Relationship Between Time Interval From Primary Surgery to the Start of Taxane- Plus Platinum-Based Chemotherapy and Clinical Outcome of Pat
http://www.100md.com
《临床肿瘤学》
the Department of Gynecology and Obstetrics, Department of Experimental Pathology, University of Pisa
Institute of Clinical Physiology, National Research Council, Pisa
Department of Gynecology and Obstetrics, University of Brescia, Brescia
Department of Gynecology and Obstetrics, University of Turin, Turin
Department of Gynecology and Obstetrics, University of Padua, Padua
European Institute of Oncology, Milan, Italy
ABSTRACT
PATIENTS AND METHODS: The study was conducted on 313 patients who underwent surgery followed by taxane- plus platinum-based chemotherapy. The median follow-up of survivors was 30.7 months (range, 6 to 109 months).
RESULTS: The 25%, 50%, and 75% quantiles of intervals from surgery to the start of chemotherapy were 11, 21, and 31 days, respectively. After the sixth cycle, 102 patients achieved a pathologic complete response at second-look surgery and 98 obtained a clinical complete response but were not submitted to second-look surgery. Taking into consideration the best assessed response, a complete (either clinical or pathologic) response was found in 200 patients. Residual disease (≤ 1 v > 1 cm; P < .0001) and ascites (absent v present; P = .003) were independent predictive factors for achieving a complete response, whereas residual disease (P = .001) and stage (IIc to III v IV; P = .04) were independent prognostic variables for survival. Conversely, statistical analyses failed to detect significant differences in complete response rates and survival among patients with an interval from surgery to chemotherapy shorter than 11 days, 12 to 21 days, 22 to 31 days, and longer than 31 days.
CONCLUSION: The interval from surgery to the start of taxane- plus platinum-based chemotherapy seems to have neither a predictive value for response to treatment nor a prognostic relevance for survival of advanced ovarian cancer patients.
INTRODUCTION
Some experimental investigations on different animal models showed that the removal of the primary tumor accelerated metastatic tumor growth assessed as both gross tumor size and metastatic cell kinetics.22-26 The increase in tumor growth is probably due to a conversion of noncycling cells in G0 phase into proliferation.26 However, limited and conflicting data are currently available about the relationship between the time interval from surgery to the start of chemotherapy and treatment effectiveness in animal tumor models,27-29 and in human malignancies including epithelial ovarian cancer.30-35
The aim of this retrospective investigation was to assess whether the length of the interval from primary surgery to taxane- plus platinum-based chemotherapy has any impact on response to treatment and survival of patients with advanced epithelial ovarian cancer.
PATIENTS AND METHODS
The tumor stage and histologic diagnosis of each patient were determined according to FIGO criteria and the histologic typing system of the WHO, respectively. Tumors were graded as well (G1), moderately (G2), or poorly (G3) differentiated.
The planned combination chemotherapy consisted of six cycles of paclitaxel plus carboplatin in 258 patients, epirubicin plus paclitaxel plus carboplatin in 18 patients, docetaxel plus carboplatin in 15 patients, ifosfamide plus paclitaxel plus cisplatin in 10 patients, paclitaxel plus cisplatin in seven patients, and epirubicin plus paclitaxel plus cisplatin in five patients.
The evaluation of the clinical course of disease was based on clinical examination, serum CA-125 assay, chest x-ray, abdominal-pelvic ultrasound, and computed tomography scan. Additional investigations were performed when appropriate. After the sixth cycle of chemotherapy, patients with no evidence of disease at clinical, serologic, sonographic, and radiologic examinations were defined as being in clinical complete response. Three to 5 weeks after the end of chemotherapy, a second-look surgery was usually proposed to clinically complete responders, mostly to patients enrolled onto clinical trials. A pathologic complete response at second-look surgery was defined as the disappearance of all macroscopic tumor deposits with negative peritoneal washing and negative multiple random biopsies. All patients with clinically or surgically detectable persistent disease, as well as some pathologically complete responders, received additional chemotherapy.
All patients were observed until they died or until July 2003. The median follow-up of survivors was 30.7 months (range, 6 to 109 months).
The SAS statistical package (release 8.2; SAS Institute, Cary, NC) was used for computations.
Time intervals from primary surgery to the start of chemotherapy were related to tumor stage, residual disease, and presence or absence of ascites using the median test.
Rates of complete response were compared to explicative variables using Pearson's {chi}2 test (or two-tailed Fisher's exact test when appropriate). Multiple logistic regression was carried out to investigate the relationship among the probability of achieving a complete response and the explanatory variables.
The cumulative probability of overall survival from the time of initial surgery was estimated by the product-limit method. The log-rank test was used to compare the homogeneity of survival functions across strata defined by categories of prognostic variables. The relationship between time interval from primary surgery to the start of chemotherapy and overall survival was also estimated using the nonparametric Spearman rank correlation coefficient (computed on unrecorded values). A multiple regression analysis based on the Cox proportional hazards model was used to test jointly the relative importance of variables as predictors of survival times.
RESULTS
Time intervals from primary surgery to the start of chemotherapy were not related to residual disease (≤ 1 v > 1 cm; median, 20 v 22 days; range, 5 to 62 v 3 to 60 days; P = not significant [ns]) or absence or presence of ascites (median, 22.5 v 20 days; range, 6 to 60 v 3 to 62 days; P = ns). Conversely, time interval was shorter for patients with stage IV disease compared with those with stage IIc to IV disease (median, 14 v 21 days; range, 6 to 47 v 3 to 62 days; P = .0419).
Sixteen patients experienced disease progression early during first-line chemotherapy. After the sixth cycle of chemotherapy, 102 patients achieved a pathologic complete response at second-look surgery, 98 patients obtained a clinical complete response but were not submitted to second-look surgery, and 113 patients had clinically or surgically detectable persistent disease. Therefore, taking into consideration the best assessed response, a complete (either clinical or pathologic) response was observed in 200 patients.
Residual disease (≤ 1 v > 1 cm) and ascites (absent v present) were the only variables related to the chance of achieving a complete response to chemotherapy at both univariate (P < .0001 and P = .0002, respectively; Table 1) and multivariate analysis (P < .0001 and P = .003, respectively; Table 2), whereas the interval from primary surgery to chemotherapy had no predictive value.
By log-rank test, overall survival was related to residual disease (≤ 1 cm v > 1 cm; P = .0003; Fig 1), ascites (absent v present; P = .0161; Fig 2), and tumor stage (IIc to III v IV; P = .0055; Fig 3), but not to interval from primary surgery to chemotherapy (Fig 4), age (data not shown), histologic type (data not shown), and histologic grade (data not shown).
The nonparametric correlation between time interval from primary surgery to the start of chemotherapy and overall survival did not show any statistical significance (Spearman rank correlation coefficient rS = 0.02; P = ns; Fig 5).
The Cox proportional hazards model showed that residual disease (P = .001) and tumor stage (P = .04) were the only independent prognostic variables for overall survival (Table 3).
DISCUSSION
Residual disease after initial surgery is the most important prognostic factor for advanced epithelial ovarian cancer.2-6 For instance, according to the FIGO Annual Report No. 24, the 5-year survival rates in stage IIIc disease were 55%, 42.3%, and 15.2%, respectively, for patients with no macroscopic residuum, macroscopic residuum less than 2 cm, and residuum more than 2 cm.1 Several other clinicopathologic and biologic variables have been related to the clinical outcome of patients with this malignancy,2-21 whereas the predictive and prognostic relevance of the interval time from primary surgery to the start of chemotherapy has not yet been clarified.33,35 There are little data regarding the effectiveness of chemotherapy in relation to timing of such therapy from surgery in animal tumor models27-29 as well as in human malignancies including epithelial ovarian cancer.30-35 By assessing how a variation in the time interval between primary tumor removal and cyclophosphamide administration affected residual tumor cell kinetics and animal survival in a murine mammary adenocarcinoma, Fisher et al27 detected that the shorter the time after operation that therapy is begun, the more complete is the abrogation of the kinetic changes in distant tumor foci, the more effective becomes the suppression of residual tumor burden, and the more prolonged is the survival. When cyclophosphamide was given before the operation, it completely prevented the increase in labeling index resulting from tumor removal, and prolonged mice survival to the greatest extent. In a murine osteosarcoma model, the perioperative administration of cytotoxic drugs demonstrated a significant advantage in preventing systemic relapses when compared with postoperative chemotherapy.28 Conversely, in the study of Berg et al29 there was no significant difference in survival between dogs with osteosarcoma that began cisplatin and doxorubicin chemotherapy 2 days after amputation and those that started chemotherapy 10 days after surgery.
In a series including 460 stage I and II breast cancer patients who received adjuvant chemotherapy consisting of fluorouracil, doxorubicin, and cyclophosphamide, there was no difference in 4-year disease-free survival for patient subgroups with interval times from surgery to chemotherapy of less than 10 weeks, 10 to 13, 14 to 17, or ≥ 18 weeks (64%, 68%, 60%, and 63%, respectively).30 Conversely, in the study of Pronzato et al,32 which enrolled 229 patients with node-positive primary operable breast cancer who underwent adjuvant chemotherapy consisting of fluorouracil, methotrexate, and cyclophosphamide, survival was significantly improved in patients who began chemotherapy within 35 days from surgery compared with those who started adjuvant treatment later (P = .01). Colleoni et al34 investigated the relationship between early initiation of chemotherapy, estrogen receptor (ER) status, and prognosis in 1,788 premenopausal, node-positive patients treated on different International Breast Cancer Study Group trials. Among patients with ER-negative tumors, 10-year disease-free survival was 60% for patients who started chemotherapy within 20 days compared with 34% for those who started chemotherapy later (P = .0003). Conversely, timing of chemotherapy initiation had no prognostic relevance for patients with ER-positive tumors.
For epithelial ovarian cancer, in the cohort study of Warwick et al33 including 362 patients with advanced disease treated with surgery followed by platinum-based chemotherapy, those patients with a longer interval appeared to have a worse outcome, but the interval was not an independent prognostic factor at multivariate analysis. The Scottish Gynaecological Cancer Trials Group investigated whether the length of the interval from primary surgery to chemotherapy has any effect on the progression-free survival of 472 patients enrolled onto four studies who had all received platinum-containing chemotherapy in combination with either a taxane (paclitaxel or docetaxel) or with cyclophosphamide.35 The median interval from surgery to chemotherapy was 22 days (range, 5 to 113 days). Univariate analysis showed a trend for worse progression-free survival for patients with earlier therapy, but women treated earlier tended to have bulkier residual disease. Therefore, multivariate analysis revealed that the interval from surgery to chemotherapy is not an independent prognostic factor for progression-free survival.
The predictive or prognostic relevance of a variable should be assessed in a group of patients who receive homogenous treatments. In our study, we investigated the clinical relevance of time interval from primary surgery to chemotherapy in a series of 313 patients with advanced epithelial ovarian cancer who had all undergone taxane- plus platinum-based chemotherapy. The 25%, 50%, and 75% quantiles of intervals were 11, 21, and 31 days, respectively. Residual disease after initial surgery and the absence or presence of ascites were independent predictive factors for the chance of achieving a complete response, whereas residual disease and tumor stage were independent prognostic variables for overall survival. Conversely, statistical analyses failed to detect significant differences in complete response rates and survival among patients with time interval from surgery to chemotherapy shorter than 11, 12 to 21, 22 to 31, and longer than 31 days.
a theoretical viewpoint, residual lesions after cytoreductive surgery have a high growth fraction, and therefore the earlier the start of chemotherapy, the greater is the chance that chemotherapy controls residual disease. The currently available chemotherapy regimens obtain satisfactory response rates in patients with advanced epithelial ovarian cancer, but most responders will subsequently experience tumor recurrence and up to more than 80% of patients will need a second-line treatment for chemotherapy-resistant disease.47,48 Drug resistance is the major obstacle in developing systemic therapies for advanced cancer and might be involved particularly in the secondary treatment failure frequently seen in epithelial ovarian cancer.49-51 On the basis of somatic mutation theory, it can be hypothesized that resistant mutants arise spontaneously early in the natural history of cancers and that the likelihood of developing genetically resistant clones is closely related to cell number.52 The onset of permanent resistance accounts for the inverse relationship between cell number and curability by drugs. At the time of clinical detection, advanced epithelial ovarian cancer consists of 1012 to 1013 tumor cells and therefore often contains a high rate of genetically chemotherapy-resistant clones. This can explain why an early administration of chemotherapy after surgery seems to give no clinical benefit when compared with a more delayed treatment.
In the clinical practice, the start of chemotherapy can be delayed because of different situations, such as when patients are referred from other institutions some weeks after surgery; when patients are submitted to aggressive cytoreductive surgery with consequent recovery delay; when patients present low hemoglobin levels and need more time to recover after surgery; when patients need to be discharged home earlier after surgery to get adjusted to their cancer diagnosis before starting chemotherapy that can be administered in a outpatient facility; and in difficult cases for the pathologist, for which the morphological interpretation is not unequivocal and more time is required for additional investigations (ie, immunohistochemistry and molecular analysis) to define with certainty the histologic type of the tumor. Only a prospective, specifically planned study can definitely clarify the clinical relevance of interval time between surgery and chemotherapy. However, the currently available data failed to detect that a few weeks of delay in starting chemotherapy influences the clinical outcome of patients with advanced epithelial ovarian cancer.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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18. Gasparini G, Bonoldi E, Viale G, et al: Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas. Int J Cancer 69:205-211, 1996
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20. Terai Y, Ueda M, Kumagai K, et al: Tumor angiogenesis and thymidine phosphorylase expression in ovarian carcinomas including serous surface papillary adenocarcinoma of the peritoneum. Int J Gynecol Pathol 19:354-360, 2000
21. Bamberger ES, Perrett CW: Angiogenesis in epithelial ovarian cancer. Mol Pathol 55:348-359, 2002
22. Sheldon PW, Fowler JF: The effect of irradiating a transplanted murine lymphosarcoma on the subsequent development of metastases. Br J Cancer 28:508-514, 1973
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26. Gunduz N, Fisher B, Saffer EA: Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res 39:3861-3865, 1979
27. Fisher B, Gunduz N, Saffer EA: Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43:1488-1492, 1983
28. Bell RS, Roth YF, Gebhardt MC, et al: Timing of chemotherapy and surgery in a murine osteosarcoma model. Cancer Res 48:5533-5538, 1988
29. Berg J, Gebhardt MC, Rand WM: Effect of timing of postoperative chemotherapy on survival of dogs with osteosarcoma. Cancer 79:1343-1350, 1997
30. Buzdar AU, Smith TL, Powell KC, et al: Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat 2:163-169, 1982
31. The Ludwig Breast Cancer Study Group: Combination adjuvant chemotherapy for node-positive breast cancer: Inadequacy of a single perioperative cycle. N Engl J Med 319:677-683, 1988
32. Pronzato P, Campora E, Amoroso D, et al: Impact of administration-related factors on outcome of adjuvant chemotherapy for primary breast cancer. Am J Clin Oncol 12:481-485, 1989
33. Warwick J, Kehoe S, Earl H, et al: Long-term follow-up of patients with advanced ovarian cancer treated in randomised clinical trials. Br J Cancer 72:1513-1517, 1995
34. Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors: The International Breast Cancer Study Group. J Clin Oncol 18:584-590, 2000
35. Flynn PM, Paul J, Cruickshank DJ: Does the interval from primary surgery to chemotherapy influence progression-free survival in ovarian cancer Gynecol Oncol 86:354-357, 2002
36. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996
37. du Bois A, Luck HJ, Meier W, et al: Carboplatin/paclitaxel versus cisplatin/paclitaxel as first-line chemotherapy in advanced ovarian cancer: An interim analysis of a randomized phase III trial of the Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group. Semin Oncol 24:15-52, 1997 (suppl 15)
38. Conte PF, Cianci C, Gadducci A: Up date in the management of advanced ovarian carcinoma. Crit Rev Oncol Hematol 32:49-58, 1999
39. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699-708, 2000
40. Piccart MJ, Du Bois A, Gore ME, et al: A new standard of care for treatment of ovarian cancer. Eur J Cancer 36:10-12, 2000
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42. Ozols RF: Paclitaxel (taxol)/carboplatin combination chemotherapy in the treatment of advanced ovarian cancer. Semin Oncol 27:3-7, 2000 (suppl 7)
43. Harries M, Gore M: Part I: Chemotherapy for epithelial ovarian cancer-treatment at first diagnosis. Lancet Oncol 3:529-536, 2002
44. du Bois A, Luck HJ, Meier W, et al: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/ paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1309-1329, 2003
45. Vasey PA: Survival and longer-term toxicity results of the SCOTROC study: Docetaxel-carboplatin (DC) vs. paclitaxel-carboplatin (PC) in epithelial ovarian cancer (EOC). Proc Am Soc Clin Oncol 21:202, 2002 (abstr 804)
46. Vasey PA: Role of docetaxel in the treatment of newly diagnosed advanced ovarian cancer. J Clin Oncol 21:136-144, 2003 (suppl 10)
47. McGuire WP, Ozols RF: Chemotherapy of advanced ovarian cancer. Semin Oncol 25:340-348, 1998
48. Conte PF, Gadducci A, Cianci C: Second-line treatment and consolidation therapies in advanced ovarian cancer. Int J Gynecol Cancer 11:52-56, 2001
49. Sood AK, Buller RE: Drug resistance in ovarian cancer: From the laboratory to the clinic. Obstet Gynecol 92:312-319, 1998
50. Goldie JH: Drug resistance in cancer: A perspective. Cancer Metastasis Rev 20:63-68, 2001
51. Schondorf T, Kurbacher CM, Gohring UJ, et al: Induction of MDR1-gene expression by antineoplastic agents in ovarian cancer cell lines. Anticancer Res 22:2199-2203, 2002
52. DeVita VT Jr: The James Ewing lecture: The relationship between tumor mass and resistance to chemotherapy—Implications for surgical adjuvant treatment of cancer. Cancer 51:1209-1220, 1983(Angiolo Gadducci, Enrico )
Institute of Clinical Physiology, National Research Council, Pisa
Department of Gynecology and Obstetrics, University of Brescia, Brescia
Department of Gynecology and Obstetrics, University of Turin, Turin
Department of Gynecology and Obstetrics, University of Padua, Padua
European Institute of Oncology, Milan, Italy
ABSTRACT
PATIENTS AND METHODS: The study was conducted on 313 patients who underwent surgery followed by taxane- plus platinum-based chemotherapy. The median follow-up of survivors was 30.7 months (range, 6 to 109 months).
RESULTS: The 25%, 50%, and 75% quantiles of intervals from surgery to the start of chemotherapy were 11, 21, and 31 days, respectively. After the sixth cycle, 102 patients achieved a pathologic complete response at second-look surgery and 98 obtained a clinical complete response but were not submitted to second-look surgery. Taking into consideration the best assessed response, a complete (either clinical or pathologic) response was found in 200 patients. Residual disease (≤ 1 v > 1 cm; P < .0001) and ascites (absent v present; P = .003) were independent predictive factors for achieving a complete response, whereas residual disease (P = .001) and stage (IIc to III v IV; P = .04) were independent prognostic variables for survival. Conversely, statistical analyses failed to detect significant differences in complete response rates and survival among patients with an interval from surgery to chemotherapy shorter than 11 days, 12 to 21 days, 22 to 31 days, and longer than 31 days.
CONCLUSION: The interval from surgery to the start of taxane- plus platinum-based chemotherapy seems to have neither a predictive value for response to treatment nor a prognostic relevance for survival of advanced ovarian cancer patients.
INTRODUCTION
Some experimental investigations on different animal models showed that the removal of the primary tumor accelerated metastatic tumor growth assessed as both gross tumor size and metastatic cell kinetics.22-26 The increase in tumor growth is probably due to a conversion of noncycling cells in G0 phase into proliferation.26 However, limited and conflicting data are currently available about the relationship between the time interval from surgery to the start of chemotherapy and treatment effectiveness in animal tumor models,27-29 and in human malignancies including epithelial ovarian cancer.30-35
The aim of this retrospective investigation was to assess whether the length of the interval from primary surgery to taxane- plus platinum-based chemotherapy has any impact on response to treatment and survival of patients with advanced epithelial ovarian cancer.
PATIENTS AND METHODS
The tumor stage and histologic diagnosis of each patient were determined according to FIGO criteria and the histologic typing system of the WHO, respectively. Tumors were graded as well (G1), moderately (G2), or poorly (G3) differentiated.
The planned combination chemotherapy consisted of six cycles of paclitaxel plus carboplatin in 258 patients, epirubicin plus paclitaxel plus carboplatin in 18 patients, docetaxel plus carboplatin in 15 patients, ifosfamide plus paclitaxel plus cisplatin in 10 patients, paclitaxel plus cisplatin in seven patients, and epirubicin plus paclitaxel plus cisplatin in five patients.
The evaluation of the clinical course of disease was based on clinical examination, serum CA-125 assay, chest x-ray, abdominal-pelvic ultrasound, and computed tomography scan. Additional investigations were performed when appropriate. After the sixth cycle of chemotherapy, patients with no evidence of disease at clinical, serologic, sonographic, and radiologic examinations were defined as being in clinical complete response. Three to 5 weeks after the end of chemotherapy, a second-look surgery was usually proposed to clinically complete responders, mostly to patients enrolled onto clinical trials. A pathologic complete response at second-look surgery was defined as the disappearance of all macroscopic tumor deposits with negative peritoneal washing and negative multiple random biopsies. All patients with clinically or surgically detectable persistent disease, as well as some pathologically complete responders, received additional chemotherapy.
All patients were observed until they died or until July 2003. The median follow-up of survivors was 30.7 months (range, 6 to 109 months).
The SAS statistical package (release 8.2; SAS Institute, Cary, NC) was used for computations.
Time intervals from primary surgery to the start of chemotherapy were related to tumor stage, residual disease, and presence or absence of ascites using the median test.
Rates of complete response were compared to explicative variables using Pearson's {chi}2 test (or two-tailed Fisher's exact test when appropriate). Multiple logistic regression was carried out to investigate the relationship among the probability of achieving a complete response and the explanatory variables.
The cumulative probability of overall survival from the time of initial surgery was estimated by the product-limit method. The log-rank test was used to compare the homogeneity of survival functions across strata defined by categories of prognostic variables. The relationship between time interval from primary surgery to the start of chemotherapy and overall survival was also estimated using the nonparametric Spearman rank correlation coefficient (computed on unrecorded values). A multiple regression analysis based on the Cox proportional hazards model was used to test jointly the relative importance of variables as predictors of survival times.
RESULTS
Time intervals from primary surgery to the start of chemotherapy were not related to residual disease (≤ 1 v > 1 cm; median, 20 v 22 days; range, 5 to 62 v 3 to 60 days; P = not significant [ns]) or absence or presence of ascites (median, 22.5 v 20 days; range, 6 to 60 v 3 to 62 days; P = ns). Conversely, time interval was shorter for patients with stage IV disease compared with those with stage IIc to IV disease (median, 14 v 21 days; range, 6 to 47 v 3 to 62 days; P = .0419).
Sixteen patients experienced disease progression early during first-line chemotherapy. After the sixth cycle of chemotherapy, 102 patients achieved a pathologic complete response at second-look surgery, 98 patients obtained a clinical complete response but were not submitted to second-look surgery, and 113 patients had clinically or surgically detectable persistent disease. Therefore, taking into consideration the best assessed response, a complete (either clinical or pathologic) response was observed in 200 patients.
Residual disease (≤ 1 v > 1 cm) and ascites (absent v present) were the only variables related to the chance of achieving a complete response to chemotherapy at both univariate (P < .0001 and P = .0002, respectively; Table 1) and multivariate analysis (P < .0001 and P = .003, respectively; Table 2), whereas the interval from primary surgery to chemotherapy had no predictive value.
By log-rank test, overall survival was related to residual disease (≤ 1 cm v > 1 cm; P = .0003; Fig 1), ascites (absent v present; P = .0161; Fig 2), and tumor stage (IIc to III v IV; P = .0055; Fig 3), but not to interval from primary surgery to chemotherapy (Fig 4), age (data not shown), histologic type (data not shown), and histologic grade (data not shown).
The nonparametric correlation between time interval from primary surgery to the start of chemotherapy and overall survival did not show any statistical significance (Spearman rank correlation coefficient rS = 0.02; P = ns; Fig 5).
The Cox proportional hazards model showed that residual disease (P = .001) and tumor stage (P = .04) were the only independent prognostic variables for overall survival (Table 3).
DISCUSSION
Residual disease after initial surgery is the most important prognostic factor for advanced epithelial ovarian cancer.2-6 For instance, according to the FIGO Annual Report No. 24, the 5-year survival rates in stage IIIc disease were 55%, 42.3%, and 15.2%, respectively, for patients with no macroscopic residuum, macroscopic residuum less than 2 cm, and residuum more than 2 cm.1 Several other clinicopathologic and biologic variables have been related to the clinical outcome of patients with this malignancy,2-21 whereas the predictive and prognostic relevance of the interval time from primary surgery to the start of chemotherapy has not yet been clarified.33,35 There are little data regarding the effectiveness of chemotherapy in relation to timing of such therapy from surgery in animal tumor models27-29 as well as in human malignancies including epithelial ovarian cancer.30-35 By assessing how a variation in the time interval between primary tumor removal and cyclophosphamide administration affected residual tumor cell kinetics and animal survival in a murine mammary adenocarcinoma, Fisher et al27 detected that the shorter the time after operation that therapy is begun, the more complete is the abrogation of the kinetic changes in distant tumor foci, the more effective becomes the suppression of residual tumor burden, and the more prolonged is the survival. When cyclophosphamide was given before the operation, it completely prevented the increase in labeling index resulting from tumor removal, and prolonged mice survival to the greatest extent. In a murine osteosarcoma model, the perioperative administration of cytotoxic drugs demonstrated a significant advantage in preventing systemic relapses when compared with postoperative chemotherapy.28 Conversely, in the study of Berg et al29 there was no significant difference in survival between dogs with osteosarcoma that began cisplatin and doxorubicin chemotherapy 2 days after amputation and those that started chemotherapy 10 days after surgery.
In a series including 460 stage I and II breast cancer patients who received adjuvant chemotherapy consisting of fluorouracil, doxorubicin, and cyclophosphamide, there was no difference in 4-year disease-free survival for patient subgroups with interval times from surgery to chemotherapy of less than 10 weeks, 10 to 13, 14 to 17, or ≥ 18 weeks (64%, 68%, 60%, and 63%, respectively).30 Conversely, in the study of Pronzato et al,32 which enrolled 229 patients with node-positive primary operable breast cancer who underwent adjuvant chemotherapy consisting of fluorouracil, methotrexate, and cyclophosphamide, survival was significantly improved in patients who began chemotherapy within 35 days from surgery compared with those who started adjuvant treatment later (P = .01). Colleoni et al34 investigated the relationship between early initiation of chemotherapy, estrogen receptor (ER) status, and prognosis in 1,788 premenopausal, node-positive patients treated on different International Breast Cancer Study Group trials. Among patients with ER-negative tumors, 10-year disease-free survival was 60% for patients who started chemotherapy within 20 days compared with 34% for those who started chemotherapy later (P = .0003). Conversely, timing of chemotherapy initiation had no prognostic relevance for patients with ER-positive tumors.
For epithelial ovarian cancer, in the cohort study of Warwick et al33 including 362 patients with advanced disease treated with surgery followed by platinum-based chemotherapy, those patients with a longer interval appeared to have a worse outcome, but the interval was not an independent prognostic factor at multivariate analysis. The Scottish Gynaecological Cancer Trials Group investigated whether the length of the interval from primary surgery to chemotherapy has any effect on the progression-free survival of 472 patients enrolled onto four studies who had all received platinum-containing chemotherapy in combination with either a taxane (paclitaxel or docetaxel) or with cyclophosphamide.35 The median interval from surgery to chemotherapy was 22 days (range, 5 to 113 days). Univariate analysis showed a trend for worse progression-free survival for patients with earlier therapy, but women treated earlier tended to have bulkier residual disease. Therefore, multivariate analysis revealed that the interval from surgery to chemotherapy is not an independent prognostic factor for progression-free survival.
The predictive or prognostic relevance of a variable should be assessed in a group of patients who receive homogenous treatments. In our study, we investigated the clinical relevance of time interval from primary surgery to chemotherapy in a series of 313 patients with advanced epithelial ovarian cancer who had all undergone taxane- plus platinum-based chemotherapy. The 25%, 50%, and 75% quantiles of intervals were 11, 21, and 31 days, respectively. Residual disease after initial surgery and the absence or presence of ascites were independent predictive factors for the chance of achieving a complete response, whereas residual disease and tumor stage were independent prognostic variables for overall survival. Conversely, statistical analyses failed to detect significant differences in complete response rates and survival among patients with time interval from surgery to chemotherapy shorter than 11, 12 to 21, 22 to 31, and longer than 31 days.
a theoretical viewpoint, residual lesions after cytoreductive surgery have a high growth fraction, and therefore the earlier the start of chemotherapy, the greater is the chance that chemotherapy controls residual disease. The currently available chemotherapy regimens obtain satisfactory response rates in patients with advanced epithelial ovarian cancer, but most responders will subsequently experience tumor recurrence and up to more than 80% of patients will need a second-line treatment for chemotherapy-resistant disease.47,48 Drug resistance is the major obstacle in developing systemic therapies for advanced cancer and might be involved particularly in the secondary treatment failure frequently seen in epithelial ovarian cancer.49-51 On the basis of somatic mutation theory, it can be hypothesized that resistant mutants arise spontaneously early in the natural history of cancers and that the likelihood of developing genetically resistant clones is closely related to cell number.52 The onset of permanent resistance accounts for the inverse relationship between cell number and curability by drugs. At the time of clinical detection, advanced epithelial ovarian cancer consists of 1012 to 1013 tumor cells and therefore often contains a high rate of genetically chemotherapy-resistant clones. This can explain why an early administration of chemotherapy after surgery seems to give no clinical benefit when compared with a more delayed treatment.
In the clinical practice, the start of chemotherapy can be delayed because of different situations, such as when patients are referred from other institutions some weeks after surgery; when patients are submitted to aggressive cytoreductive surgery with consequent recovery delay; when patients present low hemoglobin levels and need more time to recover after surgery; when patients need to be discharged home earlier after surgery to get adjusted to their cancer diagnosis before starting chemotherapy that can be administered in a outpatient facility; and in difficult cases for the pathologist, for which the morphological interpretation is not unequivocal and more time is required for additional investigations (ie, immunohistochemistry and molecular analysis) to define with certainty the histologic type of the tumor. Only a prospective, specifically planned study can definitely clarify the clinical relevance of interval time between surgery and chemotherapy. However, the currently available data failed to detect that a few weeks of delay in starting chemotherapy influences the clinical outcome of patients with advanced epithelial ovarian cancer.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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