The If and When of Surgical Debulking for Ovarian Carcinoma
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《新英格兰医药杂志》
Celomic epithelial carcinoma of the ovary, in contrast to most other gynecologic cancers, often causes no symptoms in its early stages and is usually diagnosed only after it has spread to other parts of the peritoneal cavity or to more distant sites. As a result, curative surgical resection is not an option for most patients. Moreover, ovarian carcinoma, unlike most other solid tumors, typically spreads by seeding throughout the peritoneal cavity. For these reasons, the disease is most commonly diagnosed at stage III, in which the process is grossly confined to the peritoneal cavity. Such cases are not amenable to curative surgical resection, but as early as 1934 it was suggested that aggressive removal of tumor might enhance the effects of postoperative irradiation in patients with advanced disease.1 Four decades later, Griffiths and colleagues published evidence suggesting that reducing the tumor to nodules less than 1.5 cm in diameter by means of surgical bulk reduction followed by chemotherapy increased survival.2,3,4 Subsequent long-term follow-up by these investigators suggested that, regardless of the initial size of the tumor, successful cytoreduction to small-volume disease increased the frequency of complete responses and enhanced survival.5
These observations have been corroborated by others. Two meta-analyses of chemotherapy trials summarized most of the results. The first included 16 studies and 2659 patients.6 The second involved 53 studies and 6885 patients.7 Both meta-analyses suggested that the presence of small-volume residual disease was associated with improved survival; the highest survival rate was among patients who had no gross residual tumor after debulking surgery. In the study by Bristow and colleagues, each 10 percent decrease in residual tumor volume produced a 5.5 percent increase in median survival.7
In none of these trials were patients randomly assigned to debulking surgery or no debulking surgery, but the results convinced the gynecologic oncology community in the United States of the value of cytoreductive surgery. The line of reasoning most frequently cited to explain the apparent value of surgical debulking included five points.8 First, the surgery was thought to remove resistant clones of tumor cells and thus decrease the likelihood of the early onset of drug resistance. Second, the removal of large masses likely to be associated with poorly vascularized areas of tumor purportedly improved the probability of delivering adequate drug doses to the remaining cancer cells. Third, the higher growth fraction in better vascularized small masses enhanced the effect of chemotherapy. Fourth, in principle, smaller masses required fewer cycles of chemotherapy and thus decreased the likelihood of drug resistance. Finally, removal of bulky disease theoretically enhanced the immune system. These five points, if correct, support the use of initial surgical debulking followed by chemotherapy, rather than the reverse.
Despite the general acceptance of the value of initial surgical debulking, the results of the trials could also be explained by the biology of the cancer. This biologic explanation was grounded in two main points.8 First, a substantial proportion of patients had small-volume disease before undergoing surgical resection. Second, in patients in whom a small volume was achieved surgically, this approach was technically feasible. These facts identified the tumors as distinctly different biologically from others. They were presumably less aggressive than larger tumors or those that were not amenable to primary surgical debulking and thus would be associated with improved survival whether or not surgical debulking was performed.
To determine whether the favorable outcome associated with small-volume residual disease was indeed the result of surgery or a consequence of the biology of the tumors, the Gynecologic Oncology Group (GOG) initiated Protocol 80 in the mid-1980s. Patients with bulky stage III disease were randomly assigned to undergo initial surgical debulking followed by eight cycles of cisplatin, doxorubicin, and cyclophosphamide (PAC) or eight cycles of PAC followed by surgical debulking. The study was stopped after two years because only two patients were enrolled. The most common reason cited for the lack of participation in the trial was that patients should not be deprived of the presumed benefits of initial surgical debulking. No other prospective attempt to investigate the efficacy of initial surgical debulking has succeeded.
Subsequently, GOG investigators retrospectively examined the effect of the volume of disease on the outcome in two large trials of chemotherapy. The first study, GOG Protocol 52, included only patients with small-volume residual disease (nodules were no more than 1 cm in diameter).9 Patients were randomly assigned to receive either cisplatin plus cyclophosphamide or PAC. Since there was no significant difference in the outcome between the two regimens, the results of the two groups were combined. The patients fell into two categories of roughly equal size: those in whom surgical debulking was not required to achieve small-volume residual disease and those in whom debulking was required. These patients were, in turn, compared with patients with bulky disease who were enrolled in a parallel study of large-volume residual disease. Patients who did not require surgery to achieve small-volume disease, in fact, did better than those who did require surgery; hence, this study failed to show that cytoreductive surgery conferred a survival advantage. Patients who had small-volume residual disease as a result of surgical debulking, however, fared better than patients who had large-volume disease at the start of chemotherapy.
The second GOG study was an investigation of dose intensity in patients with large-volume residual disease (nodules were larger than 1 cm in diameter).10 Patients who started chemotherapy with residual nodules that were less than 2 cm in diameter had a higher rate of survival than patients with residual nodules of at least 2 cm. Grouping the patients with nodules that were at least 2 cm in diameter according to the size of the largest nodule did not yield significant differences in the outcome.
None of these observations directly address whether the improvement in outcome associated with a small volume of residual disease is the result of tumor biology or of surgical bulk reduction.11,12,13 The answer ultimately requires a randomized trial, an approach that does not appear to be feasible because the value of initial surgical debulking has already been assumed.
The first large, randomized trial of surgical debulking did not evaluate initial surgical debulking. This study, conducted by the European Organisation for Research and Treatment of Cancer (EORTC), instead randomly assigned patients in whom the initial debulking attempt was not considered to be successful. These patients received six cycles of chemotherapy (cisplatin plus cyclophosphamide) alone or three cycles of the same chemotherapy followed by an attempt at surgical cytoreduction and then three more cycles of chemotherapy.14 Patients assigned to secondary surgical cytoreduction had improved rates of progression-free and overall survival. The results of this prospective, randomized trial support the value of surgical debulking.
The GOG study reported in this issue of the Journal by Rose and colleagues15 was designed to confirm the results of the EORTC study of secondary surgical cytoreduction. The results, which show no significant difference between the group that underwent secondary surgical cytoreduction and the group that did not, seem at first glance to contradict the results of the EORTC study.14 As discussed by Rose and colleagues, however, differences between the two trials may explain the apparent contradiction. Although Rose et al. used paclitaxel plus cisplatin rather than cyclophosphamide plus cisplatin, the key difference lies in their requirement that all patients undergo an initial maximal surgical effort to debulk the tumor. The GOG trial was actually evaluating a second maximal surgical effort. The extent of the initial surgical effort in patients in the EORTC trial was not clearly specified, but most patients appear to have received what would be considered less than a maximal effort according to GOG standards on the basis of the reported size of the tumor at study entry.
What conclusions can be drawn from these two randomized trials and the abundance of nonrandomized data in the literature? First, in patients with advanced ovarian carcinoma, there appears to be a clear direct relationship between the volume of residual disease and the outcome.6,7 Second, the biology of the tumor is important. The findings of the retrospective GOG trial9 support the contention that patients whose tumor burden is 1 cm in diameter or less without debulking surgery do better than those who require surgical debulking. Third, surgical debulking is also an important component of therapy. The two randomized studies of secondary surgical cytoreduction support the need for one maximal surgical effort.14,15 Fourth, the five points cited as the rationale for surgical debulking support the contention that such surgery should be performed before the initiation of chemotherapy. This approach is consistent with the current standard of care for advanced ovarian carcinoma in the United States: initial surgical cytoreduction is followed by chemotherapy with paclitaxel plus carboplatin. Secondary surgical cytoreduction should be reserved for patients in whom the initial surgical effort at cytoreduction was not considered to be maximal.
Source Information
From the Division of Oncology, Department of Medicine, University of Mississippi School of Medicine, Jackson.
References
Meigs JV. Tumors of the female pelvic organs. New York: Macmillan, 1934.
Griffiths CT, Grogan RH, Hall TC. Advanced ovarian cancer: primary treatment with surgery, radiotherapy, and chemotherapy. Cancer 1972;29:1-7.
Tobias JS, Griffiths CT. Management of ovarian carcinoma: current concepts and future prospects. N Eng J Med 1976;294:818-22, 877-82.
Griffiths CT, Parker LM, Fuller AF Jr. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Treat Rep 1979;63:235-240.
Griffiths CT, Parker LM, Lee S, Finkler NJ. The effect of residual mass size on response to chemotherapy after surgical cytoreduction for advanced ovarian cancer: long-term results. Int J Gynecol Cancer 2002;12:323-331.
Allen DG, Heintz APM, Touw FWMM. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol 1995;16:349-356.
Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248-1259.
Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269-274.
Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47:159-166.
Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170:974-980.
Le T, Krepart GV, Lotocki RJ, Heywood MS. Does debulking surgery improve survival in biologically aggressive ovarian carcinoma? Gynecol Oncol 1997;67:208-214.
Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction of ovarian cancer: is there a correlation with "biological aggressiveness" and survival? Gynecol Oncol 2001;82:435-441.
Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390-396.
van der Burg MEL, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629-634.
Rose PG, Nerenstone S, Brady MF, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351:2489-2497.(Tate Thigpen, M.D.)
These observations have been corroborated by others. Two meta-analyses of chemotherapy trials summarized most of the results. The first included 16 studies and 2659 patients.6 The second involved 53 studies and 6885 patients.7 Both meta-analyses suggested that the presence of small-volume residual disease was associated with improved survival; the highest survival rate was among patients who had no gross residual tumor after debulking surgery. In the study by Bristow and colleagues, each 10 percent decrease in residual tumor volume produced a 5.5 percent increase in median survival.7
In none of these trials were patients randomly assigned to debulking surgery or no debulking surgery, but the results convinced the gynecologic oncology community in the United States of the value of cytoreductive surgery. The line of reasoning most frequently cited to explain the apparent value of surgical debulking included five points.8 First, the surgery was thought to remove resistant clones of tumor cells and thus decrease the likelihood of the early onset of drug resistance. Second, the removal of large masses likely to be associated with poorly vascularized areas of tumor purportedly improved the probability of delivering adequate drug doses to the remaining cancer cells. Third, the higher growth fraction in better vascularized small masses enhanced the effect of chemotherapy. Fourth, in principle, smaller masses required fewer cycles of chemotherapy and thus decreased the likelihood of drug resistance. Finally, removal of bulky disease theoretically enhanced the immune system. These five points, if correct, support the use of initial surgical debulking followed by chemotherapy, rather than the reverse.
Despite the general acceptance of the value of initial surgical debulking, the results of the trials could also be explained by the biology of the cancer. This biologic explanation was grounded in two main points.8 First, a substantial proportion of patients had small-volume disease before undergoing surgical resection. Second, in patients in whom a small volume was achieved surgically, this approach was technically feasible. These facts identified the tumors as distinctly different biologically from others. They were presumably less aggressive than larger tumors or those that were not amenable to primary surgical debulking and thus would be associated with improved survival whether or not surgical debulking was performed.
To determine whether the favorable outcome associated with small-volume residual disease was indeed the result of surgery or a consequence of the biology of the tumors, the Gynecologic Oncology Group (GOG) initiated Protocol 80 in the mid-1980s. Patients with bulky stage III disease were randomly assigned to undergo initial surgical debulking followed by eight cycles of cisplatin, doxorubicin, and cyclophosphamide (PAC) or eight cycles of PAC followed by surgical debulking. The study was stopped after two years because only two patients were enrolled. The most common reason cited for the lack of participation in the trial was that patients should not be deprived of the presumed benefits of initial surgical debulking. No other prospective attempt to investigate the efficacy of initial surgical debulking has succeeded.
Subsequently, GOG investigators retrospectively examined the effect of the volume of disease on the outcome in two large trials of chemotherapy. The first study, GOG Protocol 52, included only patients with small-volume residual disease (nodules were no more than 1 cm in diameter).9 Patients were randomly assigned to receive either cisplatin plus cyclophosphamide or PAC. Since there was no significant difference in the outcome between the two regimens, the results of the two groups were combined. The patients fell into two categories of roughly equal size: those in whom surgical debulking was not required to achieve small-volume residual disease and those in whom debulking was required. These patients were, in turn, compared with patients with bulky disease who were enrolled in a parallel study of large-volume residual disease. Patients who did not require surgery to achieve small-volume disease, in fact, did better than those who did require surgery; hence, this study failed to show that cytoreductive surgery conferred a survival advantage. Patients who had small-volume residual disease as a result of surgical debulking, however, fared better than patients who had large-volume disease at the start of chemotherapy.
The second GOG study was an investigation of dose intensity in patients with large-volume residual disease (nodules were larger than 1 cm in diameter).10 Patients who started chemotherapy with residual nodules that were less than 2 cm in diameter had a higher rate of survival than patients with residual nodules of at least 2 cm. Grouping the patients with nodules that were at least 2 cm in diameter according to the size of the largest nodule did not yield significant differences in the outcome.
None of these observations directly address whether the improvement in outcome associated with a small volume of residual disease is the result of tumor biology or of surgical bulk reduction.11,12,13 The answer ultimately requires a randomized trial, an approach that does not appear to be feasible because the value of initial surgical debulking has already been assumed.
The first large, randomized trial of surgical debulking did not evaluate initial surgical debulking. This study, conducted by the European Organisation for Research and Treatment of Cancer (EORTC), instead randomly assigned patients in whom the initial debulking attempt was not considered to be successful. These patients received six cycles of chemotherapy (cisplatin plus cyclophosphamide) alone or three cycles of the same chemotherapy followed by an attempt at surgical cytoreduction and then three more cycles of chemotherapy.14 Patients assigned to secondary surgical cytoreduction had improved rates of progression-free and overall survival. The results of this prospective, randomized trial support the value of surgical debulking.
The GOG study reported in this issue of the Journal by Rose and colleagues15 was designed to confirm the results of the EORTC study of secondary surgical cytoreduction. The results, which show no significant difference between the group that underwent secondary surgical cytoreduction and the group that did not, seem at first glance to contradict the results of the EORTC study.14 As discussed by Rose and colleagues, however, differences between the two trials may explain the apparent contradiction. Although Rose et al. used paclitaxel plus cisplatin rather than cyclophosphamide plus cisplatin, the key difference lies in their requirement that all patients undergo an initial maximal surgical effort to debulk the tumor. The GOG trial was actually evaluating a second maximal surgical effort. The extent of the initial surgical effort in patients in the EORTC trial was not clearly specified, but most patients appear to have received what would be considered less than a maximal effort according to GOG standards on the basis of the reported size of the tumor at study entry.
What conclusions can be drawn from these two randomized trials and the abundance of nonrandomized data in the literature? First, in patients with advanced ovarian carcinoma, there appears to be a clear direct relationship between the volume of residual disease and the outcome.6,7 Second, the biology of the tumor is important. The findings of the retrospective GOG trial9 support the contention that patients whose tumor burden is 1 cm in diameter or less without debulking surgery do better than those who require surgical debulking. Third, surgical debulking is also an important component of therapy. The two randomized studies of secondary surgical cytoreduction support the need for one maximal surgical effort.14,15 Fourth, the five points cited as the rationale for surgical debulking support the contention that such surgery should be performed before the initiation of chemotherapy. This approach is consistent with the current standard of care for advanced ovarian carcinoma in the United States: initial surgical cytoreduction is followed by chemotherapy with paclitaxel plus carboplatin. Secondary surgical cytoreduction should be reserved for patients in whom the initial surgical effort at cytoreduction was not considered to be maximal.
Source Information
From the Division of Oncology, Department of Medicine, University of Mississippi School of Medicine, Jackson.
References
Meigs JV. Tumors of the female pelvic organs. New York: Macmillan, 1934.
Griffiths CT, Grogan RH, Hall TC. Advanced ovarian cancer: primary treatment with surgery, radiotherapy, and chemotherapy. Cancer 1972;29:1-7.
Tobias JS, Griffiths CT. Management of ovarian carcinoma: current concepts and future prospects. N Eng J Med 1976;294:818-22, 877-82.
Griffiths CT, Parker LM, Fuller AF Jr. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Treat Rep 1979;63:235-240.
Griffiths CT, Parker LM, Lee S, Finkler NJ. The effect of residual mass size on response to chemotherapy after surgical cytoreduction for advanced ovarian cancer: long-term results. Int J Gynecol Cancer 2002;12:323-331.
Allen DG, Heintz APM, Touw FWMM. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol 1995;16:349-356.
Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248-1259.
Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 2000;78:269-274.
Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47:159-166.
Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170:974-980.
Le T, Krepart GV, Lotocki RJ, Heywood MS. Does debulking surgery improve survival in biologically aggressive ovarian carcinoma? Gynecol Oncol 1997;67:208-214.
Eisenkop SM, Spirtos NM. Procedures required to accomplish complete cytoreduction of ovarian cancer: is there a correlation with "biological aggressiveness" and survival? Gynecol Oncol 2001;82:435-441.
Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390-396.
van der Burg MEL, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629-634.
Rose PG, Nerenstone S, Brady MF, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351:2489-2497.(Tate Thigpen, M.D.)