| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Surgical Metabolism Section, Surgery Branch, Division of Clinical Sciences, National Cancer Institute [H. R. A., S. K. L., D. L. B., M. P., D. L. F.], and Department of Anesthesia [L. C. B.], Warren G. Magnuson Clinical Center, NIH, Bethesda, Maryland 20892
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
IHP2 is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused using an extracorporeal recirculating circuit comprised of a roller pump, reservoir, heat exchanger, and oxygenator (9) . When IHP is administered using a standard surgical technique, complete and sustained vascular isolation of the liver can be achieved, allowing delivery of regional hyperthermia and high doses of chemotherapeutics or biological agents (10) . In initial clinical studies conducted at a limited number of centers 15–20 years ago, IHP was associated with substantial toxicity and morbidity without clearly documented efficacy, and therefore, it has not had widespread or consistent clinical evaluation (9) . However, over the past 5 years, we (11) and others (12, 13, 14) have conducted clinical trials evaluating IHP using melphalan with or without TNF and demonstrated response rates as high as 74% with acceptably low morbidity. Because of the remarkable antitumor efficacy of TNF when applied in isolated limb perfusion for advanced refractory in-transit melanoma (15, 16, 17) and because melphalan is actively taken up by melanocytes (18) , these agents may be ideally suited for regional perfusion in patients with ocular melanoma metastatic to the liver. We report our results using IHP with melphalan alone or with TNF, with specific reference to results obtained in patients with metastatic ocular melanoma to the liver.
|
PATIENTS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1.5 mg/dl. Patients who had minor,
1–2-s abnormalities on either prothrombin time or partial
thromboplastin time but who otherwise appeared to have adequate
hepatic reserve based upon complete evaluation of radiographic and
laboratory tests were considered eligible. Patients were excluded who
had biopsy-proven cirrhosis or evidence of significant portal
hypertension by history, endoscopy, or radiological studies. Patients
with very limited resectable extrahepatic disease who had clearly
progressive advanced hepatic metastases were considered eligible for
the study. The dose of recombinant human TNF was 1.0 mg (Knoll
Pharmaceuticals, Whippany, NJ) and melphalan was 1.5–2.5 mg/kg
(Burroughs-Glaxo/Wellcome, Research Triangle Park, NC). Three of six
patients treated with doses >1.5 mg/kg melphalan on Phase I protocols
experienced dose-limiting toxicity, and the maximum tolerated dose of
melphalan with or without TNF was defined as 1.5 mg/kg. All patients
were followed until disease progression with physical exam, laboratory
tests, computed tomographic scan of the chest abdomen and pelvis, and
MRI of the liver every 3 months for the first year after IHP, every 4
months during the second year, and every 6 months thereafter. One
patient who received 2.5 mg/kg melphalan died 7 days post-IHP and was
not included in analysis of response but was included in analysis of
survival.
IHP.
The treatment technique of IHP was performed as described previously
(9)
. In brief, via a laparotomy the liver is extensively
mobilized. The right lobe is retracted anteriorly and medially, and the
IVC from the level of the renal veins to the diaphragm is completely
dissected from the retroperitoneum. The portahepatis structures are
completely dissected and skeletonized, and a cholecystectomy is
performed. A 2-cm segment of GDA is dissected and serves as the
arterial cannulation site during IHP. The portal vein and common bile
duct are mobilized from the head of the pancreas to the inferior border
of the liver. All lymph node-bearing tissues around the portahepatis
structures are resected. A saphenous vein and left axillary cutdown are
performed.
The patient is systemically heparinized with 200 units/kg, and cannulae are inserted into the saphenous and axillary veins and connected to a veno-veno bypass circuit. The IVC is occluded above the renal veins, and infrahepatic IVC blood flow is shunted to the axillary vein using a centrifugal pump. A short segment of infrahepatic IVC is isolated between vascular occluding clamps, and a cannula is inserted into the retrohepatic IVC beneath the hepatic veins. This cannula is connected to the venous outflow line of the extracorporeal bypass circuit. The portal vein blood flow is shunted by inserting a cannula distally and incorporating it into the veno-veno bypass circuit. The common hepatic artery is occluded, and a 3–4-mm GDA cannula is positioned at the orifice of the common hepatic artery. In five patients, infusion via the portal vein and GDA was performed. Finally, the suprahepatic IVC is cross-clamped just below the diaphragm, and isolated hepatic perfusion is initiated.
The extracorporeal bypass circuit consists of a roller pump, membrane oxygenator, and heat exchanger. The perfusate consists of 700 ml of balanced salt solution primed with 300 ml of packed RBCs and 2000 units of heparin. Hepatic parenchymal temperature probes are placed at various positions, and perfusate temperature is controlled using a Hemotherm cooler heated model #4 (Cincinnati SubZero Products, Cincinnati, Ohio). Usually, stable perfusion parameters are achieved almost immediately, and there is rapid and uniform heating of the liver to target temperatures of 39.5–40°C. Melphalan at a dose of 1.5–2.5 mg/kg (Burroughs-Glaxo/Wellcome, Research Triangle Park, NC) and 1.0 mg TNF (Knoll Pharmaceuticals) are added sequentially to the perfusion circuit at time 0, and the perfusion is continued for 60 min. At the conclusion of the perfusion, the liver is flushed through the arterial inflow cannula with 1500 ml of crystalloid, followed by 1500 ml of colloid, and the proximal portal vein is flushed with 1 liter of normal saline. After decannulation and repair of the venotomies, normal physiological blood flow is reestablished promptly to the liver.
Continuous Intraoperative Leak Monitoring.
A modification of the 131I human serum albumin
leak monitoring system used during isolated limb perfusion with TNF and
melphalan (10
, 19)
is used in all patients. In brief, once
stable perfusion parameters are established, a gamma detection camera
is positioned over the centrifugal pump housing, which serves as a
stable reservoir of systemic blood for the purposes of determining cpm.
A dose of 20 or 40 µCi of radiolabeled 131I
human serum albumin (Merck-Frosst, Quebec, Canada) is
administered via a central vein, and a baseline level of cpm is
determined on a strip chart recorder. After a stable baseline cpm is
obtained, a 10-fold higher dose of 131I human
serum albumin is injected into the perfusion circuit. If any increase
in cpm is detected on the strip chart recorder, this would indicate a
leak from the perfusion circuit into the systemic circulation. Because
the dose of radioisotope in the perfusion circuit is 10-fold greater
than that administered systemically, a doubling in the cpm over
baseline would represent a 10% leak of perfusate, and leak rates as
small as 1% can be reliably measured using this system.
Toxicity.
Systemic and regional toxicity was graded according to the National
Cancer Institute Common Toxicity Criteria, version
2.0.3
Because IHP is being administered in the context of a major operative
procedure, systemic toxicities were graded as those that were not
reversed within 24 h postoperatively. Regional (hepatic)
toxicities were graded as elevations in hepatic transaminases or
bilirubin that did not correct within 7 days of the procedure.
Response.
All patients had measurable disease, and 19 were assessable for
response. One patient suffered perioperative mortality, and two others
treated on a Phase I protocol experienced dose-limiting toxicity and
did not undergo follow-up imaging for assessment of response. Because
the IHP is a regional treatment, response and duration of response were
scored for lesions in the liver, and recurrences were noted as
intrahepatic or extrahepatic. A CR was defined as complete
disappearance of all established tumor on standard imaging studies
without evidence of new lesions for 30 days. A PR was defined as >50%
reduction in the sum of the product of the perpendicular diameters of
all measurable lesions in the liver for no less than 30 days without
progression of any single lesion or development of new sites of hepatic
disease.
Statistics.
All data are presented as mean + SE or SD, as indicated. Kaplan-Meier
liver progression-free and overall survival plots were generated using
Sigma Plot (SPSS, Inc., Chicago, IL) and analyzed using the
Mantel-Haenszel test. All Ps are two-tailed.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. There were 9 men and 13 women, with a mean age of 49 years, and 36%
had undergone previous treatment. The number of metastatic lesions in
the liver was assessed intraoperatively and was invariably far greater
than the number observed on preoperative imaging studies. Because the
maximum number of lesions counted in any individual patient was 50
(those with more were scored as 50), and there were a large number of
patients who had >50 lesions, the calculated median for all groups was
25. The size of the largest lesion and the percentage of hepatic
replacement were assessed radiographically. The mean size of the
largest lesion was >7 cm, and the mean percentage of hepatic
replacement was 25. Taken together, these parameters highlight the
advanced tumor burden in the majority of patients at the time of
treatment.
|
. The mean operative time of just over 8 h and the mean estimated
blood loss of almost 2 liters reflect the major nature of the procedure
and the time necessary to prepare the liver for IHP. IHP was terminated
after 10 min in 1 patient because of the development of hemodynamic
instability, presumably attributable to a very advanced stage of
hepatic disease (
75% hepatic replacement). The patient expired
72 h later because of multiple organ failure. The remaining 21
patients completed the planned 60-min IHP; there were no differences in
treatment or perfusion characteristics between those who did or did not
receive TNF. All patients had complete vascular isolation with no leak
of perfusate, as measured by the continuous intraoperative
131I radiolabeled albumin technique, which is
sensitive in detecting a leak rate of <1% (10
, 20)
. The
mean line pressure of 157 mm Hg reflects the pressure in the perfusion
circuit, which is generated by a mean flow of 854 ml/min through a
small (3-mm) arterial cannula. The pressure within the proper hepatic
artery itself when assessed by direct palpation was always estimated to
be lower and <100 mm Hg. Five patients treated with melphalan alone
had inflow cannulae in the GDA and portal vein. The higher flow rates
and lower line pressures generally observed in the five patients who
had inflow into both vessels were not great enough to be reflected in
differences in the means or ranges between the TNF and no-TNF groups.
Veno-veno bypass flow rates of almost 2 l/min during IHP may have
contributed to the stable mean arterial pressure. The larger
number of units of fresh frozen plasma used in patients treated
with TNF reflects our practice of routinely giving 4 units after
reversal of heparinization because of the known coagulopathic effects
of TNF after IHP in a previous Phase I trial (21)
. Fresh
frozen plasma was given to patients after IHP with melphalan
alone, based upon clinical need. The median length of hospitalization
was 12 days (range, 7–46).
|
. Seven of 10 patients (70%) had a radiographic response with
melphalan alone compared with 6 of 11 (54%) with TNF. The median
duration of response in 13 patients who had a PR or CR was
significantly longer in those treated with TNF and melphalan
(n = 6) compared with melphalan alone
(n = 7; 14 versus 6 months,
P = 0.04; Fig. 1
), and the only CRs were observed in those patients who received TNF
(Fig. 2)
. One patient treated with melphalan alone has an ongoing response in
liver at 13 months. Remarkably, two patients treated with TNF and
melphalan had very durable responses, one ongoing at 33 months and
another that lasted 50 months (Fig. 3
and 4)
. The median overall survival in all 22 patients is 11 months and not
different between groups (P = 0.17; Fig. 5
).
|
|
|
|
|
|
shows toxicity secondary to IHP. Four patients (18%) experienced
significant transient hypotension (grade III or greater; National
Cancer Institute Common Toxicity Criteria, version 2.0). Over 80% of
patients experienced elevations in hepatic transaminases, and
two-thirds had hyperbilirubinemia. Six patients were treated in a Phase
I setting at 2.0 mg/kg (n = 5) or 2.5 mg/kg
(n = 1) of melphalan, a dose level greater than the
currently established maximum safe tolerated dose level of 1.5 mg/kg.
Three had dose-limiting toxicity including transient renal failure
(n = 1), partial portal vein thrombosis (n =
1), and coagulopathy followed by multisystem organ failure and death
(n = 1). The remaining patients had transient hepatic
toxicity with bilirubin and hepatic transaminase levels returning
toward baseline by 7–10 days after IHP (11)
. One patient
treated with TNF experienced a brief grade IV tachyarrythmia
immediately after the operation but had no evidence of myocardial
injury on subsequent evaluation.
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
It is noteworthy that overall median survival in this series was 11 months, which is comparable with the survival observed after regional therapy with chemoembolization or intra-arterial fotemustine (6 , 7) . Systemic tumor progression was a site of initial failure in half of those who had an initial response to IHP in this study. Two patients who survived longer than 3 years after IHP with stable responses in the liver did develop systemic metastases that were initially controlled with surgical resection and radiation. These data indicate that if an efficacious regimen was available, additional adjuvant therapy after regional treatment of apparently isolated hepatic metastases from ocular melanoma would be justified. We have investigated previously the possibility that IHP may result in significant embolization of tumor cells as a potential cause of subsequent systemic tumor progression. Using PCR with primers for tyrosinase or carcinoembryonic antigen with a sensitivity of detecting 1–10 cells/ml of blood, we were unable to detect any circulating tumor cells systemically or in perfusate samples in patients with ocular melanoma or colorectal cancer during or immediately after IHP (24) .
Despite considerable interest and extensive clinical evaluation, the role of TNF in isolation organ perfusion has not been demonstrated conclusively. When administered in isolation perfusion, TNF without melphalan does not appear to have any significant antitumor activity against any histology at any site (25, 26, 27, 28) . In our own experience, there was only a 20% response rate in 17 patients treated with 0.2 mg of IFN and escalating-dose TNF administered via IHP (21) . Of note, all of the responses were short lived and were observed only in the first few patients treated with the lowest doses of TNF. In a small Phase III random assignment trial of ILP for in-transit melanoma response rates were similar between those receiving melphalan alone versus TNF, IFN, and melphalan (29) .
The data in this report suggest that melphalan alone has comparable initial antitumor activity to TNF and melphalan, but TNF may prolong the duration of response, although the number of patients overall in this study is small. Furthermore, melphalan is actively taken up by cells of melanocyte origin (18) , and the additional benefit, if any, of using TNF in this histology may be limited. Although the complete and overall response rates were similar in the random assignment trial of ILP using melphalan alone versus melphalan, TNF, and IFN, in an unplanned subset analysis of those with bulky or extensive disease, TNF had a higher CR rate than melphalan alone (29) . A subsequent multicenter trial is now being conducted.
The present series represents results of consecutively treated patients on two Phase I protocols evaluating escalating-dose melphalan with or without TNF and a Phase II protocol using the maximum safe doses of these agents. Three patients suffered dose-limiting toxicity in a Phase I setting. Five of the patients who received melphalan alone had infusion through both the portal vein and hepatic artery. This practice has been abandoned at our institution because there was no clear advantage compared with hepatic artery infusion alone. Of the 11 patients treated with melphalan alone, 4 had the double inflow technique. Except for that one factor, the treatment parameters were otherwise identical.
The systemic toxicities associated with the addition of TNF appear minimal because of the fact that complete vascular isolation is routinely achieved. Systemic toxicity after ILP from TNF appears related to degree of perfusate leak into the systemic circulation during isolation perfusion (30) . Although there was no measurable leak in our series of patients, three patients had transient hypotension that responded to fluid support and may have been related to release of secondary inflammatory cytokines from liver (11) . One patient had a transient cardiac tachyarrythmia that appeared idiosyncratic and not clearly related to the use of TNF per se. On the basis of the doses of 1.0 mg of TNF and 1.5 mg/kg of melphalan determined from Phase I studies, the regional toxicity with or without TNF is acceptable; almost 80% of patients have transient elevations in liver transaminases.4 Although 90% of those receiving TNF had grade III or greater hyperbilirubinemia compared with 45% with melphalan alone, these effects were transient, and no permanent hepatic toxicity was observed.
In summary, IHP using melphalan can result in significant regression of liver metastases secondary to ocular melanoma in the majority of patients with acceptable morbidity. In light of limited treatment options, continued clinical evaluation of this strategy is warranted, perhaps combining IHP with additional intraarterial chemotherapy. Because our data indicate that most patients with ocular melanoma metastatic to liver present with extensive disease that is immediately life-threatening and the duration of response is significantly prolonged with TNF, its continued clinical evaluation is justified.
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be
addressed, at Surgical Metabolism Section, Surgery Branch/Division
of Clinical Sciences/National Cancer Institute, Building 10,
Room 2B07, 10 Center Drive, NIH, Bethesda, MD 20892. Phone:
(301) 496-5049; Fax: (301) 402-1788. 
2 The abbreviations used are: IHP, isolated
hepatic perfusion; TNF, tumor necrosis factor; MRI, magnetic resonance
imaging; IVC, inferior vena cava; GDA, gastroduodenal artery; CR,
complete response; PR, partial response; ILP, isolated limb
perfusion.
3 Internet address:
http://www.ctep.info.nih.gov.
4 H. R. Alexander, unpublished data.
Received 11/ 9/99; revised 4/23/00; accepted 4/24/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and melphalan: Swedish experience. Recent Results Cancer Res., 147: 120-126, 1998.[Medline]
and melphalan: experimental studies in pigs and Phase I data from humans. Recent Results Cancer Res., 147: 107-119, 1998.[Medline]
: results of a TNF dose escalation study. J. Clin. Oncol., 14: 479-489, 1996. in combination with interferon- and melphalan in isolation perfusion. World J. Surg., 16: 234-240, 1992.[CrossRef][Medline]
(IFN): an initial report. Soc. Surg. Oncol., 49: 6 1996.
and melphalan. J. Clin. Oncol., 13: 264-273, 1995.This article has been cited by other articles:
|
|
 |
|
  T. Sato, D. J. Eschelman, C. F. Gonsalves, M. Terai, I. Chervoneva, P. A. McCue, J. A. Shields, C. L. Shields, A. Yamamoto, D. Berd, et al. Immunoembolization of Malignant Liver Tumors, Including Uveal Melanoma, Using Granulocyte-Macrophage Colony-Stimulating Factor J. Clin. Oncol., November 20, 2008; 26(33): 5436 - 5442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. J. van Iersel, E. J. Hoekman, H. Gelderblom, A. L. Vahrmeijer, E. L. van Persijn van Meerten, F. G. J. Tijl, H. H. Hartgrink, P. J. K. Kuppen, J. W. R. Nortier, R. A. E. M. Tollenaar, et al. Isolated Hepatic Perfusion with 200 mg Melphalan for Advanced Noncolorectal Liver Metastases Ann. Surg. Oncol., July 1, 2008; 15(7): 1891 - 1898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mocellin, P. Pilati, P. Da Pian, M. Forlin, S. Corazzina, C. R. Rossi, F. Innocente, C. Ori, D. Casara, F. Ujka, et al. Correlation Between Melphalan Pharmacokinetics and Hepatic Toxicity Following Hyperthermic Isolated Liver Perfusion for Unresectable Metastatic Disease Ann. Surg. Oncol., February 1, 2007; 14(2): 802 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rietschel, K. S. Panageas, C. Hanlon, A. Patel, D. H. Abramson, and P. B. Chapman Variates of Survival in Metastatic Uveal Melanoma J. Clin. Oncol., November 1, 2005; 23(31): 8076 - 8080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Pingpank, S. K. Libutti, R. Chang, B. J. Wood, Z. Neeman, A. W. Kam, W. D. Figg, S. Zhai, T. Beresneva, G. D. Seidel, et al. Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies J. Clin. Oncol., May 20, 2005; 23(15): 3465 - 3474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Diener-West, S. M. Reynolds, D. J. Agugliaro, R. Caldwell, K. Cumming, J. D. Earle, D. L. Green, B. S. Hawkins, J. Hayman, I. Jaiyesimi, et al. Screening for Metastasis From Choroidal Melanoma: The Collaborative Ocular Melanoma Study Group Report 23 J. Clin. Oncol., June 15, 2004; 22(12): 2438 - 2444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. van Etten, F. Brunstein, M. G. A. van IJken, A. W. K. S. Marinelli, C. Verhoef, J. R. M. van der Sijp, G. Guetens, G. de Boeck, E. A. de Bruijn, J. H. W. de Wilt, et al. Isolated Hypoxic Hepatic Perfusion With Orthograde or Retrograde Flow in Patients With Irresectable Liver Metastases Using Percutaneous Balloon Catheter Techniques: A Phase I and II Study Ann. Surg. Oncol., June 1, 2004; 11(6): 598 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Feldman, J. F. Pingpank, and H. R. Alexander Jr. Regional Treatment Options for Patients With Ocular Melanoma Metastatic to the Liver Ann. Surg. Oncol., March 1, 2004; 11(3): 290 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Duh, A. P. Schachat, D. M. Albert, and S. M. Patel Long-term Survival in a Patient With Uveal Melanoma and Liver Metastasis Arch Ophthalmol, February 1, 2004; 122(2): 285 - 287. [Full Text] [PDF]
|
|
|
|
 |
|
 H. R. Alexander Jr., S. K. Libutti, J. F. Pingpank, S. M. Steinberg, D. L. Bartlett, C. Helsabeck, and T. Beresneva Hyperthermic Isolated Hepatic Perfusion Using Melphalan for Patients with Ocular Melanoma Metastatic to Liver Clin. Cancer Res., December 15, 2003; 9(17): 6343 - 6349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Witcher, D. T. Ross, C. Rousseau, L. Deluca, and W. H. Miller Jr Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells Blood, July 1, 2003; 102(1): 237 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rothbarth, R. A. Woutersen, R. W. Sparidans, C. J. H. van de Velde, and G. J. Mulder Melphalan Antitumor Efficacy and Hepatotoxicity: The Effect of Variable Infusion Duration in the Hepatic Artery J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1098 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Savier, D. Azoulay, E. Huguet, F. Lokiec, M. Gil-Delgado, and H. Bismuth Percutaneous Isolated Hepatic Perfusion for Chemotherapy: A Phase 1 Study Arch Surg, March 1, 2003; 138(3): 325 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A Vertrees, A. Leeth, M. Girouard, J. D Roach, and J. B Zwischenberger Whole-body hyperthermia: a review of theory, design and application Perfusion, July 1, 2002; 17(4): 279 - 290. [Abstract] [PDF]
|
|
|
|
|
|
S. K. Libutti, H. R. Alexander Jr, P. Choyke, D. L. Bartlett, S. L. Bacharach, M. Whatley, F. Jousse, W. C. Eckelman, K. Kranda, R. D. Neumann, et al. A Prospective Study of 2-[18F] Fluoro-2-Deoxy-D-Glucose/Positron Emission Tomography Scan, 99mTc-Labeled Arcitumomab (CEA-Scan), and Blind Second-Look Laparotomy for Detecting Colon Cancer Recurrence in Patients With Increasing Carcinoembryonic Antigen Levels Ann. Surg. Oncol., December 1, 2001; 8(10): 779 - 786. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
