Randomized Trial of Neoadjuvant Chemotherapy Comparing Paclitaxel, Ifosfamide, and Cisplatin With Ifosfamide and Cisplatin Followed by Radic
http://www.100md.com
《临床肿瘤学》
the Department of Obstetrics and Gynecology, University of Milano-Bicocca, San Gerardo Hospital, Monza
Istituto di Ricerche Farmacologiche "Mario Negri"
European Institute of Oncology, Milan
Cervello Hospital, Palermo
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, University of Turin
Gynecological Oncology Department, Mauriziano Umberto I Hospital Mauriziano Hospital, Turin
Department of Gynecology and Obstetrics, University of Brescia
Clinica Malzoni, Avellino
Cannizzaro Hospital, Catania
ABSTRACT
PURPOSE: Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival.
PATIENTS AND METHODS: Patients (n = 219) were randomly assigned to ifosfamide 5 g/m2 during 24 hours plus cisplatin 75 mg/m2, or paclitaxel 175 mg/m2 plus ifosfamide 5 g/m2 during 24 hours and cisplatin 75 mg/m2 every 3 weeks for three courses.
RESULTS: Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%
odds ratio, 3.22
95% CI, 1.69 to 5.88
P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75
95% CI, 0.48 to 1.17
P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66
95% CI, 0.39 to 1.10
P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88
95% CI, 2.50 to 13.84
P < .0001).
CONCLUSION: The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.
INTRODUCTION
At present, concomitant chemoradiotherapy is considered the standard treatment of locally advanced cervical cancer. The 1999 National Cancer Institute Alert strongly supported its use in all patients with cancer of the uterine cervix requiring radiation, and a meta-analysis pooling the data on 4,580 patients from 19 randomized trials showed a highly significant absolute survival improvement of 12% in favor of concurrent chemoradiotherapy compared with radiotherapy alone.1,2 Neoadjuvant chemotherapy may represent an alternative to surgery and irradiation as initial treatment of locally advanced cervical cancer. There are several potential benefits of such an approach: it can eradicate or biologically alter micrometastases, debulk the tumor, and thus render inoperable tumors (International Federation of Gynecology and Obstetrics [FIGO] stages IIB to IIIB) operable or improve the outcome of radiotherapy. Finally, when a pelvic recurrence occurs, the morbidity of salvage surgery after radiotherapy has failed is often higher than the morbidity of salvage radiotherapy after neoadjuvant chemotherapy followed by radical surgery has failed. The advantages of downstaging the disease without the use of irradiation are tempting and open a completely new philosophy of radical treatment for locally advanced cervical cancer.
Several compounds have been tested in squamous cell carcinoma. Cisplatin and ifosfamide are considered among the most active drugs in both neoadjuvant and salvage treatments.3-6
The publication of the large randomized trial by Omura et al,7 in which 454 patients with advanced squamous carcinoma were assigned to receive cisplatin, cisplatin plus ifosfamide, or cisplatin plus mitolactol, immediately preceded the inception of our study. This trial showed that the cisplatin plus ifosfamide combination had a significantly higher response rate (31.1% v 17.8%
P = .004) and a significantly longer progression-free survival (P = .003) compared with cisplatin alone, albeit with more toxicity and no overall survival benefit. Paclitaxel has proven effective in several squamous cell human carcinomas,8 and promising results have been presented for cervical carcinoma as a single agent or in combination with a platinum compound both in the neoadjuvant and salvage settings.9,10
To determine the optimal neoadjuvant drug regimen in the treatment of locally advanced squamous cell cervical carcinoma, we set up this multicentric randomized trial aimed at comparing the three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) with a two-drug regimen of cisplatin and ifosfamide (IP). The purpose of this trial was to select the best drug combination as a basis to compare the neoadjuvant chemotherapy followed by radical surgery versus concomitant chemoradiotherapy, which represents the current standard of treatment in this subgroup of patients. This trial also aimed to validate our previous findings, which showed that the achievement of an optimal response (OR
ie, complete response [CR] or partial response [PR] with microinvasive residual lesion [< 3 mm] on histology) after neoadjuvant chemotherapy was a significant prognostic factor and a possible candidate as a surrogate end point for survival.11 The 3-mm threshold used to set the lowest limit of the OR category was chosen because it represents the maximal extension of FIGO stage IA1 cervical tumor, which is usually considered cured after local resection, and the prognosis of which is exceedingly good.
PATIENTS AND METHODS
Eligibility and Random Assignment
Pretreatment evaluation included history, physical examination, biopsy, complete blood analysis, and chest x-ray. Tumor imaging by means of magnetic resonance imaging (MRI) and urography were done to determine the extent of disease and to assess renal function. Patients with histologically confirmed locally advanced squamous cervical carcinoma (FIGO stage IB2 to IVA)12 were eligible for the study. Additional eligibility criteria included WHO performance status 2
adequate bone marrow reserve (absolute granulocyte count 2,000/μL, platelet count 100,000/μL)
adequate renal, hepatic, and cardiac function.
Approval to conduct the study was obtained independently from an internal review board at each participating institution. Informed consent was obtained from all patients in accordance with local and national legislation. Randomization with equal probability of assignment to each treatment arm (IP versus TIP) was carried out by telephone at the Mario Negri Institute (Milan, Italy) by a block arrangement balancing the treatment assignment within FIGO stage and tumor grade.
Chemotherapy Regimens
The TIP regimen was administered as follows: paclitaxel was given at the dose of 175 mg/m2 as a 3-hour infusion. Premedication given to reduce the risk of paclitaxel hypersensitivity was as follows: methylprednisolone 250 mg intravenously 60 minutes before and chlorpheniramine 10 mg and cimetidine 300 mg intravenously 30 minutes before treatment delivery. After a bolus of mesna 400 mg/m2 intravenously, ifosfamide 5 g/m2 and mesna 5 g/m2 were infused intravenously during 24 hours in 1 L of normal saline, followed by mesna 3 g/m2 given intravenously in 1 L of normal saline during 24 hours. Hydration with 3 L of 5% dextrose solution during 24 hours was infused simultaneously. Cisplatin 75 mg/m2 was administered on day 2 as a 60-minute infusion after prehydration with 1 L of normal saline added with 10 mEq/L of potassium chloride and 10 mEq/L of MgSO4, and was followed by post-hydration with 1 L of 5% dextrose solution added to 20 mEq/L of KCL and 20 mEq/L of MgSO4 given during 2 hours. In the IP regimen, the two drugs (ifosfamide and cisplatin) were given as in the TIP regimen. In both arms, treatment was administered every 3 weeks for a total of three courses.
Treatment Modifications
CBCs were performed weekly or more often if toxicity occurred
evaluation of renal and hepatic function was repeated before each cycle.
Treatment administration was based on evaluation of blood cell count before the start of each cycle. Treatment was administered if the absolute granulocyte count was 1,500/μL and the platelet count was 100,000/μL. Treatment was to be delayed week to week until minimum hematologic parameters were met. After two consecutive treatment delays, on the basis of physician judgment, treatment was either interrupted or continued with the support of recombinant human granulocyte colony-stimulation factor in instances of persistent grade 4 myelotoxicity. In the latter case, ifosfamide was to be reduced to 25% of the initial dose. Delays were not permitted other than for documented toxicity.
Treatment After Neoadjuvant Chemotherapy and Evaluation of Response
Tumor extension was assessed clinically and by MRI after three courses and all patients deemed operable underwent radical hysterectomy13 and pelvic lymphadenectomy within 3 or 4 weeks after the administration of the third cycle. Patients with inoperable tumors because of progression after adjuvant chemotherapy were offered radical radiotherapy. Clinical responses were determined according to the WHO criteria.14 Pathologic responses were defined as follows: OR included a complete disappearance of tumor in the cervix with negative nodes (CR), or a residual disease with less than 3 mm stromal invasion including in situ carcinoma (PR1)
suboptimal response consisted of persistent residual disease with more than 3 mm stromal invasion on surgical specimen (PR2). Women with positive nodes, parametrial involvement, cut-through or suboptimal response, or OR but still with positive nodes underwent additional treatment (external-beam irradiation or chemoradiotherapy). Patients who achieved an OR (CR + PR1) received two additional courses of chemotherapy after surgery with the same agents used in neoadjuvant treatment.
Toxicity Assessment
All patients who had received at least one cycle were assessable. Toxicity was graded according to WHO criteria.14
Follow-Up Procedures
Patients were monitored for assessment of disease status 1 month after the end of treatment and every 3 months thereafter. Monitoring comprised pelvic examination and vaginal cytology
MRI or computed tomography scan of the pelvis and abdomen and chest x-ray were performed every 6 months for 2 years and once a year thereafter.
Statistical Methods
This was a randomized, multicentric, phase II study aimed at comparing the activity and toxicity of TIP versus IP in the neoadjuvant setting for patients with locally advanced squamous cell cervical cancer.
The primary efficacy parameter was the OR (CR + PR1) rate. Secondary end points were overall survival and disease-free survival.15 The accrual goal was set at 206 patients. This sample size would provide a statistical power of 80% to detect a 20% increase in response rate when testing at the .05 level (two-sided test).
Response to chemotherapy treatments was compared using a multiple logistic regression model with a dichotomous dependent variable: OR (CR + PR1) versus PR2/stable disease/progressive disease. Independent variables included treatment arm and stage of disease. The response odds ratio was defined as the odds of achieving OR in the TIP group divided by the odds of achieving OR in the IP group. As a consequence, an odds ratio larger than unity indicates that the TIP treatment is associated with an increase in the probability of OR compared with IP treatment.
Comparisons of the rates of OR and maximum grade of toxicity between the two arms were carried out by use of a two-sided 2 test or a two-sided Fisher's exact test if the number of patients in a given category was five or fewer.
Overall survival was defined as the time from random treatment allocation to death as a result of any cause
patients known to be alive at the time of analysis were censored at the time of their last contact. Progression-free survival was defined as the time from randomization to first appearance of progressive disease or death as a result of any cause
patients known to be alive and without progressive disease at the time of analysis were censored at the time of their last contact.
We compared Kaplan-Meier curves for overall survival and progression-free survival using the log-rank test.16 The proportional-hazards regression model17 was also used for progression-free and overall survival to estimate the treatment-related hazard ratios (HRs) while adjusting for other pretreatment factors. To verify if neoadjuvant regimens exert their effect on survival through improvements in tumor shrinkage, we used a multivariate Cox regression model containing the candidate surrogate end point (OR) and the treatment received. If OR is a surrogate end point, then the survival becomes independent of the treatment received, and therefore the treatment HR would change approaching unity (ie, no treatment effect).
All analyses were done on an intention-to-treat basis except for the analyses of toxicity. The latter analyses were restricted to all patients who received at least one cycle of allocated treatment. All P values are two-sided. Analyses were carried out using SAS software (Version 8.20
SAS Institute, Cary, NC)
RESULTS
April 1997 to January 2000, 219 patients entered the SNAP01 (Studio Neo-Adjuvante Portio) randomized trial from 21 Italian centers. Of the 219 patients, 113 were assigned to receive the IP combination regimen and 106 patients received the TIP combination regimen. Fifteen patients were excluded from the analysis because of eligibility criteria violations (five in the IP arm and 10 in the TIP arm
reasons for ineligibility are listed in Fig 1 18).
As shown in Table 1, both groups were well matched for age, WHO performance status, FIGO stage, tumor grade, and proportion of patients with radiologic lymph node involvement at random assignment.
Compliance and Toxicity
We collected full details about the IP and TIP treatments received by 103 (95%) and 94 (98%) patients, respectively. Similar proportions of patients in each arm completed the planned treatment (90% in the IP group and 94% in the TIP group), but 18% of patients did so with some dose adjustment or delay in the IP arm compared with 35% of patients in the TIP group.
No differences emerged between the median cisplatin and ifosfamide dose given per cycle in the IP arm and in the TIP arm: 74.6 mg/m2 (25th to 75th percentiles, 72.7 to 75.3 mg/m2) v 73.6 mg/m2 (25th to 75th percentiles, 66.7 to 75.0 mg/m2) and 5.0 g/m2 (25th to 75th percentiles, 4.9 to 5.0 g/m2) v 4.9 g/m2 (25th to 75th percentiles, 4.6 to 5.0 g/m2), respectively. Median paclitaxel dose was 173.6 mg/m2 (25th to 75th percentiles, 169.2 to 175.0 mg/m2).
Analysis of toxicity was performed in 194 patients receiving their initial chemotherapy regimen. Toxicity data are listed in Table 2.
Hematologic toxicity was relevant in both arms. TIP was associated with significant higher rates of grade 3 or 4 hematologic toxicity than the IP schedule (P = .02). Nausea and vomiting were similar in both arms. As expected, more patients in the TIP group experienced neurosensory symptoms.
In this study population, we recorded four (2%) deaths related to toxicity: three patients received the IP schedule and one patient received the TIP regimen. Three women received just one cycle of chemotherapy before death.
The first patient was a 71-year-old woman with a stage IB2 cervical cancer. At enrollment, all of the eligibility criteria were met and she was randomly assigned to TIP, although because of unspecified clinical considerations, she received the IP schedule. Nine days after the first course, she experienced severe thrombocytopenia and neutropenia and she died as a result of acute cardiovascular complication 10 days after the first course.
The second patient was a 74-year-old woman with stage IIB cervical cancer. She was randomly assigned to receive IP treatment. After the first course of chemotherapy she developed severe hematologic toxicity with bone marrow aplasia, and she died as a result of acute renal failure 2 weeks later.
The third patient was a 75-year-old woman with stage IIIB cervical cancer. She was enrolled onto the study to receive TIP schedule and completed the three courses of chemotherapy with reduction of doses because of grade 4 neutropenia and thrombocytopenia after the first course. She died 10 days after the last cycle as a result of hematologic toxicity and renal failure.
The fourth patient was a 29-year-old woman who had hepatitis C virus with a stage IIB cervical cancer. Her liver and renal parameters were in the normal range at the time of enrollment and she was assigned to the TIP arm, but received the IP schedule for unspecified clinical considerations. Seven days after the first course she experienced fever, diarrhea, and severe granulocytopenia. Within 15 days she also developed renal and liver failure. She died as a result of bone marrow aplasia 3 weeks and 1 day after the first course.
Effect of Treatment on Tumor Response
One hundred eighty-nine of 204 fully eligible patients (93%) were assessed for clinical response (100 in the IP arm and 89 in the TIP arm
Fig 1).
The proportion of patients assessable for pathologic responses who underwent surgical interventions after chemotherapy was 94% (90% in the IP group and 98% in the TIP group)
surgery was not performed in 11 patients because of minimal clinical response, stable disease, or overt clinical progression, and in two patients because of patient refusal. Five of those patients who achieved a clinical PR were considered to have had a suboptimal response (PR2). Three to 4 weeks after completion of neoadjuvant chemotherapy, all but three of the operable women underwent radical surgery to include pelvic bilateral lymphadenectomy that was tailored on the basis of the anatomic state of patients. Of the 176 operated patients, 141 underwent a Meigs-Magara or type III Piver-Rutledge radical hysterectomy, 33 underwent a Wertheim or type II Piver-Rutledge radical hysterectomy. Two women underwent total simple hysterectomy because of local extension of disease and bulky lymph node metastases. No significant differences in the surgical approach emerged between the two treatment groups.
The OR rate in the IP group was 23% (9% CR, 14% PR1), and it was 48% (20% CR, 28% PR1) in the TIP group (P = .0004, 2 test
Table 3). The overall OR odds ratio showed a highly significant benefit of TIP over IP in a logistic multivariate analysis that contained stage as a covariate (odds ratio, 3.2
95% CI, 1.69 to 5.88
P = .0003). Twenty-six percent of patients with stage Ib2 in the IP arm had an OR
58% of patients with stage Ib2 had an OR in the TIP arm. In patients with stage IIa or IIb, the OR rate was 25% in the IP group and 47% in the TIP group
in patients with stage III to IVa, the OR rate was 7% and 17%, respectively.
Information about postoperative radiation therapy was known for 182 patients (96%). Two of the 43 patients who achieved OR in the TIP arm (5%) and none of the 22 patients in the IP arm underwent postoperative radiotherapy. Among the 45 patients who did not achieved OR on TIP, 28 had postoperative radiotherapy (62%) and a similar proportion (49 of 72
68%) of patients had radiotherapy in the IP treatment group.
Effect of Treatment on Progression-Free and Overall Survival
At a median follow-up of 43 months (25th to 75th percentiles, 31 to 56 months), 79 women have experienced progression of disease or died (46 patients in the IP arm, 33 patients in the TIP arm). The sites of recurrence are listed in Table 4. The plots of the cumulative proportion of patients surviving progression-free for the two treatments are displayed in Figure 2. Those patients receiving TIP experienced a 25% lower rate of treatment failure than those receiving IP but this difference was not statistically significant (HR, 0.75
95% CI, 0.48 to 1.17
P = .20). At the time of this analysis, 61 patients have died (37 patients in the IP arm, 24 patients in the TIP arm). Figure 3 depicts the overall survival curves for the two treatments. Comparison of the survival curves showed a statistically insignificant HR of 0.66 in favor of TIP (95% CI, 0.39 to 1.10
P = .11). The difference in the overall death rates between treatment groups remained practically unchanged, and still was statistically insignificant when stage, age, and lymph node status at randomization were taken into account in a Cox regression analysis (Table 5).
Evaluation of Tumor Response As a Surrogate End Point for Survival
A Cox multivariate regression model was used to assess if OR (CR + PR1) is a prognostic factor for survival. In the subset of the 189 patients assessable for response, data in Table 6 show that relative to the OR group, the average death rates are much greater in the suboptimal response group (HR, 5.88
95% CI, 2.50 to 13.84
P < .0001). In the subset of patients assessable for response, the HR favoring the TIP regimen was 0.55 (95% CI, 0.32 to 0.94
P = .030). When tumor response and treatment arm were added to the model, the HR in favor of TIP decreased to 0.80 (95% CI, 0.46 to 1.41
P = .447), thus indicating that although a residual benefit beyond that captured by response was still attributable to treatment, such a benefit no longer appeared to be statistically significant.
DISCUSSION
This multicenter randomized trial strongly suggests that the neoadjuvant three-drug combination containing paclitaxel (TIP) is more active than the two-drug regimen (IP) in terms of response rates, although the relative hazard of first progression or death is not significantly different between the treatment groups. This study also confirms that the achievement of OR is a good prognostic factor and may be a surrogate end point for survival in this clinical setting.
The OR rate for those receiving the TIP combination was more than twice that observed with IP, and although this study was not powered to detect either progression-free or overall survival differences, the effect on both was in the direction of statistical significance. Only one occurrence of progressive disease was observed in those patients receiving TIP. These findings are in keeping with the pilot study by Zanetta et al10 that enrolled 38 patients with locally advanced cervical cancer treated with TIP. These investigators observed that the TIP regimen not only yielded a promising 84% objective response rate, but also that the OR rate achieved with TIP (34%) was higher than that observed by the same investigators on similar patients who had received the cisplatin, bleomycin, and vincristine regimen (19%).11 The results of our study confirm that the TIP regimen is one of the most active neoadjuvant chemotherapeutic regimens,19 although hematologic toxicity associated with this treatment is considerable and was significantly higher than that with the IP regimen. Nonetheless, three of the four deaths as a result of toxicity that occurred in this study were attributed to IP and only one death was attributed to TIP. Three of these patients were older than 70 years and one presented with stage IIIB disease based on ureteral obstruction. Such findings suggest that women older than 70 years or with renal comorbidity secondary to ureteral obstruction probably should not be treated with intense neoadjuvant chemotherapy. Although TIP has proved to be active in locally advanced cervix cancer as a neoadjuvant regimen, there is an urgent need for new chemotherapeutic regimens with similar efficacy but less toxicity. To resolve this issue, the SNAP02 multicentric trial ongoing in Italy will compare the TIP schedule (which emerged as the more successful treatment arm of our current study) with the paclitaxel-cisplatin combination. The SNAP02 study is specifically meant to better define the role of ifosfamide in preoperative chemotherapy in terms of added activity and toxicity.
The neoadjuvant setting simplified validation of the intermediate outcome of OR rate as a surrogate for survival. It was possible to evaluate the effect of achieving optimal tumor response on survival without running the risk of introducing a well-known bias into the analysis: patients who survive a sufficient duration to have an opportunity to experience a response will have a predictably longer survival than will other patients, even if the therapy has no effect on survival. In fact, the short duration of chemotherapy and the homogeneous time point of response assessment (ie, surgery) allowed the use of a standard Cox multivariate model to analyze the prognostic effect of OR on survival.
Optimal pathologic response (OR) turned out to be a strong independent predictor of survival (HR, 5.88
95% CI, 2.50 to 13.84
P < .0001), whereas standard objective response (CR + PR1 + PR2) was not. Previous reports were able to detect a link between response criteria that are stricter than the standard CR + PR and overall survival. Kim et al20 described a 100% 2-year survival rate in 22 patients achieving a complete or optimal partial pathologic response (only microscopic foci of residual tumor) after neoadjuvant treatment, irrespective of the stage. Giaroli et al21 reported a 2-year disease-free interval of 97.7% in 43 patients with CR or residual tumor smaller than 5 mm in diameter. Panici et al22 found that only one of 20 patients with depth of cervical infiltration less than 5 mm experienced recurrence, compared with 11 of 42 with deeper invasion. In a retrospective analysis of the database of two large Italian gynecologic-oncologic departments, Colombo et al11 observed that the achievement of a pathologically documented CR or an optimal partial response with a residual tumor 3 mm was indeed an independent favorable prognostic factor for survival (when patients received neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin).
In our study we also found evidence that the OR was a surrogate end point of survival
that is, the gain in survival brought about by TIP was mediated through improvements in optimal tumor response. In fact, when the multivariable Cox regression model exploring the influence of treatment on survival was adjusted for OR, the treatment HR shifted toward unity. This analysis showed that survival was still statistically associated with the surrogate end point but no longer associated with the initial treatment. If OR is a good predictor of survival and a surrogate end point for treatment, then it can be used to more quickly obtain information about the efficacy of a new treatment. That would increase the efficiency of design and management of randomized trials comparing different therapeutic options. For example, a smaller sample size and a shorter follow-up could be used if the power calculation for the study were based on the surrogate marker rather than on survival. The difference in OR could be monitored as an early indictor of the presence or absence of a treatment difference with respect to survival duration.
A recent meta-analysis23 collected individual patient data from 21 randomized trials of neoadjuvant chemotherapy in locally advanced cervical cancer. This analysis included data for comparison of the benefits of neoadjuvant chemotherapy followed by radical radiotherapy versus radical radiotherapy alone (2,074 patients), and for comparison of neoadjuvant chemotherapy followed by surgery (± radiotherapy) versus radical radiotherapy alone (872 patients). The first comparison was hindered by heterogeneity between trials and gave conflicting results depending on how trials were grouped by chemotherapy cycle length or dose-intensity. The second comparison showed that patients treated with neoadjuvant chemotherapy had a highly significant 35% reduction in the risk of death (P = .0004) that translated into a 14% absolute increase in 5-year overall survival. The protocol of this large meta-analytic project was finalized in 1999 when radiotherapy was still the standard treatment. Meanwhile, as mentioned, concurrent chemoradiotherapy has become the treatment of choice and the proper comparator for neoadjuvant chemotherapy. The new challenge in clinical research is the management of randomized trials comparing neoadjuvant chemotherapy with the standard represented by concomitant radiochemotherapy
such a trial has been designed and proposed from the European Organisation for Research and Treatment of Cancer, and currently is recruiting patients. Until the results of this direct comparison are published, no new evidence-based paradigms can be formulated to govern the treatment of locally advanced cervical cancer.
Appendix
The following institutions and consultants contributed patients to SNAP01 protocol (the number in parentheses indicates the number of patients enrolled): Ospedale San Gerardo dei Tintori, Monza (107): C. Bonazzi, A. Maneo, A. Pellegrino, G.M. Zanetta (deceased)
Istituto Europeo di Oncologia, Milano (27): G. Parma
Casa di Cura Malzoni, Avellino (12): M. Balestrino (deceased), A. Vernaglia Lombardi, Ospedali Civili, Brescia (12): A. Gambino
Ospedale Mauriziano, Torino (11): A.M. Ferrero
Dipartimento Discipline Ginecologiche e Ostetriche, Università di Torino, Torino (9): R. Bellino, I.A. Rigault de la Longrais
Ospedale V. Cervello, Palermo (7): D. Gueli Alletti, F. Lionti
Divisione di Ginecologia, Ospedale Chiavari-Lavagna (5): D. Dodero, M.G. Centurioni
Clinica Mangiagalli, Milano (4): R. Maggi, R. Carlini
Ospedale Cannizzaro, Catania (4): G. Scibilia
Ospedale Maggiore, Lodi (3): M. Luerti
Ospedale Sant'Orsola, Bologna (2): A. Martoni
Dipartimento di Oncologia, Ospedale Ramazzini, Carpi (2): F. Artioli
Ospedale Valduce, Como (2): R. Colleoni
Azienda Ospedaliera Universitaria S. Anna, Ferrara (2): R. Martinello
Ospedale Civile, Padova (2): T. Maggino
Policlinico Umberto I, Università La Sapienza, Roma (2): L. Marzetti
Ospedale Regionale S. Chiara, Trento (2): C. Arcuri
Azienda Ospedaliera Treviglio (2): R. Grassi
Ospedale degli Infermi ASL 12, Biella (1): A. Monaco
Ospedale SS Trinità, Borgomanero (1): P.G. Fornara.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank all of the women who participated in this trial. We also thank all the research staff at centers who helped to recruit patients and provide data.
NOTES
Support for data management was provided by Fondazione Mattioli.
Presented in part at the 39th Annual Meeting of American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Istituto di Ricerche Farmacologiche "Mario Negri"
European Institute of Oncology, Milan
Cervello Hospital, Palermo
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, University of Turin
Gynecological Oncology Department, Mauriziano Umberto I Hospital Mauriziano Hospital, Turin
Department of Gynecology and Obstetrics, University of Brescia
Clinica Malzoni, Avellino
Cannizzaro Hospital, Catania
ABSTRACT
PURPOSE: Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival.
PATIENTS AND METHODS: Patients (n = 219) were randomly assigned to ifosfamide 5 g/m2 during 24 hours plus cisplatin 75 mg/m2, or paclitaxel 175 mg/m2 plus ifosfamide 5 g/m2 during 24 hours and cisplatin 75 mg/m2 every 3 weeks for three courses.
RESULTS: Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%
odds ratio, 3.22
95% CI, 1.69 to 5.88
P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75
95% CI, 0.48 to 1.17
P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66
95% CI, 0.39 to 1.10
P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88
95% CI, 2.50 to 13.84
P < .0001).
CONCLUSION: The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.
INTRODUCTION
At present, concomitant chemoradiotherapy is considered the standard treatment of locally advanced cervical cancer. The 1999 National Cancer Institute Alert strongly supported its use in all patients with cancer of the uterine cervix requiring radiation, and a meta-analysis pooling the data on 4,580 patients from 19 randomized trials showed a highly significant absolute survival improvement of 12% in favor of concurrent chemoradiotherapy compared with radiotherapy alone.1,2 Neoadjuvant chemotherapy may represent an alternative to surgery and irradiation as initial treatment of locally advanced cervical cancer. There are several potential benefits of such an approach: it can eradicate or biologically alter micrometastases, debulk the tumor, and thus render inoperable tumors (International Federation of Gynecology and Obstetrics [FIGO] stages IIB to IIIB) operable or improve the outcome of radiotherapy. Finally, when a pelvic recurrence occurs, the morbidity of salvage surgery after radiotherapy has failed is often higher than the morbidity of salvage radiotherapy after neoadjuvant chemotherapy followed by radical surgery has failed. The advantages of downstaging the disease without the use of irradiation are tempting and open a completely new philosophy of radical treatment for locally advanced cervical cancer.
Several compounds have been tested in squamous cell carcinoma. Cisplatin and ifosfamide are considered among the most active drugs in both neoadjuvant and salvage treatments.3-6
The publication of the large randomized trial by Omura et al,7 in which 454 patients with advanced squamous carcinoma were assigned to receive cisplatin, cisplatin plus ifosfamide, or cisplatin plus mitolactol, immediately preceded the inception of our study. This trial showed that the cisplatin plus ifosfamide combination had a significantly higher response rate (31.1% v 17.8%
P = .004) and a significantly longer progression-free survival (P = .003) compared with cisplatin alone, albeit with more toxicity and no overall survival benefit. Paclitaxel has proven effective in several squamous cell human carcinomas,8 and promising results have been presented for cervical carcinoma as a single agent or in combination with a platinum compound both in the neoadjuvant and salvage settings.9,10
To determine the optimal neoadjuvant drug regimen in the treatment of locally advanced squamous cell cervical carcinoma, we set up this multicentric randomized trial aimed at comparing the three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) with a two-drug regimen of cisplatin and ifosfamide (IP). The purpose of this trial was to select the best drug combination as a basis to compare the neoadjuvant chemotherapy followed by radical surgery versus concomitant chemoradiotherapy, which represents the current standard of treatment in this subgroup of patients. This trial also aimed to validate our previous findings, which showed that the achievement of an optimal response (OR
ie, complete response [CR] or partial response [PR] with microinvasive residual lesion [< 3 mm] on histology) after neoadjuvant chemotherapy was a significant prognostic factor and a possible candidate as a surrogate end point for survival.11 The 3-mm threshold used to set the lowest limit of the OR category was chosen because it represents the maximal extension of FIGO stage IA1 cervical tumor, which is usually considered cured after local resection, and the prognosis of which is exceedingly good.
PATIENTS AND METHODS
Eligibility and Random Assignment
Pretreatment evaluation included history, physical examination, biopsy, complete blood analysis, and chest x-ray. Tumor imaging by means of magnetic resonance imaging (MRI) and urography were done to determine the extent of disease and to assess renal function. Patients with histologically confirmed locally advanced squamous cervical carcinoma (FIGO stage IB2 to IVA)12 were eligible for the study. Additional eligibility criteria included WHO performance status 2
adequate bone marrow reserve (absolute granulocyte count 2,000/μL, platelet count 100,000/μL)
adequate renal, hepatic, and cardiac function.
Approval to conduct the study was obtained independently from an internal review board at each participating institution. Informed consent was obtained from all patients in accordance with local and national legislation. Randomization with equal probability of assignment to each treatment arm (IP versus TIP) was carried out by telephone at the Mario Negri Institute (Milan, Italy) by a block arrangement balancing the treatment assignment within FIGO stage and tumor grade.
Chemotherapy Regimens
The TIP regimen was administered as follows: paclitaxel was given at the dose of 175 mg/m2 as a 3-hour infusion. Premedication given to reduce the risk of paclitaxel hypersensitivity was as follows: methylprednisolone 250 mg intravenously 60 minutes before and chlorpheniramine 10 mg and cimetidine 300 mg intravenously 30 minutes before treatment delivery. After a bolus of mesna 400 mg/m2 intravenously, ifosfamide 5 g/m2 and mesna 5 g/m2 were infused intravenously during 24 hours in 1 L of normal saline, followed by mesna 3 g/m2 given intravenously in 1 L of normal saline during 24 hours. Hydration with 3 L of 5% dextrose solution during 24 hours was infused simultaneously. Cisplatin 75 mg/m2 was administered on day 2 as a 60-minute infusion after prehydration with 1 L of normal saline added with 10 mEq/L of potassium chloride and 10 mEq/L of MgSO4, and was followed by post-hydration with 1 L of 5% dextrose solution added to 20 mEq/L of KCL and 20 mEq/L of MgSO4 given during 2 hours. In the IP regimen, the two drugs (ifosfamide and cisplatin) were given as in the TIP regimen. In both arms, treatment was administered every 3 weeks for a total of three courses.
Treatment Modifications
CBCs were performed weekly or more often if toxicity occurred
evaluation of renal and hepatic function was repeated before each cycle.
Treatment administration was based on evaluation of blood cell count before the start of each cycle. Treatment was administered if the absolute granulocyte count was 1,500/μL and the platelet count was 100,000/μL. Treatment was to be delayed week to week until minimum hematologic parameters were met. After two consecutive treatment delays, on the basis of physician judgment, treatment was either interrupted or continued with the support of recombinant human granulocyte colony-stimulation factor in instances of persistent grade 4 myelotoxicity. In the latter case, ifosfamide was to be reduced to 25% of the initial dose. Delays were not permitted other than for documented toxicity.
Treatment After Neoadjuvant Chemotherapy and Evaluation of Response
Tumor extension was assessed clinically and by MRI after three courses and all patients deemed operable underwent radical hysterectomy13 and pelvic lymphadenectomy within 3 or 4 weeks after the administration of the third cycle. Patients with inoperable tumors because of progression after adjuvant chemotherapy were offered radical radiotherapy. Clinical responses were determined according to the WHO criteria.14 Pathologic responses were defined as follows: OR included a complete disappearance of tumor in the cervix with negative nodes (CR), or a residual disease with less than 3 mm stromal invasion including in situ carcinoma (PR1)
suboptimal response consisted of persistent residual disease with more than 3 mm stromal invasion on surgical specimen (PR2). Women with positive nodes, parametrial involvement, cut-through or suboptimal response, or OR but still with positive nodes underwent additional treatment (external-beam irradiation or chemoradiotherapy). Patients who achieved an OR (CR + PR1) received two additional courses of chemotherapy after surgery with the same agents used in neoadjuvant treatment.
Toxicity Assessment
All patients who had received at least one cycle were assessable. Toxicity was graded according to WHO criteria.14
Follow-Up Procedures
Patients were monitored for assessment of disease status 1 month after the end of treatment and every 3 months thereafter. Monitoring comprised pelvic examination and vaginal cytology
MRI or computed tomography scan of the pelvis and abdomen and chest x-ray were performed every 6 months for 2 years and once a year thereafter.
Statistical Methods
This was a randomized, multicentric, phase II study aimed at comparing the activity and toxicity of TIP versus IP in the neoadjuvant setting for patients with locally advanced squamous cell cervical cancer.
The primary efficacy parameter was the OR (CR + PR1) rate. Secondary end points were overall survival and disease-free survival.15 The accrual goal was set at 206 patients. This sample size would provide a statistical power of 80% to detect a 20% increase in response rate when testing at the .05 level (two-sided test).
Response to chemotherapy treatments was compared using a multiple logistic regression model with a dichotomous dependent variable: OR (CR + PR1) versus PR2/stable disease/progressive disease. Independent variables included treatment arm and stage of disease. The response odds ratio was defined as the odds of achieving OR in the TIP group divided by the odds of achieving OR in the IP group. As a consequence, an odds ratio larger than unity indicates that the TIP treatment is associated with an increase in the probability of OR compared with IP treatment.
Comparisons of the rates of OR and maximum grade of toxicity between the two arms were carried out by use of a two-sided 2 test or a two-sided Fisher's exact test if the number of patients in a given category was five or fewer.
Overall survival was defined as the time from random treatment allocation to death as a result of any cause
patients known to be alive at the time of analysis were censored at the time of their last contact. Progression-free survival was defined as the time from randomization to first appearance of progressive disease or death as a result of any cause
patients known to be alive and without progressive disease at the time of analysis were censored at the time of their last contact.
We compared Kaplan-Meier curves for overall survival and progression-free survival using the log-rank test.16 The proportional-hazards regression model17 was also used for progression-free and overall survival to estimate the treatment-related hazard ratios (HRs) while adjusting for other pretreatment factors. To verify if neoadjuvant regimens exert their effect on survival through improvements in tumor shrinkage, we used a multivariate Cox regression model containing the candidate surrogate end point (OR) and the treatment received. If OR is a surrogate end point, then the survival becomes independent of the treatment received, and therefore the treatment HR would change approaching unity (ie, no treatment effect).
All analyses were done on an intention-to-treat basis except for the analyses of toxicity. The latter analyses were restricted to all patients who received at least one cycle of allocated treatment. All P values are two-sided. Analyses were carried out using SAS software (Version 8.20
SAS Institute, Cary, NC)
RESULTS
April 1997 to January 2000, 219 patients entered the SNAP01 (Studio Neo-Adjuvante Portio) randomized trial from 21 Italian centers. Of the 219 patients, 113 were assigned to receive the IP combination regimen and 106 patients received the TIP combination regimen. Fifteen patients were excluded from the analysis because of eligibility criteria violations (five in the IP arm and 10 in the TIP arm
reasons for ineligibility are listed in Fig 1 18).
As shown in Table 1, both groups were well matched for age, WHO performance status, FIGO stage, tumor grade, and proportion of patients with radiologic lymph node involvement at random assignment.
Compliance and Toxicity
We collected full details about the IP and TIP treatments received by 103 (95%) and 94 (98%) patients, respectively. Similar proportions of patients in each arm completed the planned treatment (90% in the IP group and 94% in the TIP group), but 18% of patients did so with some dose adjustment or delay in the IP arm compared with 35% of patients in the TIP group.
No differences emerged between the median cisplatin and ifosfamide dose given per cycle in the IP arm and in the TIP arm: 74.6 mg/m2 (25th to 75th percentiles, 72.7 to 75.3 mg/m2) v 73.6 mg/m2 (25th to 75th percentiles, 66.7 to 75.0 mg/m2) and 5.0 g/m2 (25th to 75th percentiles, 4.9 to 5.0 g/m2) v 4.9 g/m2 (25th to 75th percentiles, 4.6 to 5.0 g/m2), respectively. Median paclitaxel dose was 173.6 mg/m2 (25th to 75th percentiles, 169.2 to 175.0 mg/m2).
Analysis of toxicity was performed in 194 patients receiving their initial chemotherapy regimen. Toxicity data are listed in Table 2.
Hematologic toxicity was relevant in both arms. TIP was associated with significant higher rates of grade 3 or 4 hematologic toxicity than the IP schedule (P = .02). Nausea and vomiting were similar in both arms. As expected, more patients in the TIP group experienced neurosensory symptoms.
In this study population, we recorded four (2%) deaths related to toxicity: three patients received the IP schedule and one patient received the TIP regimen. Three women received just one cycle of chemotherapy before death.
The first patient was a 71-year-old woman with a stage IB2 cervical cancer. At enrollment, all of the eligibility criteria were met and she was randomly assigned to TIP, although because of unspecified clinical considerations, she received the IP schedule. Nine days after the first course, she experienced severe thrombocytopenia and neutropenia and she died as a result of acute cardiovascular complication 10 days after the first course.
The second patient was a 74-year-old woman with stage IIB cervical cancer. She was randomly assigned to receive IP treatment. After the first course of chemotherapy she developed severe hematologic toxicity with bone marrow aplasia, and she died as a result of acute renal failure 2 weeks later.
The third patient was a 75-year-old woman with stage IIIB cervical cancer. She was enrolled onto the study to receive TIP schedule and completed the three courses of chemotherapy with reduction of doses because of grade 4 neutropenia and thrombocytopenia after the first course. She died 10 days after the last cycle as a result of hematologic toxicity and renal failure.
The fourth patient was a 29-year-old woman who had hepatitis C virus with a stage IIB cervical cancer. Her liver and renal parameters were in the normal range at the time of enrollment and she was assigned to the TIP arm, but received the IP schedule for unspecified clinical considerations. Seven days after the first course she experienced fever, diarrhea, and severe granulocytopenia. Within 15 days she also developed renal and liver failure. She died as a result of bone marrow aplasia 3 weeks and 1 day after the first course.
Effect of Treatment on Tumor Response
One hundred eighty-nine of 204 fully eligible patients (93%) were assessed for clinical response (100 in the IP arm and 89 in the TIP arm
Fig 1).
The proportion of patients assessable for pathologic responses who underwent surgical interventions after chemotherapy was 94% (90% in the IP group and 98% in the TIP group)
surgery was not performed in 11 patients because of minimal clinical response, stable disease, or overt clinical progression, and in two patients because of patient refusal. Five of those patients who achieved a clinical PR were considered to have had a suboptimal response (PR2). Three to 4 weeks after completion of neoadjuvant chemotherapy, all but three of the operable women underwent radical surgery to include pelvic bilateral lymphadenectomy that was tailored on the basis of the anatomic state of patients. Of the 176 operated patients, 141 underwent a Meigs-Magara or type III Piver-Rutledge radical hysterectomy, 33 underwent a Wertheim or type II Piver-Rutledge radical hysterectomy. Two women underwent total simple hysterectomy because of local extension of disease and bulky lymph node metastases. No significant differences in the surgical approach emerged between the two treatment groups.
The OR rate in the IP group was 23% (9% CR, 14% PR1), and it was 48% (20% CR, 28% PR1) in the TIP group (P = .0004, 2 test
Table 3). The overall OR odds ratio showed a highly significant benefit of TIP over IP in a logistic multivariate analysis that contained stage as a covariate (odds ratio, 3.2
95% CI, 1.69 to 5.88
P = .0003). Twenty-six percent of patients with stage Ib2 in the IP arm had an OR
58% of patients with stage Ib2 had an OR in the TIP arm. In patients with stage IIa or IIb, the OR rate was 25% in the IP group and 47% in the TIP group
in patients with stage III to IVa, the OR rate was 7% and 17%, respectively.
Information about postoperative radiation therapy was known for 182 patients (96%). Two of the 43 patients who achieved OR in the TIP arm (5%) and none of the 22 patients in the IP arm underwent postoperative radiotherapy. Among the 45 patients who did not achieved OR on TIP, 28 had postoperative radiotherapy (62%) and a similar proportion (49 of 72
68%) of patients had radiotherapy in the IP treatment group.
Effect of Treatment on Progression-Free and Overall Survival
At a median follow-up of 43 months (25th to 75th percentiles, 31 to 56 months), 79 women have experienced progression of disease or died (46 patients in the IP arm, 33 patients in the TIP arm). The sites of recurrence are listed in Table 4. The plots of the cumulative proportion of patients surviving progression-free for the two treatments are displayed in Figure 2. Those patients receiving TIP experienced a 25% lower rate of treatment failure than those receiving IP but this difference was not statistically significant (HR, 0.75
95% CI, 0.48 to 1.17
P = .20). At the time of this analysis, 61 patients have died (37 patients in the IP arm, 24 patients in the TIP arm). Figure 3 depicts the overall survival curves for the two treatments. Comparison of the survival curves showed a statistically insignificant HR of 0.66 in favor of TIP (95% CI, 0.39 to 1.10
P = .11). The difference in the overall death rates between treatment groups remained practically unchanged, and still was statistically insignificant when stage, age, and lymph node status at randomization were taken into account in a Cox regression analysis (Table 5).
Evaluation of Tumor Response As a Surrogate End Point for Survival
A Cox multivariate regression model was used to assess if OR (CR + PR1) is a prognostic factor for survival. In the subset of the 189 patients assessable for response, data in Table 6 show that relative to the OR group, the average death rates are much greater in the suboptimal response group (HR, 5.88
95% CI, 2.50 to 13.84
P < .0001). In the subset of patients assessable for response, the HR favoring the TIP regimen was 0.55 (95% CI, 0.32 to 0.94
P = .030). When tumor response and treatment arm were added to the model, the HR in favor of TIP decreased to 0.80 (95% CI, 0.46 to 1.41
P = .447), thus indicating that although a residual benefit beyond that captured by response was still attributable to treatment, such a benefit no longer appeared to be statistically significant.
DISCUSSION
This multicenter randomized trial strongly suggests that the neoadjuvant three-drug combination containing paclitaxel (TIP) is more active than the two-drug regimen (IP) in terms of response rates, although the relative hazard of first progression or death is not significantly different between the treatment groups. This study also confirms that the achievement of OR is a good prognostic factor and may be a surrogate end point for survival in this clinical setting.
The OR rate for those receiving the TIP combination was more than twice that observed with IP, and although this study was not powered to detect either progression-free or overall survival differences, the effect on both was in the direction of statistical significance. Only one occurrence of progressive disease was observed in those patients receiving TIP. These findings are in keeping with the pilot study by Zanetta et al10 that enrolled 38 patients with locally advanced cervical cancer treated with TIP. These investigators observed that the TIP regimen not only yielded a promising 84% objective response rate, but also that the OR rate achieved with TIP (34%) was higher than that observed by the same investigators on similar patients who had received the cisplatin, bleomycin, and vincristine regimen (19%).11 The results of our study confirm that the TIP regimen is one of the most active neoadjuvant chemotherapeutic regimens,19 although hematologic toxicity associated with this treatment is considerable and was significantly higher than that with the IP regimen. Nonetheless, three of the four deaths as a result of toxicity that occurred in this study were attributed to IP and only one death was attributed to TIP. Three of these patients were older than 70 years and one presented with stage IIIB disease based on ureteral obstruction. Such findings suggest that women older than 70 years or with renal comorbidity secondary to ureteral obstruction probably should not be treated with intense neoadjuvant chemotherapy. Although TIP has proved to be active in locally advanced cervix cancer as a neoadjuvant regimen, there is an urgent need for new chemotherapeutic regimens with similar efficacy but less toxicity. To resolve this issue, the SNAP02 multicentric trial ongoing in Italy will compare the TIP schedule (which emerged as the more successful treatment arm of our current study) with the paclitaxel-cisplatin combination. The SNAP02 study is specifically meant to better define the role of ifosfamide in preoperative chemotherapy in terms of added activity and toxicity.
The neoadjuvant setting simplified validation of the intermediate outcome of OR rate as a surrogate for survival. It was possible to evaluate the effect of achieving optimal tumor response on survival without running the risk of introducing a well-known bias into the analysis: patients who survive a sufficient duration to have an opportunity to experience a response will have a predictably longer survival than will other patients, even if the therapy has no effect on survival. In fact, the short duration of chemotherapy and the homogeneous time point of response assessment (ie, surgery) allowed the use of a standard Cox multivariate model to analyze the prognostic effect of OR on survival.
Optimal pathologic response (OR) turned out to be a strong independent predictor of survival (HR, 5.88
95% CI, 2.50 to 13.84
P < .0001), whereas standard objective response (CR + PR1 + PR2) was not. Previous reports were able to detect a link between response criteria that are stricter than the standard CR + PR and overall survival. Kim et al20 described a 100% 2-year survival rate in 22 patients achieving a complete or optimal partial pathologic response (only microscopic foci of residual tumor) after neoadjuvant treatment, irrespective of the stage. Giaroli et al21 reported a 2-year disease-free interval of 97.7% in 43 patients with CR or residual tumor smaller than 5 mm in diameter. Panici et al22 found that only one of 20 patients with depth of cervical infiltration less than 5 mm experienced recurrence, compared with 11 of 42 with deeper invasion. In a retrospective analysis of the database of two large Italian gynecologic-oncologic departments, Colombo et al11 observed that the achievement of a pathologically documented CR or an optimal partial response with a residual tumor 3 mm was indeed an independent favorable prognostic factor for survival (when patients received neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin).
In our study we also found evidence that the OR was a surrogate end point of survival
that is, the gain in survival brought about by TIP was mediated through improvements in optimal tumor response. In fact, when the multivariable Cox regression model exploring the influence of treatment on survival was adjusted for OR, the treatment HR shifted toward unity. This analysis showed that survival was still statistically associated with the surrogate end point but no longer associated with the initial treatment. If OR is a good predictor of survival and a surrogate end point for treatment, then it can be used to more quickly obtain information about the efficacy of a new treatment. That would increase the efficiency of design and management of randomized trials comparing different therapeutic options. For example, a smaller sample size and a shorter follow-up could be used if the power calculation for the study were based on the surrogate marker rather than on survival. The difference in OR could be monitored as an early indictor of the presence or absence of a treatment difference with respect to survival duration.
A recent meta-analysis23 collected individual patient data from 21 randomized trials of neoadjuvant chemotherapy in locally advanced cervical cancer. This analysis included data for comparison of the benefits of neoadjuvant chemotherapy followed by radical radiotherapy versus radical radiotherapy alone (2,074 patients), and for comparison of neoadjuvant chemotherapy followed by surgery (± radiotherapy) versus radical radiotherapy alone (872 patients). The first comparison was hindered by heterogeneity between trials and gave conflicting results depending on how trials were grouped by chemotherapy cycle length or dose-intensity. The second comparison showed that patients treated with neoadjuvant chemotherapy had a highly significant 35% reduction in the risk of death (P = .0004) that translated into a 14% absolute increase in 5-year overall survival. The protocol of this large meta-analytic project was finalized in 1999 when radiotherapy was still the standard treatment. Meanwhile, as mentioned, concurrent chemoradiotherapy has become the treatment of choice and the proper comparator for neoadjuvant chemotherapy. The new challenge in clinical research is the management of randomized trials comparing neoadjuvant chemotherapy with the standard represented by concomitant radiochemotherapy
such a trial has been designed and proposed from the European Organisation for Research and Treatment of Cancer, and currently is recruiting patients. Until the results of this direct comparison are published, no new evidence-based paradigms can be formulated to govern the treatment of locally advanced cervical cancer.
Appendix
The following institutions and consultants contributed patients to SNAP01 protocol (the number in parentheses indicates the number of patients enrolled): Ospedale San Gerardo dei Tintori, Monza (107): C. Bonazzi, A. Maneo, A. Pellegrino, G.M. Zanetta (deceased)
Istituto Europeo di Oncologia, Milano (27): G. Parma
Casa di Cura Malzoni, Avellino (12): M. Balestrino (deceased), A. Vernaglia Lombardi, Ospedali Civili, Brescia (12): A. Gambino
Ospedale Mauriziano, Torino (11): A.M. Ferrero
Dipartimento Discipline Ginecologiche e Ostetriche, Università di Torino, Torino (9): R. Bellino, I.A. Rigault de la Longrais
Ospedale V. Cervello, Palermo (7): D. Gueli Alletti, F. Lionti
Divisione di Ginecologia, Ospedale Chiavari-Lavagna (5): D. Dodero, M.G. Centurioni
Clinica Mangiagalli, Milano (4): R. Maggi, R. Carlini
Ospedale Cannizzaro, Catania (4): G. Scibilia
Ospedale Maggiore, Lodi (3): M. Luerti
Ospedale Sant'Orsola, Bologna (2): A. Martoni
Dipartimento di Oncologia, Ospedale Ramazzini, Carpi (2): F. Artioli
Ospedale Valduce, Como (2): R. Colleoni
Azienda Ospedaliera Universitaria S. Anna, Ferrara (2): R. Martinello
Ospedale Civile, Padova (2): T. Maggino
Policlinico Umberto I, Università La Sapienza, Roma (2): L. Marzetti
Ospedale Regionale S. Chiara, Trento (2): C. Arcuri
Azienda Ospedaliera Treviglio (2): R. Grassi
Ospedale degli Infermi ASL 12, Biella (1): A. Monaco
Ospedale SS Trinità, Borgomanero (1): P.G. Fornara.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank all of the women who participated in this trial. We also thank all the research staff at centers who helped to recruit patients and provide data.
NOTES
Support for data management was provided by Fondazione Mattioli.
Presented in part at the 39th Annual Meeting of American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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