37. The Systemic Oncologic Implications of Surgery

37. The Systemic Oncologic Implications of Surgery

Sang W. Lee, M.D.

The use of minimally invasive methods for the curative resection of malig- nancies has been and remains a highly controversial indication. Legitimate con- cerns regarding the extent and adequacy of resection, port wound tumor recurrences, and the lack of long-term outcome data were raised by many sur- geons early after the introduction of advanced laparoscopic methods. However, a decade after the introduction of laparoscopic-assisted colectomy, the first two of these issues, for the most part, have been addressed, at least in regard to colon cancer. It has been demonstrated through both prospective and retrospective studies that an equivalent oncologic colorectal resection can be performed laparoscopically [1, 2]. Reasonably sized prospective series have demonstrated that, in experienced hands, the incidence of port wound tumors is comparable to the rate of incisional recurrences after open tumor resection [3, 4]. Most importantly and to the surprise of most surgeons, the interim results of a single center randomized trial of colorectal cancer patients, summarized at the end of this chapter, suggest that there might be a long-term oncologic benefit associ- ated with the use of minimally invasive methods. Despite these encouraging clin- ical findings, some critics still believe that there may be something inherently dangerous about minimal access surgery in the setting of malignancy, especially when carried out under a CO

pneumoperitoneum.

It is interesting to note that at the same time reports regarding port site tumors were raising fears regarding the safety of laparoscopic cancer operations, the results of a number of animal studies suggested that minimally invasive surgery may be associated with distinct systemic oncologic benefits when com- pared to open methods. This chapter briefly reviews the existing data regarding the systemic oncologic impact of both open and closed surgical approaches.

A. Animal Data

It had been well established in small animal models, before the introduction of advanced minimally invasive methods, that laparotomy was associated with accelerated tumor growth and an increased rate of metastatic tumor formation in the early postoperative period when compared to anesthesia control animals [5, 6]. In an effort to determine the impact of laparoscopic methods on tumor behav- ior, a number of investigators carried out a series of experiments in mice and rats.

Allendorf et al. demonstrated, in a murine study, that preexisting subcuta-

neous adenocarcinomas, distant from the abdominal incision, grew significantly

larger following laparotomy than after peritoneal insufflation with carbon dioxide gas [7]. In the same study it was shown that, when intradermal tumor cell inoculation was carried on the day of surgery, tumors were more easily estab- lished and grew larger after laparotomy than after CO

insufflation. Subsequent investigations by the same group demonstrated similar results for two additional tumor cell lines [8]. DaCosta et al., in a similar experiment comparing sham pro- cedures, noted that the open group tumors were significantly larger than the tumors of the CO

insufflation or the anesthesia control groups [9]. Of note, although smaller than the open group tumors, the insufflation group tumors were found to be significantly larger than those of the control group. Allendorf et al., in a later study, demonstrated that the differences in tumor establishment and growth between the open and laparoscopic groups persisted in the setting of a bowel resection [10]. Similar to the DaCosta et al. study, there was a stepwise increase in the mass of the tumors from the control group to the CO

insuffla- tion and, finally, the laparotomy group.

Lee et al. determined the proliferation and apoptotic rates of murine dorsal tumors, established on the day of surgery, via high-dose subcutaneous injection of tumor cells, 14 days after sham laparotomy or CO

insufflation [11]. Tumors from the laparotomy group mice had significantly greater proliferation rates than those of the insufflation group, which in turn were significantly greater than the results of the control groups tumors. Conversely, the laparotomy group tumors demonstrated significantly lower rates of apoptosis than the tumors from the CO

group, which in turn were significantly lower than the control group tumor apop- totic rates.

A murine study that compared tumor growth after laparotomy, CO

insuf- flation, and anesthesia alone in nude (athymic) and immunocompetent mice sought to determine the impact of cell-mediated immune function on postoper- ative tumor growth. It had been shown previously that full sham laparotomy is associated with a period of cell-mediated immunosuppression. In the immuno- competent mice, after laparotomy, subcutaneous tumors were shown to grow sig- nificantly larger than in mice that underwent CO

insufflation, similar to the results mentioned previously. In the athymic mice, however, following surgery there was no significant difference in tumor size between the laparotomy and the CO

insufflation groups. This result suggested that the differences in tumor growth that were noted between open and laparoscopic groups in the immuno- competent mice were due, at least in part, to differences in postoperative immune function. Although there was no difference in tumor size between the open and the laparoscopic athymic mice groups, tumors of both groups were significantly larger than those of the anesthesia control group. This finding suggested that after surgery, in addition to immune function considerations, other tumor growth-altering factors are at work [12].

Lee et al. examined the possibility that a surgery-related plasma factor may

exist that influences tumor growth [13]. It was determined that cancer cells incu-

bated in vitro with plasma from mice that had undergone sham laparotomy

proliferated significantly faster than cells incubated with plasma from the insuf-

flation group. In the same study, Lee et al. determined that the factor respon-

sible for this increase in tumor growth was heat labile and nondialyzable. These

results suggested that a plasma-soluble factor was responsible, in part, for the

increase in tumor growth after laparotomy. In a subsequent study, the same group

of investigators attempted to isolate and characterize the factor(s) responsible for increased systemic tumor growth following laparotomy [14]. The results sug- gested that the plasma level of a heparin-binding growth factor consistent with platelet-derived growth factor (PDGF) is significantly higher after laparotomy and that this increase in PDGF may account for the noted increase in in vitro tumor growth. A human study was next carried out to determine if major abdom- inal surgery was associated with oncologically relevant plasma compositional changes.

B. Human Studies

Kirman et al. assessed in vitro tumor growth in cultures to which either pre- operative or postoperative plasma samples had been added. Plasma samples were obtained from a total of 84 patients undergoing either colorectal resection or gastric bypass. Comparable numbers of open and laparoscopic patients for each type of operation were evaluated. Postoperative day 1 plasma from open surgery patients was associated with significantly greater in vitro tumor growth when compared to results obtained with their preoperative plasma. The rate of tumor cell proliferation correlated with the length of incision. No in vitro tumor growth differences were noted when the laparoscopic group preoperative and postoper- ative plasma were likewise assessed. The investigators next sought to determine the mechanism of the observed effect. Despite the murine study results, no dif- ferences in PDGF levels were noted. However, the plasma levels of a tumor inhibitory protein, insulin-like growth factor-binding protein 3 (IGF-BP3), were noted to be appreciably diminished 1 day following surgery in the great major- ity of open surgical patients. (The laparoscopic group’s IGF-BP-3 levels were similar before and after surgery.) The addition of IGF-BP3 to the postoperative plasma samples prevented the increase in tumor growth observed with “raw”

postoperative plasma; further, the supplementation of preoperative plasma with antibodies to IGF-BP3 increased in vitro tumor proliferation rates [15]. To sum- marize, major open surgery is associated with a decrease in a protein normally found in the blood that inhibits tumor growth. It is not clear whether this dif- ference will have any clinical relevance in regard to long-term outcome.

Both open and laparoscopic abdominal surgical methods influence tumor growth and behavior in the postoperative period. Tumors are more readily estab- lished, grow more rapidly, and demonstrate lower rates of apoptosis after surgery than after anesthesia alone. Full laparotomy is associated with the greatest changes. Laparoscopy is associated with similar, but significantly less marked, effects on tumor behavior. Surgery-related immunosuppression and one or more alterations in the makeup of the plasma may be responsible for these postsurgi- cal tumor growth alterations. The possibility exists that minimally invasive approaches may be associated with improved survival and recurrence rates.

The intermediate oncologic results of the Lacy et al. single center randomized trial of colon cancer patients, published in Lancet in June 2002, support this conclusion.

This study involved 208 patients; the demographics, extent of resection,

and stage distribution were similar between the open and laparoscopic-assisted

groups. When all the patients in each group were considered, with a mean follow- up of 43 months, the laparoscopic group had a significantly higher disease free survival rate than the open group. Furthermore, a significantly lower rate of tumor recurrence was noted for the minimally invasive group. When each stage of disease was independently assessed, it was noted that the stage 3 open and laparoscopic subgroups manifested the greatest differences in recurrence and survival [16]. Obviously, it is not possible to make definitive conclusions on the basis of a single study. Nonetheless, the results of Lacy et al. have far-reaching implications. The multicenter randomized trials that are underway worldwide will, hopefully, settle this question.

C. Summary

Most published animal studies that have assessed postoperative tumor growth have noted that laparotomy is associated with a period of accelerated tumor growth. Of note, CO

pneumoperitoneum and laparoscopic procedures have been found to be associated with significantly smaller increases in tumor growth in animal studies when compared to open procedures. Although unproven, the greater immunosuppression that is attendant to open procedures may be the cause, at least in part, of the accelerated tumor growth noted after laparotomy. Similarly, both animal studies and one human study suggest that surgery-related changes in the plasma protein composition are likely to account for part of the tumor growth alterations. From a basic science point of view, the avoidance of a large incision and the use of minimally invasive methods, in theory, may be associated with oncologic benefits. The results of a single center randomized human trial of colon cancer patients support these conclusions. The long-term results of the ongoing randomized and prospective colectomy trials will, it is hoped, shed further light on this matter.

D. References

1. Lacy AM, Delgado S, Garcia-Valdecasas JC, et al. Port site metastases and recurrence after laparoscopic colectomy: a randomized trial. Surg Endsoc 1998;12:1039–1042.

2. Milsom JW, Bartholomaus B, Hammerhofer KA, et al. A prospective randomized trial comparing laparoscopic versus conventional techniques in colorectal cancer surgery:

a preliminary report. J Am Coll Surg 1998;187:46–57.

3. Fielding GA, Lumley J, Nathanson L, et al. Laparoscopic colectomy. Surg Endosc 1997;11:745–749.

4. Franklin ME, Rosenthal D, Abrego-Medina D, et al. Prospective comparison of open vs. laparoscopic colon surgery for carcinoma: five year results. Dis Col Rectum 1996;39:s35–s46.

5. Ergomont AM, Steller EP, Marquet RL, et al. Local regional promotion of tumor

growth after abdominal surgery is dominant over immuno therapy with interleukin-2

and lymphokine activated killer cells. Cancer Detect Prevent 1988;12:421–429.

6. Goshima H, Saji S, Furata T, et al. Experimental study on preventive effects of lung metastases using LAK cells induced from various lymphocytes: special references to enhancement of lung metastasis after laparotomy stress. J Jpn Surg Soc 1989;90:

1245–1250.

7. Allendorf JDF, Bessler M, Kayton ML, et al. Increased tumor establishment and growth after laparotomy vs. laparoscopy in a murine model. Arch Surg 1995;130:

649–653.

8. Southall JC, Lee SW, Allendorf JD, et al. Colon adenocarcinoma and B-16 melanoma grow larger following laparotomy vs. pneumoperitoneum in a murine model. Dis Colon Rectum 1998;41(5):564–569.

9. DaCosta ML, Redmond P, Finnegan N, et al. Laparotomy and laparoscopy differen- tially accelerate experimental flank tumor growth. Br J Surg 1998;85:1439–1442.

10. Allendorf JD, Bessler M, Horvath KD, et al. Increased tumor establishment and growth after open versus laparoscopic bowel resection in mice. Surg Endosc 1998;12:

1035–1038.

11. Lee SW, Gleason NR, Blanco I, et al. Higher colon cancer tumor proliferative index and tumor cell death rate in mice undergoing laparotomy versus insufflation. Surg Endosc 2002;16(1):36–39.

12. Allendorf JD, Bessler M, Horvath KD, et al. Increased tumor establishment and growth after open versus laparoscopic surgery in mice may be related to differences in post operative T-cell function. Surg Endosc 1999;13:233–235.

13. Lee SW, Gleason NR, Southall JC, et al. A serum soluble factor(s) stimulates tumor growth following laparotomy in a murine model. Surg Endosc 2000;14(5):490–494.

14. Lee SW, Gleason NR, Stapleton GS, et al. Increased platelet-derived growth factor (PDGF) release after laparotomy stimulates systemic tumor growth in mice. Surg Endosc 2001;15(9):981–985.

15. Kirman I, Cekic V, Poltaratskaia N, et al. Plasma from patients undergoing major open surgery stimulates in vitro tumor growth; lower IGF-BP3 levels may, in part, account for this change. Surgery 2002;132:186–192.

16. Lacy AM, Garcia-Valdecasas JC, Delgado S, et al. Laparoscopically-assisted colec-

tomy versus open colectomy for treatment of non-metastatic colon cancer: a random-

ized trial. Lancet 2002;359:2224–2229.