Research Article
Isolated Chemotherapeutic Perfusion as Neoadjuvant Therapy for Advanced/Unresectable Pelvic Malignancy
Harold J Wanebo1*, Giovanni Begossi2, James Belliveau1 and Eric Gustafson1
1Department of Surgical Oncology, Boston University, USA
2Alta Bates Summit Medical Center, Canada
*Corresponding author: Harold J Wanebo, Department of Surgical Oncology, Boston University, 206 Cass Avenue, Woonsocket, Rhode Island 029895
Published: 30 Dec, 2016
Cite this article as: Wanebo HJ, Begossi G,
Belliveau J, Gustafson E. Isolated
Chemotherapeutic Perfusion as
Neoadjuvant Therapy for Advanced/
Unresectable Pelvic Malignancy. Clin
Surg. 2016; 1: 1282.
Abstract
Introduction: Previous chemo radiation (CRT) usually precludes neoadjuvant therapy for
advanced pelvic malignancy. Neoadjuvant isolated pelvic perfusion (IPP) provides higher tissue
drug levels with less toxicity than systemic therapy and may enhance resectability of advanced pelvic
malignancy. We have performed 113 IPP in 75 such patients (pts) 59 for pre operative therapy and
16 palliative.
Methods: There were 50 pts with advanced, irradiated recurrent rectal cancer (34 pre-op and 16
palliative), 8 pts had advanced anal squamous cancer (SCC), 6 pts with pelvic sarcoma; 4 pts with
pelvic/perineal melanoma (MEL), and 7 other advanced cancers (endometrial (2), ovarian cancer
(3), and bladder cancer (BC) 2 pts. Hyperthermic IPP for (60 minutes) utilized regimens targeted to
malignancy type. High dose IPP with stem cell support was utilized in 3 advanced chemo resistant
pts.
Results: Neoadjuvant IPP in 26 recurrent rectal cancer pts rendered 15 potentially resectable
achieving a complete path CR in 2 patients and facilitating curative pelvic resection in 7 pts. The
remaining 8 pts were non-resected because of disease/medical status (5 pts) or patient refusal (3 pts).
Median overall survival (OS) post IPP was 24 mos in 15 resectable pts, 30 mos in the 7 resected pts (2
survived >5 yrs) and 8 mos in 11 non-resectable pts. It was 23 and 8 mos (resected vs. non resected)
months in 8 advanced SCC anal pts and 28 and 24 mo in advanced gyn cancer pts (endometrial/
ovarian), 13 mos in 4 advanced melanoma pts and was only 5 mos in 6 sarcoma pts (only 1
resectable). High dose IPP with stem cell support induced significant regression (with resection)
in 2 of 3 pts with advanced chemo resistant (Endometrial/Melanoma) malignancy. Overall of 59
neoadjuvant pts, 34 (58%) responded to IPP, 21 (36%) were resected, and the remaining 25 pts
(42%) were considered reasonably palliated.
Conclusion: IPP has promise in augmenting resectability (or palliating) selected patients with
advanced pelvic malignancy not amenable to p or previously treated with conventional chemo RT.
IPP responsive tumors included recurrent rectal and anorectal cancers, and localized gyn cancers
and melanoma, whereas sarcomas were quite resistant. Biologic therapy or stem cell supports are
viable future options to enhance outcome of IPP.
Keywords: Pelvic malignancy as neoadjuvant therapy; Pelvic Perfusion; Neoadjuvant; Perfusion; Chemoperfusion
Synopsis
Isolated pelvic perfusion was performed as planned neoadjuvant therapy in 59 pts with advanced pelvic malignancy of which 38% responded and 36% were resected and the remaining reasonably palliated (74%).
Introduction
Preoperative chemo radiation therapy for advanced pelvic malignancy is often precluded
by previous radiation exposure or chemo resistant progression. Isolated pelvic perfusion (IPP)
provides high tissue drug exposure without the toxicity of high-dose systemic therapy and may
benefit patients with advanced malignancy. We have performed 113 IPP in 75 patients (16 for
palliation, and 59 with pre op intent) using a simplified groin accessed balloon occlusion technique.
Creech and Associates introduced isolated regional perfusion in 1958 [1] to treat advanced
extremity melanoma, based on pioneering efforts by Klopp with
regional intra arterial therapy with nitrogen mustard in 1950 [2],
and experimental perfusion studies by Ryan [3]. Initial studies
demonstrated regional therapy achieved local drug levels of 6-10
times higher than achieved by systemic therapy with minimal tissue
edema/local toxicity. The Tulane group initially focused on perfusion
therapy for advanced extremity melanoma but subsequently treated a
variety of cancers of limbs, head and neck, pelvis and liver combining
perfusion with surgical resection [4,5].
Austen et al. [6] pioneered treatment of malignant pelvic tumors
by extra corporeal perfusion and obtained a clinical response in 4 of
7 pts with advanced cancers [6]. They accessed the vascular circuit
intra abdominally effort and obtained pelvic isolation utilizing an
abdominal tourniquet with groin inserted catheters in 7 pts [6].
Watkins obtained pelvic isolation by placing groin accessed balloon
catheters placed 2-3 cm above the aortic bifurcation for isolated
perfusion with pump oxygenator [7]. Lawrence conducted pelvic
perfusion in 34 pts (5 open), via intra vascular balloon technique with
use of an inflatable abdominal tourniquet [8]. Dedrick 1984 (NIH)
utilized chemo filtration with charcoal column to detoxify the circuit
as demonstrated in successful studies of isolated perfusion of the head
in Rhesus Monkeys [9]. Pharmacokinetics and clinical monitoring of
regional therapy was addressed by Collins who described a regional
therapeutic index as ratio of drug concentration in the tumor (Area
under Curve in the Tumor (AUCT) versus the Systemic drug
concentration (AUCS) [10]. The therapeutic advantage (Rd) is
expressed as Rd=AUCT/AUCS. Rd depended on the potential for
metabolizing the drug (i.e. liver) and the fractions of drug removed
during single pass through target tissue. The pharmacology of
regional cancer therapy by isolated perfusion vs. regional infusion is
detailed in many review articles from this group [11-18].
Patient data
A total of 113 IPP was performed in 75 patients including 59
neoadjuvant and 16 palliative, irradiated and resected rectal cancer
pts prior to plan pelvic resection. Eight additional patients had IPP
therapy for recurrence after previous extended resection (4 ABSR, 4
APR) with a major focus on symptomatic tumor relief and palliation,
but with consideration of resection in selected responding pts. Not
included in the neoadjuvant effort was a previous group of 16 pts
who had palliative IPP for recurrence post conventional APR/AR.
Additional patients included 8 pts with advanced anal canal squamous
cancer, 6 pts with pelvic sarcoma, 4 pts with advanced melanoma of
proximal lower extremity and perineum and 5 advanced gynecologic
cancers (2 endometrial and 3 ovarian pelvic recurrences), and 2
advanced bladder cancer pts. A total of 113 Isolated pelvic perfusions
for 60 minutes utilized 5FU Paclitaxel 30-40 mg/m2, 5FU (1,500-
2,000 mg/m2), cisplatinum (100 mg/m2) or Oxaliplatin 150 mg/m2)
and mitomycin (10-20 mg/m2) for epithelial cancers and selected
agents (Adriamycin, Ifosamide, DTIC, Phenyl Alanine Mustard for
the other cancers) (Table 1).
Surgical technique
IPP was carried out under fluoroscopic control using the occlusion
and infusion catheters placed into inferior vena cava and aorta via
the femoral vein and artery as accessed through the groin [13,14,18].
Proximal large-cuff orthopedic thigh tourniquets were placed at the
groin level to limit the perfusion to the pelvis. On-table arteriograms
and venous dye injections facilitated placement of balloon occlusion
catheters above the bifurcation of aorta and IVC and below renal
artery (technique described in detail (3+5). Patients are heparinized
(initially with 5000 units of heparin) and have an additional heparin
(25,000 units) given during the 60 minute perfusion.
Technical/clinical considerations
Subjects for IPP require careful pre operative assessment by
CT or MRI and more recently by PET scan in addition to relevant
tumor biomarkers. Cardiovascular assessment included clinical
and radiologic assessment of aorto iliac and venous flow circuit. Pts
receiving thrombotic prophylaxis would be converted to IV heparin
infusion (stopped 4-6 hours prior to perfusion).
On table procedure
A fluoroscopic compatible operating table permits continuous
monitoring of aorto iliac circuit and venous circuit via frequent (5
minute reviews of balloon occlusion catheter. There is potential for
balloon leak or rupture (rare event) from aortic wall plaques which
may require replacement of the balloon catheter during procedure.
The anesthesiologist provides proximal venous access by venous
and arterial catheters for CVP and arterial pressure monitoring.
Vascular access for perfusion was obtained via balloon occlusion
catheters and perfusion in the aorta above the biforcation (below
renal artery) the location being confirmed fluoroscopically with dye
injection. The perfusion canula are inserted in the same way and
attached to perfusion circuit. The aorta and IVC are balloon occluded
and bilateral thigh tourniquets are inflated to 50 mm above mean
arterial pressure, and the perfusion circuit is completed and initiated
via cannula connectors to the extracorporeal bypass pump. On table
monitoring of balloon occlusion catheter is done by fluoroscopic
imaging over mid-lower abdomen (every 5 minutes during IPP).
In general the anesthesiologist maintains the mean arterial pressure
10-20 mm above the perfusion pressure to minimize “bleeding of
drug” into the systemic circuit. The perfusion utilizes a pump set to
deliver hyper oxygenated perfusate (blood plus chemotherapy at 39-
41°) at 750-1000cc per minute. Drugs are given at time intervals (1/3
dose) every 5 minutes in a programmed manner, terminating with a
planned wash out of saline or blood in pelvic circuit (500-700cc) at 60
minutes with equivalent systemic replacement.
At completion of perfusion the balloon occlusion catheters are
released first in the venous circuit and then the aortic circuit with close
monitoring of blood pressure with subsequent arterial and venous
suture repair. Distal pulses are measured to ensure no thrombo
occlusion. Pt is observed in an overnight, I.C.U. and transferred to
med-surg unit for longer term observation in hospital or as outpatient
daily hematologic monitoring to ensure stable WBC and to detect
signs of neutropenia (greater risk at post op days 9-12). Neupogen
is started on first post op day at 480 mcg/day (dose 5-7 mcg/kg) to
maximize the WBC. Patients are initially given subcutaneous heparin
5000 ug 8 hr and then started on Coumadin once WBC is stable to
continue for 30 days post operatively.
Table 1A
Table 1B
Table 1B
Pharmacokinetics-neoadjuvant perfusion.
Table 2
Results
The various drug combinations for IPP of different tumors are
listed in Table 1. Table 1B outlines selected pharmacokinetic results
regarding commonly used drugs for epithelial cancers, anorectal
adenocarcinoma or squamous carcinoma (5FU, Cisplatin, Oxaliplatin,
Mitomycin C). The linearity of drug dose with mean pelvic exposures
is shown in. The mean AUC pelvic to systemic drug level ratios for
ano rectal cancers are demonstrated in Table 1B. The levels include
5FU 8.4:1, Cisplatin 6.0:1, Oxaliplatin 7.3:1, and Mitomycin C 9.0.
The relation of drug dose to mean pelvic exposure is illustrated in.
Of 50 advanced/recurrent rectal cancer pts, 26 received
neoadjuvant therapy prior to planned resection for pelvic recurrence
by ABSR, 8 pts received neoadjuvant therapy prior to planned
resection of advanced rectal cancer by ABSR/APR, and 16 pts were
treated for advanced pelvic cancer (non resectable) by palliative IPP.
Neoadjuvant IPP in 26 rectal cancer pts induced an objective
response in 15 pts by clinical/imaging assessment and was considered
resectable. Two patients had a pathologic complete response (one
had an open sacral re biopsy (negative) and planned resection was
cancelled. The other pt had a path CR demonstrated at extended
APR resection. Seven of 15 pts considered resectable were resected
(6 required ABSR, and 1 an extended APR). Among the remaining
8 pts (2 were medically inoperable, 2 developed distant metastases, 3
resectable pts refused surgery and the patient with a negative sacral
rebiopsy was cancelled). Of 11 non resectable pts, 9 had palliative
therapy and 2 were treated with implanted infusion pump. The
survival data for the potentially resectable and the palliative groups.
Outcome data of 8 previously treated pts who were in the previous
extended resection group by ABSR (4 pts) APR (4 pts) (median
survival was 7 mos (4-20 mos). Eight pts had IPP for recurrent
squamous cancer. Six pts responded, and were resected (ABSR 2 pt,
Extended APR 4 pts, whereas 3 were not resectable.
Among the other patient groups, there were 6 sarcoma pts of
whom 3 of whom responded to IPP but only 1 was resected (required
extended hemi pelvectomy (Table 2). The other pts were compromised
by development of distant disease (3 pts) or were medically unfit for
extended resection (Table 2). All 4 melanoma pts responded, and 4
had limited resection with major focus on limiting disease spread
rather than attempting total tumor control, with median survival of
13 months. The Gyn cancer pts included 2 with endometrial cancer,
1 of whom had a near complete response post IPP with stem cell
support for an extensive recurrence within pelvis and abdomen and
had resection of all residual cancer surviving 48 months NED and
finally dying from non cancer related drug use) a second patient
had a near CR but survived only 7 months. The 3 ovarian cancer pts
with bulky pelvic disease responded to IPP, but refused follow-up
retrieval surgery. Of 2 recurrent bladder cancer pts, one responded
to neoadjuvant IPP and survived 14 mo post cystectomy. The other
patient had para iliac nodal mets and survived only 3 mo. Among the
total group of 59 pts an overall response (PR- 50% regression) was
observed in 32 pts (54%) of whom 29 were considered resectable and
21 (36%) were resected. The survival of each group is noted in Table
2. Palliative therapy only was delivered in 37 pts (63%).
IPP with stem cell support
Three pts underwent high dose IPP with stem cell support (patient
details in Table 2). This included a 65 yo female with advanced
endometrial cancer whose disease had progressed following surgery
and chemo therapy and was able to have a re resection following
tumor regression by IPP with stem cell support and survived NED
for 48 months before succumbing to renal failure secondary to non
cancer related drug use. A second patient with extensive penile
melanoma and had refused amputation underwent IPP with stem cell
support and had a 90% regression of extensive disease, was able to
have degloving resection of the penile melanoma and proceeded to
planned marriage although he succumbed to metastatic melanoma 6
months later. A third 63 yo male with advanced peri anal squamous
cancer who had failed the Nigro protocol and two subsequent
resections with development of new pelvic and nodal disease. He
underwent high dose chemo therapy via pelvic perfusion with stem
cell support and had nodal and pelvic regression of target lesions with
documented reduction in mitotic rate and K.67-nuclear count. The pt
unfortunately developed subsequent recurrence, disease progression
and succumbed at 90 days post IPP.
There was limited surgical toxicity (one required femoral artery
reconstruction) the other problems centered on edema or minor
groin hematoma. The most significant toxicity was hematologic with
grade III anemia (12%), thrombocytopenia 9% and neutropenia (18%)
requiring hospital support in pts with neutropenia until counts were
restored. Three mortalities in the overall group of 75 pts included an
in-house acute renal failure in a 73 year old female post IPP. Two
deaths occurred from neutropenia at day 8 and 9, in patients who had
left the institutional area and developed unrecognized neutropenic
sepsis which was diagnosed late before initiation of treatment in
their home community. These events prompted a future policy of
demanding that pts stay in the institutional area until restoration of
adequate leukocyte and neutrophil counts.
Discussion
Isolated Pelvic Perfusion (IPP) was performed as planned
neoadjuvant therapy in 59 patients with advanced pelvic malignancy.
The majority of pts were local failures of surgery for primary rectal
cancer having had resection by conventional LAR or APR (26 pts)
in addition to chemo radiation pre or post primary resection. An
additional 8 pts had secondary recurrence or persistence of disease
post previous extended resection by abdominal sacral resection (4
pts) or extended APR in 4 pts. These pts were selected on basis of
potential for re operative surgery in event of an adequate response
or who had good potential for prolonged “pain free” palliation from
IPP. Among the neoadjuvant category of 26 evaluable pts 15 (54%)
were responders on basis of clinical/radiologic exam and considered
candidates for resection. Of the 15 responders 8 were resected by
ABSR in 7 pts and extended APR in 1 pt. One pt had a path CR of
a previously biopsied sacral recurrence at re-exploratory laparotomy
after two IPP and the planned ABSR was cancelled. Another path CR
occurred in a pt in the resected groups who had a re resection APR
with lymphnode resection. Three pts were candidates for ABSR but
refused surgery and 2 became medically inoperable and, 2 pts had
an excellent pelvic response but developed distant metastases. The
overall survival was 32 mo in the resected group (2 of 8 pts were 5 year
survivors), vs. 23 mo in the non resected responders, and 8 mos in the
non responders. Among the previously resected pts for recurrence
(ABSR 4 pts, APR (extended) in 4 pts), a PR response was registered
in each sub group and one pt had a localized resection of a repeat
recurrence in the symphysis. None of the other pts in this group were
amenable to resection but most had excellent reduction in symptoms
(and survival 4-20 mos post IPP). Among the 8 pts with recurrent
anorectal squamous cancer following initial chemo radiation the
Nigro protocol, 6 considered resectable had RO resection with long
term disease free survival of 119 mos in 1 pt and mean OS in 5 pts all
of whom ultimately recurred. Two additional pts were amenable to
palliateive IPP only.
Isolated Pelvic Perfusion showed moderate value in the 4
melanoma pts with perineal-pelvic melanoma recurrence (requiring
IPP rather than isolated extremity perfusion). There was minimal
benefit in the sarcoma group. There appeared to be retrieval value
in a small number of gynecologic pts (60-80% tumor regression),
including advanced disease in 2 endometrial cancer pts. Three ovarian
cancer pts with bulky pelvic recurrence were considered potential
candidates for resection (but all refused further surgery). Their
survival of 11 mo, 28 and 33 months post IPP suggested potential
for re-operative resection in selected ovarian cancer pts with bulky
disease who are IPP responders.
Of interest combination of high dose IPP chemo (Phenylalanine
mustard and paclitaxel) with stem cell support was very beneficial in 2
of 3 pts studied. One patient with advanced and metastatic endometrial
cancer had a very high level of response with total abdominal isolated
perfusion (above and below renal artery) with stem cell support and
had RO resection of remnant abdominal disease surviving NED
over 48 mo. A young pt with advanced penile melanoma (refused
amputation) underwent IPP with stem cell support which induced
>90% regression of the melanoma and was able to have conservative
degloving surgery, (although ultimately succumbed to metastatic
melanoma at 6 months). A third pt with extensive/recurrent perianal
squamous cancer (failed multiple resections/chemotherapy)
had an initial excellent response to IPP with stem cell support but
subsequently had recurrence with death at 90 days post IPP.
Overall of 59 pts in this multi disease group with pelvic malignancy
32 responders (54%) of whom 29 (49%) pts became resectable and
resection was possible in 19 (32%) pts with OS survival post IPP (and
resection) of 30 mos median (average) (2 of 8 were 5 year survivors).
Among 40 pts whose IPP was considered palliative (68% of total
group) the mean OS was 11.7 months.
Isolated perfusion has been utilized in a variety of sites but the
greatest experience is in the limb perfusion data for melanoma
and sarcoma (reviewed by Kroon and Hoekstra) [19,20]. Because
of achievability of good isolation of the extremity perfusion circuit
there is potential to safely add other agents to mephalan such as
tumor necrosis factor (TNF) to enhance anti tumor effects with alpha
modification. The regional perfusion technique has been simplified
by use of the isolated limb infusion which is a simpler, less invasive
technique may be an equivalent method of delivering high dose
extremity chemotherapy with minimal drug leak and side effects
[21,22]. The technique is repeatable and may provide a workable
palliative approach for advanced extremity tumors.
A modification of IPP with extra corporeal chemo filtration
(IPPEC) may also have potential for future adoption [23]. This
approach utilizes percutaneous pelvic perfusion with extra
corpeal chemo filtration for advanced uterine cervical carcinoma.
Percutaneous catheters are placed in the uterine arteries bilaterally
for infusion and a specialized balloon catheter permits balloon
occlusion of the IVC with intra catheter communication for
channeling blood for dialysis and return to the circulation filtrated
blood to the systemic circulation. Activated carbon in the filtration
unit was used to remove the infused cisplatin. The pre filter vs. post
filter free platinum levels in this showed reduction from the prefilter
range72-122 ug/ml to post filter (peripheral) blood levels of 2.1-3.6
ug/ml and peripheral blood 1.0-3.8 ug/ml. Treatment of pts with
stage III to IV (FIGO) uterine carcinoma was demonstrated with an
excellent tumor response by MRI including CR (complete response)
in 13%, PR (partial response) in 74% and MR (minimal response)
or NR (no response) of 13%. Follow-up surgical resection was done
in 18 of 19 pts (78%), with negative margin (RO resection) in 16 of
18 pts (89%). The 5 yr survival was 74% in 18 pts treated by IPPEC
vs. 58% in 5 pts treated with Radiation alone and 43% in patients
treated by conventional therapy [27]. Azuma et al. [24] utilized a
similar approach for bladder cancer. In a randomized trial which
compared balloon occluded arterial infusion of cisplatin, with hemo
dialysis. Combined with concurrent radiation for advanced bladder
cancer pts followed by cystectomy compared to cystectomy alone.
The experimental regimen was resulted in a measurable response in
69/77 (86%) of pts with locally invasive bladder cancer. The 5 yr OS
was 91% in this group vs. 59.8% with cystectomy alone p< 0.0001.
There were no Gr 3/4 severe toxicities. In contrast in the cystectomy
group 50% had suffered disease progression and death from tumor at
5 years post cystectomy.
These modifications in regional therapy of pelvic cancer may have
value in selected pts with high risk primary pelvic cancers. Whether
this approach would be effective in pts with recurrent pelvic cancers
in this report i.e. recurrent rectal adenocarcinoma or anorectal
squamous cancers, or melanoma, sarcoma is less obvious because of
the extensive pelvic anatomy involved by tumor. A major problem
with pelvic IPP is the significant systemic leak (~30%). Perhaps
selective chemo filtration of out flow perfusion in conjunction with
maintenance of low mean arterial perfusion pressure, might produce
higher tissue-tumor drug concentrations with potential for increased
(anti tumor response and reduced systemic toxicity). The use of stem
cell support to enhance outcome with high dose chemo infusion may
also merit further exploration.
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