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Keywords:

  • carboplatin;
  • cervical cancer;
  • neoadjuvant chemotherapy;
  • paclitaxel;
  • weekly schedule

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

The efficacy and toxicity of neoadjuvant carboplatin and paclitaxel administered on a weekly schedule for locally advanced cervical carcinoma were evaluated. Thirty patients staged as IB2–IVA according to the FIGO were treated with carboplatin (AUC 2; an area under the time-concentration of 2 mg*min/ml based on creatinine clearance) and paclitaxel (60 mg/m2) intravenously, every week for six cycles. A type III radical hysterectomy was then undertaken. Thirty patients were enrolled in this study. An objective response was recorded in 26 patients (87%, 95% CI 70–95%). Progressive disease was not observed. Grade 3 neutropenia was observed in only two patients (7%), and grade 1 or 2 neuropathy was seen in six patients (20%). The combination of carboplatin and paclitaxel given in weekly schedule for advanced cervical carcinoma was highly active, permitting a high rate of subsequent surgical resectability. It was well tolerated. This regimen may provide improved outcomes with minimal toxicity.

Uterine cervical carcinoma remains one of the most common malignancies of women(1). Frustratingly, the survival rate of patients with locally advanced cervical carcinoma has not improved significantly. In an effort to increase survival rates, different strategies for cervical carcinoma have been developed.

Five randomized studies published in 1999–2000 demonstrated that survival with radiation therapy alone is inferior to radiation therapy with concomitant cisplatin-based chemotherapy(2–6). Furthermore, a meta-analysis based on 4580 patients from 19 trials showed that chemoradiation represents an absolute gain of 12% in 5-year survival(7). Thus, it became generally accepted in the United States that cisplatin-based chemoradiation was the standard therapy for advanced cervical carcinoma. However, some question this conclusion from the aspect of irradiation dose, interval, toxicities, and so on(8,9).

A meta-analysis of neoadjuvant chemotherapy followed by radical hysterectomy based on 872 patients has demonstrated an absolute benefit of 14% in 5-year survival(10). The investigators also suggested that a shorter, more dose-intensive regimen might be more effective.

Cisplatin has been the key drug of neoadjuvant chemotherapy for locally advanced cervical carcinoma(11–15). Recently, new anticancer drugs, including irinotecan, the taxanes, and gemcitabine, have been introduced and combined with a platinum-containing drug, producing higher response rates(16–21). The combination of cisplatin and paclitaxel has demonstrated significant activity in cervical cancer patients with advanced or recurrent disease, with response rates between 40% and 50%(22,23). Duenas-Gonzalez et al.(20) reported that neoadjuvant chemotherapy with carboplatin and paclitaxel (three cycles every 3 weeks) followed by radical hysterectomy produced a high response rate. Park et al.(21) also reported that neoadjuvant cisplatin and paclitaxel (three 10-day cycles) could be highly active.

In this study, we delivered a course of neoadjuvant carboplatin and paclitaxel consisting of six cycles given weekly to evaluate efficacy and tolerability, aiming for a well-tolerated and dose-intensive regimen, allowing for an uncomplicated transition to surgery.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Patient selection

Thirty untreated patients with a histologic diagnosis of cervical carcinoma of the nonsmall cell type (squamous cell carcinoma [SCC], adenosquamous cell carcinoma, and adenocarcinoma) were included in this study. Inclusion criteria were as follows: (1) clinically staged as IB2–IVA according to the FIGO; (2) bidimensionally measurable lesion; (3) aged 25–75 years; (4) performance status 0–2 according to World Health Organization criteria; (5) normal hematologic, renal, and hepatic function as determined by a hemoglobin 9 g/dL, leukocyte 4000/mm3, platelet count more than 100,000/mm3, total bilirubin less than 1.5 × normal upper limit, AST (asparate transaminase) and ALT (alanine transaminase) less than 1.5 × normal upper limit, and normal serum creatinine level; (6) no heart or lung disease by clinical examination; (7) no active infection; (8) no preexisting peripheral neuropathy of any cause more than grade 1.

The protocol was approved by the institutional review board. All patients or their families were required to provide informed consent before entry into this study.

Treatment regimen

This chemotherapy involved a combined regimen of paclitaxel (60 mg/m2) and carboplatin AUC 2 (an area under the time-concentration of 2 mg min/mL based on creatinine clearance). Paclitaxel was administered as a 1-h intravenous infusion followed by carboplatin, also as a 1-h infusion on day 1 of every 7-day cycle. All patients received standard premedication before paclitaxel (20 mg dexamethasone and 300 mg cimetidine by intravenous infusion, and 50 mg diphenhydramine given orally). All patients received prophylactic antiemetic agents for 3 days.

The treatment was delayed for 1 week if the neutrophil count was less than 1500/mm3 and/or the platelet count was less than 50,000/mm3 on day 1 of each cycle. If grade 4 neutropenia persisted for more than 5 days or grade 4 thrombocytopenia arose, the treatment was postponed until recovery. The use of granulocyte colony–stimulating factor was prohibited.

A radical hysterectomy was performed 6 days after the final chemotherapy infusion.

Patient evaluation

Patients who received all six cycles of chemotherapy were evaluated for response to the neoadjuvant chemotherapy by pelvic examination and magnetic resonance imaging. The measurement of response was based on the two longest perpendicular diameters. Criteria for tumor response were as follows: complete response (CR) was defined as the complete disappearance of all measurable disease. Partial response (PR) was defined as more than 50% reduction of the sum of the products of the measurable lesions. Progressive disease (PD) was defined as more than 25% increase in the sum of the products of the measurable lesion or the appearance of any new ones. Stable disease (SD) was defined by any situation that did not qualify as response or progression.

The serum squamous cell carcinoma–associated antigen (SCC antigen) level was measured before the first treatment and after the final treatment.

Toxicities were evaluated by use of the NCI-CTC (National Cancer Institute-Common Toxicity Criteria) version 2.

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Between December 2002 and January 2006, 30 patients were enrolled in this study. Patient characteristics are shown in Table 1. The median patient age was 60 years (range 29–74 years). Twenty-six patients had SCC (87%), three had adenocarcinoma (10%), and one patient had adenosquamous cell carcinoma (3%). Fourteen patients had stage IIB (47%), 11 patients had IB2–IIA (37%), and 5 had IIIA–IVA (17%). Twenty-eight of all patients enrolled in this study could undergo type III radical hysterectomy (93%) and all could be debulked, one of the remaining two patients underwent radiotherapy because of her refusal of surgery and the other could not undergo any further therapy for cervical carcinoma because of acute generalized peritonitis induced by diverticulitis. Chemotherapy was not delayed or abandoned in any patient.

Table 1.  Patient characteristics
Characteristicsn (%)
Entered on study30 (100)
Age (years)
 Median60
 Range29–74
Performance status
 026 (86.7)
 14 (13.3)
FIGO stage
 IB27 (23.3)
 IIA4 (13.3)
 IIB14 (46.7)
 IIIA1 (3.3)
 IIIB4 (13.3)
Histologic type
 Squamous cell26 (86.7)
 Adenocarcinoma3 (10.0)
 Adenosquamous1 (3.3)

Response to treatment

Objective response (CR + PR) to the treatment was recorded in 26 patients (87%) (95% CI, 70% to 95%). CR was observed in two patients (7%), one of these had pathologic CR, while PD was not shown in this treatment (Table 2). Downstaging response occurred in four patients (13%); one patient from stage IIIB to IIB, one from stage IIIA to IIB, one from IIB to CR, and one from IIB to pathologic CR. Tumor shrinkages were seen in all patients to some degree or another during treatment. Twenty-six patients had positive serum SCC antigen levels (>1.5 ng/mL) before treatment (87%), and 22 of them demonstrated a reduction after treatment (Fig. 1). None of the other four patients showed an increase of serum SCC antigen. The mean serum SCC antigen after this treatment was 3.24 ng/mL, which was significantly lower (P < 0.05) than that before this treatment (15.6 ng/mL).

Table 2.  Response according to stage
StageNumber of patientsCRPRSDPD
IB2–IIA1101010
IIB142930
IIIA-IVA50500
All3022440
image

Figure 1. The difference of SCC antigen before and after treatment. Twenty-six patients had positive serum SCC antigen levels (>1.5 ng/mL) before treatment (86.7%), and 22 of them had reduced serum SCC antigen level after treatment. None of the other four patients showed an increase of serum SCC antigen. The mean serum SCC antigen after this treatment was 3.24 ng/mL, which was significantly lower (P < 0.05) than that before this treatment (15.6 ng/mL). The statistical difference was determined by two-sided paired t test. Difference with P < 0.05 was considered significant.

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Toxicity

Table 3 shows the toxicities encountered during treatment. Most patients had only grade 1 or 2 toxicity. Neutropenia occurred in 13 patients (43%), but grade 3 neutropenia was seen only in two patients (7%). Grade 1 neuropathy was seen in six patients (20%). Alopecia was seen in 27 patients (90%). Other severe (grade 3 or more) toxicities were not observed.

Table 3.  Toxicity by use of the NCI-CTC version 2
ToxicityGrade 0 (%)1 (%)2 (%)3 (%)4 (%)
Hematologic
 Anemia22 (73.3)6 (20)2 (6.7)0 (0.0)0 (0.0)
 Neutropenia17 (56.7)6 (20.0)5 (16.7)2 (6.7)0 (0.0)
 Thrombocytopenia28 (93.3)2 (6.7)0 (0.0)0 (0.0)0 (0.0)
Nonhematologic
 Nausea23 (76.7)7 (23.3)0 (0.0)0 (0.0)0 (0.0)
 Taste disorder21 (70.0)9 (30.0)0 (0.0)
 Neuropathy24 (80.0)6 (20.0)0 (0.0)0 (0.0)0 (0.0)
 Alopecia3 (10.0)23 (76.7)4 (13.3)

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Although many investigators have reported high response rates with neoadjuvant chemotherapy for locally advanced cervical carcinoma, it remains controversial whether this tactic improves prognosis. Consequentially, the European Organization for Research and Treatment of Cancer (EORTC) is conducting a randomized phase III trial of neoadjuvant chemotherapy followed by surgery versus concomitant chemoradiation therapy in FIGO stage IB2–IIB cervical SCC and adenocarcinoma.

Paclitaxel is considered as one of the most active cytotoxic agents in the treatment of ovarian, breast, and lung carcinoma(24) and has been incorporated as a component of initial therapy of the other malignancies. The combination of paclitaxel and cisplatin has demonstrated significant activity in patients with advanced or recurrent cervical carcinoma achieving response rates between 40% and 50%(22). It has been suggested that carboplatin, an analogue of cisplatin, causes similar response to cisplatin in the treatment of gynecological malignancies including cervical carcinoma and less toxicity than cisplatin(25). Duenas-Gonzalez et al.(20) reported that neoadjuvant chemotherapy for locally advanced cervical carcinoma treated with three 3-week courses of carboplatin (AUC 6) and paclitaxel at 175 mg/m2 by 3-h infusion demonstrated highly active treatment. Markman et al.(26) reported that the administration of paclitaxel for ovarian carcinoma on every 1-week schedule, rather than the standard every 3-week schedule, might produce greater tumor cell death. In addition, Green et al.(27) reported that paclitaxel regimen had a higher pathologic CR rate than patients with paclitaxel on an every 3-week program with breast cancer conservation rates, and also in breast carcinoma, it has been shown that higher pathologic response rate with neoadjuvant chemotherapy correlates with better survival. Therefore, we hypothesized that neoadjuvant carboplatin and paclitaxel administered weekly with a shorter cycle length and dose intensity for patients with locally advanced cervical cancer would be an ideal regimen. Our present study was designed to examine the efficacy and tolerability.

The overall response rate of this study was 87%, a result similar to those previously reported. A decrease of SCC antigen by this treatment, the tumor marker which correlates with the tumor load(28), was seen in all with measurable disease. No PD was seen during the course of chemotherapy, demonstrating the safety of this regimen. The greater dose-intensity of this regimen, when compared to 3-week schedule, may account for this favorable result. A radical hysterectomy could be performed in 93% of patients, and all could be completely resected. This approximates the operability and respectability results reported for the every 3-week schedule(20). This high rate of resectability might improve prognosis.

We included patients with stage III and IV in this study because there were many previous reports that included them, and it also seemed effective if they achieved downstaging response. However, patients with stage III and IV did not obtain benefits of NAC (neoadjuvant chemotherapy) as Benedetti-Panici et al mentioned(15). Concurrent chemoradiation has been the standard of care in many countries for advanced cervical cancer patients, especially stage III and IV. Futhermore, in ongoing NAC study, stages III and IV are not eligible. In our study, there were only two patients who could obtain downstaging from stage III to II. Therefore, now we need to reconsider the setting target of clinical stage.

A number of studies of neoadjuvant chemotherapy or concurrent chemoradiation in several tumors suggested the importance of achieving pathologic response to improve survival(29,30). Recently, according to Candelaria et al.(31), in cervical cancer patients, pathologic CR is associated with longer survival. Unfortunately, in this study, only one patient (3%) could obtain pathologic CR, which showed lower result than 17% seen with the every 3-week schedule reported by Duenas-Gonzalez. Although the other patients who had response showed pathologic PR, they could not obtain pathologic CR. This is because we speculate that the duration of this regimen, total 6 weeks, is not enough for paclitaxel to achieve pathologic CR.

This treatment was well tolerated, with none postponed or discontinued. This weekly schedule did not delay surgical treatment but rather facilitated it by reducing tumor size.

In conclusion, this weekly regimen of carboplatin and paclitaxel was highly active and permitted a higher respectability rate (90%) than previously reported. It was well tolerated. This regimen may have some possibility to minimize toxicity without lowering response rate, and we need to evaluate that this regimen improves overall survival and progression-free survival compared with the result on 3-week schedule. A pending EORTC in a randomized trial (EORTC 55994) that compares NAC followed by surgery versus concurrent chemoradiation as standard arm is expected.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References
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