical staging +
First line chemotherpay
Reavaluation
(4 weeks after the end of treatment)
Ca125 +
Clinically +
APCT +
Ca125 +
Clinically –
APCT –
Ca125 –
Clinically+
APCT –
Ca125 –
Clinically –
APCT +
Ca125 –
Clinically –
APCT –
Other studies
Random 1,2
Secondary cytoreduction +
IPHP +
second line therapy
1
second line therapy
Patients deemed non-optimally cytoreducible by radiological criteria will be excluded to the random;
2
Patients with early relapse after completion of primary systemic therapy (<6 months)
APCT: adominopelvic CT scan; IPHP: intraperitoneal hyperthermic perfusion
19
20
8.
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