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Determinants of Response to a Cisplatin-Based Regimen as Neoadjuvant Chemotherapy in Stage IB–IIB Invasive Cervical Cancer
GYNECOLOGIC ONCOLOGY ARTICLE NO.
63, 62–65 (1996)
0279
Determinants of Response to a Cisplatin-Based Regimen as Neoadjuvant Chemotherapy in Stage IB–IIB Invasive Cervical Cancer GIORGIO BOLIS*,† IWONA VAN ZAINTEN-PRZYBYSZ,†,‡ GIOVANNA SCARFONE,† FLAVIA ZANABONI,§ CLAUDIO SCARABELLI,\ SAVERIO TATEO,# MARCELLA CALABRESE,† AND FABIO PARAZZINI†,Ø *Divisione di Ginecologia Oncologica, Istituto Nazionale Tumori, Milan, Italy; †Clinica Ostetrico Ginecologica, Universita` di Milano, Milan, Italy; ‡Leyden University Medical Center, Leyden, The Netherlands; §Clinica Ostetrica Ginecologica, Universita` di Pavia, sede di Varese, Varese, Italy; \Divisione di Ostetricia e Ginecologia, Ospedale di Voghera, Voghera, Italy; #Clinica Ostetrico Ginecologica, Universita` di Pavia, Pavia, Italy; and ØIstituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ via Eritrea, 62, Milan, Italy Received January 24, 1996
with first diagnosis of invasive cervical cancer stage IB– IIB treated with a platinum-based regimen as neoadjuvant chemotherapy. Main objectives of this analysis are to offer further quantitative assessment of response to platinumbased neoadjuvant chemotherapy in women with cervical cancer Ib–IIb and to analyze the determinants of response to chemotherapy, to define women who are more likely to benefit from neoadjuvant chemotherapy (NACT).
The response rate and the determinants of response to a cisplatin-based regimen of neodjuvant chemoterapy (NACT) in women with a histologically confirmed first-diagnosis of invasive bulky stage IB–IIB cervical cancer are analyzed. A total of 79 cases were treated with cisplatin (40 mg/m2) each 7 days for seven courses. During the first, fourth, and seventh cycles, ifosfamide (3.5 g/m2) was given by infusion for 24 hr. At the end of the seven cycles, 51 had a partial response (64.5%) and 4 a complete pathological response (5.1%). The overall 24-month cumulative survival was 80%, being 93% in responders and 43% in nonresponders (log-rank test, P õ 0.05). With respect to the 66 subjects for whom pretreatment status of pelvic lymph nodes was available, complete or partial response was obtained in 35 of 42 subjects with negative pelvic lymph nodes at computed tomography, but in only 13 of 24 with positive lymph nodes. The corresponding odds ratios of response was 0.2 for women with positive status in comparison with those with negative status (95% confidence interval, 0.1–0.4). With respect to the 66 women who underwent surgery after NACT, of the 24 women with pretreatment positive lymph nodal status, 15 had positive nodes at surgery, but in 9 cases the histological analysis of nodes showed negative findings. Positive nodes at surgery were observed in 2 of the 42 subjects with negative nodes before treatment. q 1996 Academic Press, Inc.
SUBJECTS AND METHODS
From January 1990 to December 1994, 79 women with first histologically confirmed diagnosis of squamous invasive bulky cervical cancer stage IB – IIB according to the FIGO classification, observed at the First Obstetric and Gynecological Clinic of the University of Milan, the Obstetric and Gynecological Clinic of the University of Pavia and Varese, and the Obstetric and Gynecological Department of the Hospital of Voghera, received weekly cisplatin-based NACT. All women had tumor diameter §4 cm proven by clinical examination and/or imaging techniques and Karnowsky index ú 80. Their median age was 50 years (range, 24 – 70). None had previously received any treatment for cervical cancer. Patients were treated with cisplatin (40 mg/m2) every 7 days for seven courses. During the first, fourth, and seventh cycles (Days 1, 21, and 42), ifosfamide (IFX, 3.5 g/m2) was given by infusion for 24 hr. Mesna was given concurrently with the IFX and continued for 32 hr to prevent urothelial toxicity, for a total of 6.5 g/m2. Before cisplatin infusion all patients received 1 hr of prehydration and antiemetics were given. If the white blood cell count was less than 2.9 1 109/liter or the platelet count less than 75 1 109/liter and/or creatine clearance was less than 40 ml/min on Day 7, the IFX dose was reduced 30% or treatment was delayed. No dose reduction was permitted for cisplatin. Before treatment all patients
Chemotherapy has been traditionally limited to a palliative role in patients with recurrent and/or metastatic cervical cancer or an adjuvant role in early disease when lymph nodes are positive at initial diagnoses [1]. In recent years, however, chemotherapy has been proposed as part of the primary treatment of cervical carcinoma. Neoadjuvant cisplatin-based regimens have been employed in untreated women to improve the effectiveness of local radiotherapy or facilitate tumor resection. Several clinical series showing response rates ranging from 36 to 70% have been published [12– 7]. Most of those studies, however, have included cases at different stages of the disease (mainly stages III and IV). In this paper we present the results of a series of 79 women 62
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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underwent clinical and instrumental examinations including transvaginal ultrasound, computed tomography, and nuclear magnetic resonance. The response to chemotherapy was assessed by clinical examination plus transvaginal ultrasound at the end of the seven cycles. Partial response was recorded if there had been a reduction in tumor size ú50%. Clinical complete response was defined as disappearance of disease determined by clinical examination and ultrasound evaluation. Pathological complete response was defined as disappearance of the disease at histological examination. Lymph nodal status of pelvic nodes before treatment was based on computed tomography. Toxicity was assessed using WHO criteria. After treatment 66 women underwent surgery and 13 radiotherapy. Radiotherapy was chosen for women aged ú65 years and/or with a Karnowsky index after chemotherapy õ80. During surgery lymphoadenectomy of pelvic nodes was routinely performed. Data analysis. All analyses are based on data obtained until December 1994. No patient was lost to follow-up. Median follow-up was 23 months (range, 3–57). Survival time was defined as the period that elapsed between the date of diagnosis and death, or follow-up data for patients still alive at the moment of data analysis. No patient died from causes other than cervical cancer. Kaplan and Meier’s method was used to estimate survival curves, and curves were compared by the usual log-rank test [8]. Odds ratios (ORs) of response for the various factors considered were computed with their 95% confidence interval (CI) in strata of tumor stage using the Mantel–Haenszel procedure [9]. When a factor could be classified in more than two levels, the significance of the linear trend was
FIG. 1. patients.
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assessed by the Mantel test [10]. With the sample size of this analysis we are able to identify an OR of response to chemotherapy according to the main factors considered of about 3.0, at the usual level of a Å 0.05 and b Å 0.20. RESULTS
Of the 79 women, 51 had a partial response (64.5%) and 4 a pathological complete one (5.1%). The overall 24-month cumulative survival was 80%, 93% for responders and 43% for nonresponders [log-rank test adjusted for tumor stage and type of treatment (surgery/radiotherapy), P õ 0.05] (Fig. 1). Frequencies of partial and complete response according to selected characteristics are listed in Table 1. Considering the 66 subjects for whom pretreatment pelvic lymph nodal status was available, complete or partial response was obtained in 35 of the 42 subjects with negative pelvic lymph nodal status as shown by imaging, but in only 13 of the 24 positive ones. The corresponding OR of response was 0.2 for women with positive status as compared with those with negative status (95% CI, 0.1–0.4) Women with grade 3 tumor tended to respond less frequently than those with grade 2 tumor, but the difference was not significant (OR Å 0.6, grade 3 vs grade 2; 95% CI, 0.2–1.6). No relationship emerged between response and age and tumor stage. Table 2 shows the distribution of the 66 women who underwent surgery with respect to pretreatment pelvic lymph nodal status and postsurgical (histologically defined) pelvic lymph nodal status. Of the 24 women with pretreatment positive lymph nodes, 15 had positive nodes at surgery, but in 9 the histological analysis gave negative findings. Nodes
Survival of 79 women with invasive cervical cancer who underwent neoadjuvant chemotherapy in Italy 1990–1994. Slashes indicate censored
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BOLIS ET AL.
TABLE 1 Distribution of 79 Women with Invasive Cervical Cancer According to Response to NACT and Selected Characteristics, Italy, 1990–1994
TABLE 3 Toxicity of NACT in 79 Women with Invasive Cervical Cancer, Italy, 1990–1994 WHO grade
Total Age (years) £45 §45 Stage IB IIA IIB x21 trend Grade 2 3 Lymph nodal status Negative Positive
Total
Complete remission
Partial remission
OR (95% CI)a
79
4
51
—
26 53
0 4
19 32
1b 0.8 (0.2–2.7)
39 15 25
1 1 2
27 9 15
1b 0.8 0.8 P Å not significant
39 40
3 1
26 25
1b 0.6 (0.2–1.6)
42c 24
2 0
33 13
1b 0.2 (0.1–0.4)
a
OR, odds ratio adjusted for tumor stage; CI, confidence interval. Reference category. c In 13 cases lymph nodal status was not evaluable. b
were positive at surgery in 2 of the 42 subjects with negative nodes before treatment. Toxicity is considered in Table 3. All patients finished the planned therapy, except one who progressed during treatment, with a median time of 47 days (range, 41–59). The IFX dose was reduced in five patients (6.3%). No major toxicity was observed with the exception of grade 4 leukopenia in two cases, grade 4 thrombocytopenia in two, and anemia grade 4 in one. Two of the 13 women who received radiotherapy after NACT had radiotherapy-related toxicity (ileitis). DISCUSSION
In this series of stage IB–IIB invasive cervical cancer the rate of response to platinum-based chemotherapy was 69.6%, with 5.1% complete responses. The response rate was largely comparable in the three disease stages. These TABLE 2 Pretreatment and Postsurgical Status of Pelvic Lymph Nodes in 66 Women with Invasive Cervical Cancer Who Underwent NACT and Surgery, Italy, 1990–1994 Pretreatment status of pelvic lymph nodes Postsurgical status of pelvic lymph nodes Positive Negative
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Positive
Negative
15 9
2 40
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Hematological Leukopenia Thrombocytopenia Anemia Other Alopecia Emesis Fever Paresthesias a
2
3
4
23 (29)a 12 (15) 27 (34)
34 (43) 5 (6) 8 (10)
2 (2) 2 (2) 1 (1)
9 21 1 1
52 (65) 16 (20) — 1 (1)
— — — —
(11) (26) (1) (1)
Percentages are given in parentheses.
estimates should not be markedly affected by bias. The same treatment scheme and criteria for response were used in the collaborating centers, and all consecutive patients with eligibility criteria observed during the study period entered the study. The reported response rate to NACT in cervical cancer ranges from 60 to 90% in studies considering stage IB–IIB. The complete response rate ranges from 5 to 30% [1, 4, 5]. It has been suggested that more cycles of chemotherapy are needed for an optimal response rate [1]. Most published studies reported fewer than seven cycles of NACT. We used a scheme of seven cycles in 6 weeks. This provides the opportunity of evaluating the efficacy of treatment in a short time. Thus, in the case of no response, the definite treatment is not delayed markedly; however, it is generally possible to evaluate the response only at the end of treatment. The response rates reported in previous studies were comparable with different platinum-based regimens, most schemes including platinum and bleomycin with or without vinblastine/ vincristine. A series of 66 women with stage IIA–IV cervical cancer treated in the United Kingdom with ifosfamide and cisplatin plus bleomycin for three cycles showed a response rate of 69%, with a complete response of 6% [3], values largely comparable to results of our study. In this series, the major determinant of response to chemotherapy was the pretreatment pelvic lymph nodal status: the response rate was only about 50% in women with positive nodes in comparison with about 85% in those with negative nodes. In a previous series including 77 patients with stage IB–III tumor, size ú5 cm and parametrial involvement were associated with responsiveness to NACT in cervical cancer [11]. In that series no association emerged between response and age, tumor grade, and tumor stage, as in the present study. An interesting observation is the lower incidence of positive lymph nodes after chemotherapy. Of 24 women with positive pelvic lymph nodes by imaging techniques before
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treatment, 9 (38%) had negative pelvic lymph nodes at surgery. Considering the women who underwent surgery, the prevalence of positive lymph nodes was about 25% after NACT. These results should be considered cautiously; in fact, pretreatment histological confirmation of lymph nodal status was not available. We used computed tomography to define presurgical pelvic lymph nodal status; the reported sensitivity and specificity of this imaging technique in the identification of positive paraaortic and pelvic lymph nodes in cervical cancer is reported to be greater than 80% [12]. All computed tomography scans were performed in two centers; a comparative assessment of accuracy and reliability of the computed tomography scans betweens these two centers is, however, not available. Despite these limitations, the results of this study are consistent with previous published data from women who underwent surgery after NACT, the reported prevalence of positive lymph nodes after NACT ranging from about 10 to 25% [1]. These values seem to be lower than for women with bulky stage IB–IIB who did not receive NACT [13, 14]. Another interesting finding of this study is the good tolerability of treatment. All women, except one who progressed during treatment, completed the treatment cycles, and the prevalence of high-grade toxicity was low. Likewise, radiotherapy-related toxicity was not apparently increased after chemotherapy. Although any definitive conclusion is prevented by the lack of a comparison group and limited sample size, the frequency of toxicity after radiotherapy, about 15%, was largely comparable to that in series including women who had received radiotherapy as first-line treatment. In conclusion, this study confirms the high rate of response after NACT with a platinum-based regimen in cervical cancer stage IB–IIB. The main factor in response was lymph nodal status, rates being highest in women with negative lymph nodes by imaging techniques. ACKNOWLEDGMENTS The authors thank Ms. Ivana Garimoldi and Ms. Judy Baggott for editorial assistance. Antonella Villa, M.D., provided help in data analysis.
REFERENCES 1. Vermorken, J. B. The role of chemotherapy in squamous cell carcinoma of the uterine cervix: A review, Int. J. Gynecol. Cancer 3, 129–142 (1993).
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2. Souhami, L., Gil, R. A., Allan, S. E., Canary, P. V. C., Araujo, C. M. M., Pinto, L. H. J., and Silveira, T. R. P. A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix, J. Clin. Oncol. 9, 970–977 (1991). 3. Tobias, J., Buxton, E. J., Blackledge, G., Mould, J. J., Monaghan, J., Spooner, D., and Chetiyawardana, A. Neoadjuvant bleomycin ifosfamide and cisplatin in cervical cancer, Cancer Chemother. Pharmacol. 26, (suppl.), 59–62 (1990). 4. Kim, D. S., Moon, H., Kim, K. T., Hwang, Y. Y., Cho, S. H., and Kim, S. R. Two-year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib and II with bulky tumors, Gynecol. Oncol. 33, 225–230 (1989). 5. Giaroli, A., Sananes, C., Sardi, J. E., Maya, A. G., Bastards, M. L., Snaids, L., Rueda, N. G., Vighi, S., and di Paola, G. Lymph node metastases in carcinoma of the cervix uteri: Response to neoadjuvant chemotherapy and its impact on survival, Gynecol. Oncol. 39, 34–39 (1990). 6. Benedetti Panici, P., Greggi, S., Scambia, G., et al. High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma: A preliminary report, Gynecol. Oncol. 41, 212–216 (1991). 7. Dottino, P. R., Plaxe, S. C., Beddoe, A., Johnson, C., and Cohen, C. J. Induction chemotherapy followed by radical surgery in cervical cancer, Gynecol. Oncol. 40, 7–11 (1991). 8. Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., McPherson, K., Peto, J., and Smith, P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br. J. Cancer 35, 1–39 (1977). 9. Mantel, N., and Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease, J. Natl. Cancer Inst. 22, 719– 748 (1959). 10. Mantel, N. Chi-square tests with one degree of freedom: Extensions of the Mantel–Haenszel procedure, J. Am. Statist. Assoc. 58, 690–700 (1963). 11. Benedetti Panici, P., Scambia, G., Baiocchi, G., Greggi, S., Ragusa, G., Gallo, A., Conte, M., Battaglia, F., Laurelli, G., Rabitti, C., Capelli, A., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer: Prognostic factors for response and survival, Cancer 67, 372–379 (1991). 12. Whitley, N. O., Brenner, D. E., Francis, A., Villa Santa, U., Aisner, J., Wiernik, P. H., and Whitley, J. Computed tomographic evaluation of carcinoma of the cervix, Radiology 142, 439–446 (1982). 13. Piver, M. S., and Chung, W. S. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma, Obstet, Gynecol 46, 507–510 (1975). 14. Chung, C. K., Nahhas, W. A., Stryker, J. A., Curry, S. L., Abt, A. B., and Mortel, R. Analysis of factors contributing to treatment failures in stage IB and IIA carcinoma of the cervix, Am. J. Obstet. Gynecol. 138, 550–556 (1980).
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0279
Determinants of Response to a Cisplatin-Based Regimen as Neoadjuvant Chemotherapy in Stage IB–IIB Invasive Cervical Cancer GIORGIO BOLIS*,† IWONA VAN ZAINTEN-PRZYBYSZ,†,‡ GIOVANNA SCARFONE,† FLAVIA ZANABONI,§ CLAUDIO SCARABELLI,\ SAVERIO TATEO,# MARCELLA CALABRESE,† AND FABIO PARAZZINI†,Ø *Divisione di Ginecologia Oncologica, Istituto Nazionale Tumori, Milan, Italy; †Clinica Ostetrico Ginecologica, Universita` di Milano, Milan, Italy; ‡Leyden University Medical Center, Leyden, The Netherlands; §Clinica Ostetrica Ginecologica, Universita` di Pavia, sede di Varese, Varese, Italy; \Divisione di Ostetricia e Ginecologia, Ospedale di Voghera, Voghera, Italy; #Clinica Ostetrico Ginecologica, Universita` di Pavia, Pavia, Italy; and ØIstituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ via Eritrea, 62, Milan, Italy Received January 24, 1996
with first diagnosis of invasive cervical cancer stage IB– IIB treated with a platinum-based regimen as neoadjuvant chemotherapy. Main objectives of this analysis are to offer further quantitative assessment of response to platinumbased neoadjuvant chemotherapy in women with cervical cancer Ib–IIb and to analyze the determinants of response to chemotherapy, to define women who are more likely to benefit from neoadjuvant chemotherapy (NACT).
The response rate and the determinants of response to a cisplatin-based regimen of neodjuvant chemoterapy (NACT) in women with a histologically confirmed first-diagnosis of invasive bulky stage IB–IIB cervical cancer are analyzed. A total of 79 cases were treated with cisplatin (40 mg/m2) each 7 days for seven courses. During the first, fourth, and seventh cycles, ifosfamide (3.5 g/m2) was given by infusion for 24 hr. At the end of the seven cycles, 51 had a partial response (64.5%) and 4 a complete pathological response (5.1%). The overall 24-month cumulative survival was 80%, being 93% in responders and 43% in nonresponders (log-rank test, P õ 0.05). With respect to the 66 subjects for whom pretreatment status of pelvic lymph nodes was available, complete or partial response was obtained in 35 of 42 subjects with negative pelvic lymph nodes at computed tomography, but in only 13 of 24 with positive lymph nodes. The corresponding odds ratios of response was 0.2 for women with positive status in comparison with those with negative status (95% confidence interval, 0.1–0.4). With respect to the 66 women who underwent surgery after NACT, of the 24 women with pretreatment positive lymph nodal status, 15 had positive nodes at surgery, but in 9 cases the histological analysis of nodes showed negative findings. Positive nodes at surgery were observed in 2 of the 42 subjects with negative nodes before treatment. q 1996 Academic Press, Inc.
SUBJECTS AND METHODS
From January 1990 to December 1994, 79 women with first histologically confirmed diagnosis of squamous invasive bulky cervical cancer stage IB – IIB according to the FIGO classification, observed at the First Obstetric and Gynecological Clinic of the University of Milan, the Obstetric and Gynecological Clinic of the University of Pavia and Varese, and the Obstetric and Gynecological Department of the Hospital of Voghera, received weekly cisplatin-based NACT. All women had tumor diameter §4 cm proven by clinical examination and/or imaging techniques and Karnowsky index ú 80. Their median age was 50 years (range, 24 – 70). None had previously received any treatment for cervical cancer. Patients were treated with cisplatin (40 mg/m2) every 7 days for seven courses. During the first, fourth, and seventh cycles (Days 1, 21, and 42), ifosfamide (IFX, 3.5 g/m2) was given by infusion for 24 hr. Mesna was given concurrently with the IFX and continued for 32 hr to prevent urothelial toxicity, for a total of 6.5 g/m2. Before cisplatin infusion all patients received 1 hr of prehydration and antiemetics were given. If the white blood cell count was less than 2.9 1 109/liter or the platelet count less than 75 1 109/liter and/or creatine clearance was less than 40 ml/min on Day 7, the IFX dose was reduced 30% or treatment was delayed. No dose reduction was permitted for cisplatin. Before treatment all patients
Chemotherapy has been traditionally limited to a palliative role in patients with recurrent and/or metastatic cervical cancer or an adjuvant role in early disease when lymph nodes are positive at initial diagnoses [1]. In recent years, however, chemotherapy has been proposed as part of the primary treatment of cervical carcinoma. Neoadjuvant cisplatin-based regimens have been employed in untreated women to improve the effectiveness of local radiotherapy or facilitate tumor resection. Several clinical series showing response rates ranging from 36 to 70% have been published [12– 7]. Most of those studies, however, have included cases at different stages of the disease (mainly stages III and IV). In this paper we present the results of a series of 79 women 62
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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underwent clinical and instrumental examinations including transvaginal ultrasound, computed tomography, and nuclear magnetic resonance. The response to chemotherapy was assessed by clinical examination plus transvaginal ultrasound at the end of the seven cycles. Partial response was recorded if there had been a reduction in tumor size ú50%. Clinical complete response was defined as disappearance of disease determined by clinical examination and ultrasound evaluation. Pathological complete response was defined as disappearance of the disease at histological examination. Lymph nodal status of pelvic nodes before treatment was based on computed tomography. Toxicity was assessed using WHO criteria. After treatment 66 women underwent surgery and 13 radiotherapy. Radiotherapy was chosen for women aged ú65 years and/or with a Karnowsky index after chemotherapy õ80. During surgery lymphoadenectomy of pelvic nodes was routinely performed. Data analysis. All analyses are based on data obtained until December 1994. No patient was lost to follow-up. Median follow-up was 23 months (range, 3–57). Survival time was defined as the period that elapsed between the date of diagnosis and death, or follow-up data for patients still alive at the moment of data analysis. No patient died from causes other than cervical cancer. Kaplan and Meier’s method was used to estimate survival curves, and curves were compared by the usual log-rank test [8]. Odds ratios (ORs) of response for the various factors considered were computed with their 95% confidence interval (CI) in strata of tumor stage using the Mantel–Haenszel procedure [9]. When a factor could be classified in more than two levels, the significance of the linear trend was
FIG. 1. patients.
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assessed by the Mantel test [10]. With the sample size of this analysis we are able to identify an OR of response to chemotherapy according to the main factors considered of about 3.0, at the usual level of a Å 0.05 and b Å 0.20. RESULTS
Of the 79 women, 51 had a partial response (64.5%) and 4 a pathological complete one (5.1%). The overall 24-month cumulative survival was 80%, 93% for responders and 43% for nonresponders [log-rank test adjusted for tumor stage and type of treatment (surgery/radiotherapy), P õ 0.05] (Fig. 1). Frequencies of partial and complete response according to selected characteristics are listed in Table 1. Considering the 66 subjects for whom pretreatment pelvic lymph nodal status was available, complete or partial response was obtained in 35 of the 42 subjects with negative pelvic lymph nodal status as shown by imaging, but in only 13 of the 24 positive ones. The corresponding OR of response was 0.2 for women with positive status as compared with those with negative status (95% CI, 0.1–0.4) Women with grade 3 tumor tended to respond less frequently than those with grade 2 tumor, but the difference was not significant (OR Å 0.6, grade 3 vs grade 2; 95% CI, 0.2–1.6). No relationship emerged between response and age and tumor stage. Table 2 shows the distribution of the 66 women who underwent surgery with respect to pretreatment pelvic lymph nodal status and postsurgical (histologically defined) pelvic lymph nodal status. Of the 24 women with pretreatment positive lymph nodes, 15 had positive nodes at surgery, but in 9 the histological analysis gave negative findings. Nodes
Survival of 79 women with invasive cervical cancer who underwent neoadjuvant chemotherapy in Italy 1990–1994. Slashes indicate censored
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TABLE 1 Distribution of 79 Women with Invasive Cervical Cancer According to Response to NACT and Selected Characteristics, Italy, 1990–1994
TABLE 3 Toxicity of NACT in 79 Women with Invasive Cervical Cancer, Italy, 1990–1994 WHO grade
Total Age (years) £45 §45 Stage IB IIA IIB x21 trend Grade 2 3 Lymph nodal status Negative Positive
Total
Complete remission
Partial remission
OR (95% CI)a
79
4
51
—
26 53
0 4
19 32
1b 0.8 (0.2–2.7)
39 15 25
1 1 2
27 9 15
1b 0.8 0.8 P Å not significant
39 40
3 1
26 25
1b 0.6 (0.2–1.6)
42c 24
2 0
33 13
1b 0.2 (0.1–0.4)
a
OR, odds ratio adjusted for tumor stage; CI, confidence interval. Reference category. c In 13 cases lymph nodal status was not evaluable. b
were positive at surgery in 2 of the 42 subjects with negative nodes before treatment. Toxicity is considered in Table 3. All patients finished the planned therapy, except one who progressed during treatment, with a median time of 47 days (range, 41–59). The IFX dose was reduced in five patients (6.3%). No major toxicity was observed with the exception of grade 4 leukopenia in two cases, grade 4 thrombocytopenia in two, and anemia grade 4 in one. Two of the 13 women who received radiotherapy after NACT had radiotherapy-related toxicity (ileitis). DISCUSSION
In this series of stage IB–IIB invasive cervical cancer the rate of response to platinum-based chemotherapy was 69.6%, with 5.1% complete responses. The response rate was largely comparable in the three disease stages. These TABLE 2 Pretreatment and Postsurgical Status of Pelvic Lymph Nodes in 66 Women with Invasive Cervical Cancer Who Underwent NACT and Surgery, Italy, 1990–1994 Pretreatment status of pelvic lymph nodes Postsurgical status of pelvic lymph nodes Positive Negative
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Negative
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2 40
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2
3
4
23 (29)a 12 (15) 27 (34)
34 (43) 5 (6) 8 (10)
2 (2) 2 (2) 1 (1)
9 21 1 1
52 (65) 16 (20) — 1 (1)
— — — —
(11) (26) (1) (1)
Percentages are given in parentheses.
estimates should not be markedly affected by bias. The same treatment scheme and criteria for response were used in the collaborating centers, and all consecutive patients with eligibility criteria observed during the study period entered the study. The reported response rate to NACT in cervical cancer ranges from 60 to 90% in studies considering stage IB–IIB. The complete response rate ranges from 5 to 30% [1, 4, 5]. It has been suggested that more cycles of chemotherapy are needed for an optimal response rate [1]. Most published studies reported fewer than seven cycles of NACT. We used a scheme of seven cycles in 6 weeks. This provides the opportunity of evaluating the efficacy of treatment in a short time. Thus, in the case of no response, the definite treatment is not delayed markedly; however, it is generally possible to evaluate the response only at the end of treatment. The response rates reported in previous studies were comparable with different platinum-based regimens, most schemes including platinum and bleomycin with or without vinblastine/ vincristine. A series of 66 women with stage IIA–IV cervical cancer treated in the United Kingdom with ifosfamide and cisplatin plus bleomycin for three cycles showed a response rate of 69%, with a complete response of 6% [3], values largely comparable to results of our study. In this series, the major determinant of response to chemotherapy was the pretreatment pelvic lymph nodal status: the response rate was only about 50% in women with positive nodes in comparison with about 85% in those with negative nodes. In a previous series including 77 patients with stage IB–III tumor, size ú5 cm and parametrial involvement were associated with responsiveness to NACT in cervical cancer [11]. In that series no association emerged between response and age, tumor grade, and tumor stage, as in the present study. An interesting observation is the lower incidence of positive lymph nodes after chemotherapy. Of 24 women with positive pelvic lymph nodes by imaging techniques before
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NEADJUVANT CHEMOTHERAPY IN CERVICAL CANCER
treatment, 9 (38%) had negative pelvic lymph nodes at surgery. Considering the women who underwent surgery, the prevalence of positive lymph nodes was about 25% after NACT. These results should be considered cautiously; in fact, pretreatment histological confirmation of lymph nodal status was not available. We used computed tomography to define presurgical pelvic lymph nodal status; the reported sensitivity and specificity of this imaging technique in the identification of positive paraaortic and pelvic lymph nodes in cervical cancer is reported to be greater than 80% [12]. All computed tomography scans were performed in two centers; a comparative assessment of accuracy and reliability of the computed tomography scans betweens these two centers is, however, not available. Despite these limitations, the results of this study are consistent with previous published data from women who underwent surgery after NACT, the reported prevalence of positive lymph nodes after NACT ranging from about 10 to 25% [1]. These values seem to be lower than for women with bulky stage IB–IIB who did not receive NACT [13, 14]. Another interesting finding of this study is the good tolerability of treatment. All women, except one who progressed during treatment, completed the treatment cycles, and the prevalence of high-grade toxicity was low. Likewise, radiotherapy-related toxicity was not apparently increased after chemotherapy. Although any definitive conclusion is prevented by the lack of a comparison group and limited sample size, the frequency of toxicity after radiotherapy, about 15%, was largely comparable to that in series including women who had received radiotherapy as first-line treatment. In conclusion, this study confirms the high rate of response after NACT with a platinum-based regimen in cervical cancer stage IB–IIB. The main factor in response was lymph nodal status, rates being highest in women with negative lymph nodes by imaging techniques. ACKNOWLEDGMENTS The authors thank Ms. Ivana Garimoldi and Ms. Judy Baggott for editorial assistance. Antonella Villa, M.D., provided help in data analysis.
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2. Souhami, L., Gil, R. A., Allan, S. E., Canary, P. V. C., Araujo, C. M. M., Pinto, L. H. J., and Silveira, T. R. P. A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix, J. Clin. Oncol. 9, 970–977 (1991). 3. Tobias, J., Buxton, E. J., Blackledge, G., Mould, J. J., Monaghan, J., Spooner, D., and Chetiyawardana, A. Neoadjuvant bleomycin ifosfamide and cisplatin in cervical cancer, Cancer Chemother. Pharmacol. 26, (suppl.), 59–62 (1990). 4. Kim, D. S., Moon, H., Kim, K. T., Hwang, Y. Y., Cho, S. H., and Kim, S. R. Two-year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib and II with bulky tumors, Gynecol. Oncol. 33, 225–230 (1989). 5. Giaroli, A., Sananes, C., Sardi, J. E., Maya, A. G., Bastards, M. L., Snaids, L., Rueda, N. G., Vighi, S., and di Paola, G. Lymph node metastases in carcinoma of the cervix uteri: Response to neoadjuvant chemotherapy and its impact on survival, Gynecol. Oncol. 39, 34–39 (1990). 6. Benedetti Panici, P., Greggi, S., Scambia, G., et al. High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma: A preliminary report, Gynecol. Oncol. 41, 212–216 (1991). 7. Dottino, P. R., Plaxe, S. C., Beddoe, A., Johnson, C., and Cohen, C. J. Induction chemotherapy followed by radical surgery in cervical cancer, Gynecol. Oncol. 40, 7–11 (1991). 8. Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., McPherson, K., Peto, J., and Smith, P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br. J. Cancer 35, 1–39 (1977). 9. Mantel, N., and Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease, J. Natl. Cancer Inst. 22, 719– 748 (1959). 10. Mantel, N. Chi-square tests with one degree of freedom: Extensions of the Mantel–Haenszel procedure, J. Am. Statist. Assoc. 58, 690–700 (1963). 11. Benedetti Panici, P., Scambia, G., Baiocchi, G., Greggi, S., Ragusa, G., Gallo, A., Conte, M., Battaglia, F., Laurelli, G., Rabitti, C., Capelli, A., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer: Prognostic factors for response and survival, Cancer 67, 372–379 (1991). 12. Whitley, N. O., Brenner, D. E., Francis, A., Villa Santa, U., Aisner, J., Wiernik, P. H., and Whitley, J. Computed tomographic evaluation of carcinoma of the cervix, Radiology 142, 439–446 (1982). 13. Piver, M. S., and Chung, W. S. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma, Obstet, Gynecol 46, 507–510 (1975). 14. Chung, C. K., Nahhas, W. A., Stryker, J. A., Curry, S. L., Abt, A. B., and Mortel, R. Analysis of factors contributing to treatment failures in stage IB and IIA carcinoma of the cervix, Am. J. Obstet. Gynecol. 138, 550–556 (1980).
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AP: Gyn Onc