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Keywords:

  • uterine cervical carcinoma;
  • intraarterial chemotherapy;
  • cisplatin;
  • nedaplatin;
  • embolization

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

Nedaplatin, a platinum analog with less renal toxicity and similar efficacy for cervical carcinoma, recently has been shown to have a synergistic effect on cervical carcinoma lines in combination with cisplatin. To determine the clinical efficacy of this combination in patients with cervical carcinoma, the authors conducted a Phase I/II study of intravenous nedaplatin and intraarterial cisplatin combined with transcatheter arterial embolization (TAE).

METHODS

Eligibility criteria were as follows: cervical carcinoma (Stages IB2–IV; International Federation of Gynecology and Obstetrics), 16–70 years of age, performance status between 0 and 2, and adequate bone marrow, renal, and hepatic function. Nedaplatin (40–70 mg/m2) was administered intravenously on Day 1 followed by intraarterial administration of cisplatin (70 mg/m2) on Day 3 via both uterine arteries by using the Seldinger method. This then was followed by TAE. This course of treatment was repeated every 3 weeks for 3 cycles.

RESULTS

Patient data were as follows: age 37–68 (median, 55 years) and Stages IB2:4, IIA:3, IIB:2, IIIA:1, IIIB:3, IVA:2 carcinoma. The response to therapy was defined by magnetic resonance imaging as follows: partial response in 60% (9 of 15) of patients, complete response in 40% (6 of 15) of patients, and an overall response rate of 100% (95% confidence interval, 78–100%). Myelosuppression was manageable. Grade 3/4 renal toxicity was observed in 2 patients who received 70 mg/m2 of nedaplatin. Thirteen patients received radical hysterectomy, 1 patient received lymph node sampling, and 11 patients received adjuvant radiotherapy or chemotherapy.

CONCLUSIONS

The maximum tolerable dose was 70 mg/m2 nedaplatin, and the dose-limiting toxicity was renal toxicity. The recommended dose was 60 mg/m2 nedaplatin intravenously followed by 70 mg/m2 cisplatin intraarterially. Intravenous nedaplatin followed by intraarterial cisplatin with TAE appears to be very effective for locally advanced cervical carcinoma. Cancer 2001;91:74–9. © 2001 American Cancer Society.

Uterine cervical carcinoma is one of the most common malignancies in women. Cervical carcinoma is classified as a chemosensitive disease. There have been many reports on the use of chemotherapy before and after surgery, as well as its use in combination with radiation therapy.1–3 Some studies have confirmed that chemotherapy improved survival compared with standard therapy,4, 5 and many investigators have reported that neoadjuvant chemotherapy is highly effective for patients with locally advanced cervical carcinoma.6, 7 All of these studies have obtained very high response rates (50–70%). Some Phase III studies also have confirmed that neoadjuvant chemotherapy improved not only the response rate but also the survival rate.4, 5

Cisplatin, both in single-agent and combination chemotherapy, has been the most effective and widely used drug for patients with cervical carcinoma. As expected, intraarterial infusion of cisplatin has shown greater efficacy than intravenous infusion8, 9 because most cervical carcinoma develops locally. However, there is no standard regimen for use in combination with intraarterial cisplatin.

Nedaplatin (glycolato-0,0′-diammine platinum (II); Shionogi Co., Ltd., Osaka, Japan), a new analog of cisplatin, has similar efficacy in the treatment of cervical carcinoma.10 In an in vitro study, the combination of nedaplatin and cisplatin showed a synergistic effect on cervical carcinoma cell lines.11 We therefore decided to conduct a Phase I/II study of a nedaplatin/cisplatin combination therapy in patients with locally advanced cervical carcinoma. However, because intraarterial infusion of nedaplatin has been shown to be less effective than intraarterial cisplatin,12 we decided to use a combination of intravenous nedaplatin with intraarterial cisplatin. Another factor in our decision was the effectiveness of intravenous chemotherapy in the treatment of lymph node metastases.13

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

All patients were treated at the Hyogo College of Medicine Hospital.

Eligibility Criteria

Patients with histologically confirmed International Federation of Gynecology and Obstetrics Stage IB2–4 cervical carcinoma14 were eligible for this study. Inclusion criteria were a performance status less than 2, younger than 70 years of age, normal bone marrow function (leukocyte count > 3.0 × 109/L; platelets > 100 × 109/L), creatinine clearance greater than 40 mL/minute, normal hepatic function (serum glutamic oxaloacetic transaminase < 2 × normal; serum glutamic pyruvic transaminase < 2 × normal), and no prior chemotherapy or radiotherapy. Exclusion criteria included concomitant malignancies and heart disease. All patients gave written informed consent. The protocol was approved by the hospital institutional review board.

Treatment Plan and Dose Escalation

On Day 1, nedaplatin was administered intravenously over 1 hour with 500 mL of saline. The starting dose of nedaplatin was 40 mg/m2; increments of 10 mg/m2 were used to establish higher dose levels (50, 60, 70 mg/m2). On Day 3, we inserted a 5-French plastic catheter from the right femoral artery by using the following method (Seldinger method) under local anesthesia. After pelvic angiography was performed, the tip of the catheter was placed in the left intrailiac artery. A 3-French polyethylene catheter then was inserted into the left uterine artery. Cisplatin was administered at a fixed dose of 35 mg/m2 via the left uterine artery. This then was followed by transcatheter arterial embolization using Gelfoam (Gelfoam; Pharmacia & Upjohn, NJ) as described in Giaroli et al.15 After embolization of the left uterine artery, the same procedure was performed and cisplatin 35 mg/m2 was administered via the right uterine artery. This then followed by transcatheter arterial embolization (TAE). Treatment was repeated every 3 weeks for 3 cycles.

Dose-limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity (leukocyte count < 1.0/L9, neutrophil count < 0.5/L9, platelet count < 25/L9), or Grade 3 or 4 nonhematologic toxicity (hepatic, renal, gastrointestinal, alopecia and neurotoxicity according to World Health Organization criteria). Dose escalation was in cohorts, not individual patients, and was permitted if no prohibitive toxicity was observed after the initial course in the last cohort treated. A minimum of three patients was treated at each dose level. If a maximum of one patient developed DLT, up to five additional patients were entered at the same dose level. The maximum tolerated dose (MTD) was defined as the dose at which greater than one-third of the patients experienced hematologic or nonhematologic DLT. The dose recommended for the Phase II study was one level below the MTD.

When the platelet count was less than 100 × 109/L, or the leukocyte count was less than 3.0 × 109/L, further treatment was withheld until recovery to 100 × 109/L or 3.0 × 109/L, respectively. In the presence of prolonged severe myelosuppression (a platelet count not > 100 × 109/L or a leukocyte count not > 3.0 × 109/L for more than 6 weeks), no further therapy was administered. When creatinine clearance was less than 40 mL/minute, no further therapy was administered. Patients were excluded from treatment if there was disease progression or unacceptable toxicity, but observed for toxicity and survival.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Fifteen patients were enrolled in this study between November 1, 1996 and July 31, 1998. All patients were examinable for toxicity and response. Forty courses of therapy were administered. The clinical features of the patients are summarized in Table 1.

Table 1. Patient Characteristics (15 Patients)
CharacteristicNo. of patients
  1. Squamous: squamous cell carcinoma; adeno-sq.: adenosquamous cell carcinoma.

Age yrs37–68 yrs (median, 50)
Stage
 IB24
 IIA3
 IIB2
 IIIA1
 IIIB3
 IVA2
Histology
 Squamous8
 Adeno-sq.3
 Adenocarcinoma4
Performance status
 010
 15
 20

Toxicity and Dose Escalation

None of the patients treated with 40 mg/m2 of nedaplatin (Patients 1–3) experienced DLT (Table 2). Accordingly, 3 patients (Patients 4–6) were treated with 50 mg/m2 of nedaplatin. Patient 5 experienced DLT (Grade 4 thrombocytopenia). Two additional patients (Patients 7 and 8) then were treated with 50 mg/m2 of nedaplatin without occurrence of DLT.

Table 2. Individual Patient Data
Patient noAge (yrs)StageHistologyDose (mg/m2)Response
  1. Adeno-sq.: adenosquamous cell carcinoma; PR: partial response; SCC: squamous cell carcinoma; adeno.: adenocarcinoma; CR: complete response.

168IVAAdeno-sq.40PR
259IIIBSCC40PR
344IB2Adeno.40CR
445IIASCC50CR
550IIIBAdeno-sq.50CR
637IB2SCC50PR
750IB2SCC50PR
860IIASCC50CR
946IIIBSCC60PR
1048IIBAdeno-sq.60CR
1153IIIAAdeno.60PR
1252IIAAdeno.60PR
1341IB2Adeno.60PR
1461IVASCC70CR
1562IIBSCC70PR

Three patients (Patients 9–11) were treated subsequently with 60 mg/m2 of nedaplatin. Patient 11 developed DLT (Grade 4 thrombocytopenia). Two additional patients (Patients 12 and 13) then were treated at 60 mg/m2 without occurrence of DLT.

Patient 14 was treated with 70 mg/m2 of nedaplatin and developed DLT (Grade 4 thrombocytopenia and Grade 4 nephrotoxicity). Patient 15 also experienced DLT (Grade 3 nephrotoxicity).

We therefore defined the MTD as 70 mg/m2 of nedaplatin and recommended that the dose for the Phase II study be set at 60 mg/m2. The data for each patient are listed in Table 2, the Grade 3/4 myelosuppression data in Table 3, and the Grade 3/4 nephrotoxicity and hepatotoxicity data in Table 4.

Table 3. Hematologic Toxicity and Dose Level
Nedaplatin (mg/m2)Patient no.LeukocytePlateletHb
4030/00/00/
5051/01/11/
6052/02/01/
7021/00/11/(Grade 3/4)
Table 4. Nonhematologic Toxicity and Dose Level
Nedaplatin (mg/m2)Patient no.RenalHepatic
4030/00/0
5050/00/0
6050/00/0
7021/11/0 (Grade 3/4)

All of the patients developed Grade 1–2 alopecia. In general, nausea and vomiting were well controlled by a 5-HT3 antagonist; Grade 3 nausea and vomiting were observed in 33% of patients (5 of 15). Neurotoxicity was minimal, and no patient experienced Grade 3 neurotoxicity or ototoxicity. All patients who developed Grade 3/4 nephrotoxicity or hepatotoxicity recovered by the next course of therapy. One patient (Patient 7) experienced hip pain after intraarterial therapy, but she did not require analgesics. All pain resolved within 1 week.

The vesical artery was mistaken for the uterine artery in one patient (Patient 12). Severe pain developed after intraarterial therapy but was controllable with analgesics. A radical hysterectomy, partial cystectomy, and right ureter implantation were then performed. After surgery, a vesicovaginal fistula developed, and the patient required additional surgery. To prevent any further recurrence of this problem a computed tomography angiography was performed before cisplatin injection whenever there was any difficulty in identifying the uterine artery. We were able to identify both uterine arteries correctly in all courses except for Patient 12 in her second course. Four patients (Patients 3, 6, 8, and 13) refused their third courses of chemotherapy, and we decided to discontinue a third course of chemotherapy for Patient 12. Then, only 10 patients received 3 cycles of intraarterial chemotherapy. However, during the third course it was sometimes not possible to insert the catheter into the uterine artery shrinkage, and we were required to use TAE (7 of 10 patients).

Response

To assess tumor response, we performed magnetic resonance imaging before the first course of therapy and before surgery or radiation (after 2 or 3 courses). Six of the 15 patients showed complete response (CR), and 9 patients showed partial response (PR). The response of patients who underwent surgery was assessed pathologically. Three of the 14 patients were found to have pathologic CR (2 with squamous cell carcinoma and 1 with adenosquamous carcinoma). The total response rate in this study was 100% (95% confidence interval, 78–100%).

Prognostic Results

Fourteen of the 15 patients underwent surgery. Eleven patients received radical hysterectomy and pelvic lymphadenectomy (Stages IB2:4, IIA:3, IIB:2, IIIB:1, IVA:1). Of the six patients with Stage IIIA–IVA disease, two patients (Patients 1 and 2) were downstaged, and they were able to undergo radical hysterectomy. Two other patients (Patients 5 and 9) were scheduled for radical hysterectomy and pelvic lymphadenectomy. However, lymph node metastases were large and invading the veins, so these patients underwent radical hysterectomy and pelvic lymph node sampling. One patient (Patient 11) was scheduled for pelvic lymphadenectomy, but only lymph node sampling was performed because of surgical difficulties. After radical surgery, four patients did not receive adjuvant therapy, five patients received radiotherapy for residual squamous cell carcinoma, and two patients received adjuvant chemotherapy for residual adenocarcinoma or adenosquamous carcinoma. Of the two patients with incomplete surgery, one received radiotherapy and the other received chemoradiotherapy. The patient who underwent lymph node sampling also received chemoradiotherapy. The vesicovaginal fistula in the one patient who did not have a radical hysterectomy (Patient 14) disappeared after two courses of therapy. After receiving a third course of therapy, this patient underwent radiotherapy treatment.

Three patients died of the disease, and there was disease progression in two other patients. The remaining patients survived and currently have no evidence of disease. The median follow-up period was 20 months (range, 8–29 months). We have not yet reached the median disease progression time.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Neoadjuvant chemotherapy for locally advanced cervical carcinoma has been used to increase operability in patients with bulky tumors. After treating Stage IB–IIIB cervical carcinoma with a combination of cisplatin, bleomycin, and methotrexate, Panici et al. achieved CR in 15% and PR in 68% of patients.1 They reported that this regimen resulted in 80% operability and some pathologic CR. Dottino et al. reported a 100% response rate in Stage IB–IVA patients treated with cisplatin, bleomycin, mitomycin, and vincristine.16 This regimen also obtained a 14% rate of pathologic CR. Some randomized studies have shown both a high response rate and improved survival with neoadjuvant chemotherapy plus surgery when compared with surgery or radiation therapy alone.4, 5

Intraarterial chemotherapy has been given to patients with locally advanced cervical carcinoma to maximize the pharmacologic effect.8, 9, 17, 18 Kigawa et al. have reported very good results with intraarterial chemotherapy using cisplatin (50 mg/m2) and bleomycin in patients with Stage IIB–IIIB uterine cervical carcinoma.18 This treatment achieved an 80% clinical response and 72% operability along with a 3-year survival rate of 76% versus 49% in patients who received radiation therapy alone. However, all resected specimens revealed only pathologic PR; no pathologic CR was observed. Park et al. reported a Phase I/II study of neoadjuvant intraarterial chemotherapy using cisplatin, mitomycin, and vincristine. They found no pathologic CR in the group receiving 50 mg/m2 of cisplatin but greater than 40% CR in the group given 75 mg/m2 of cisplatin.

Transcatheter arterial embolization therapy usually is performed in patients with hepatocellular carcinoma to intercept the tumor blood supply.19 This method is very appropriate from a pharmacologic viewpoint, and the intraarterial chemotherapy is easy to use with patients with cervical carcinoma. Hashii et al. used TAE along with intraarterial chemotherapy (cisplatin and mitomycin or doxorubicin) for the treatment of cervical carcinoma.20 Even though the study included some patients with Stage 1B1 carcinoma, pathologic CR was observed in 11 of 15 patients (73%). This finding suggested that intraarterial chemotherapy in combination with TAE might increase the pathologic CR rate for cervical carcinoma. Therefore, we decided to include TAE in our treatment schedule.

Intraarterial chemotherapy gives good results with respect to local control, but advanced cervical carcinoma often is accompanied by metastases to lymph nodes and other distant sites.21 Lymph node metastasis is associated with a poor prognosis in patients with advanced cervical carcinoma, and the efficacy of intraarterial chemotherapy for the treatment of such metastases is unknown. We considered that intravenous chemotherapy might be more effective than intraarterial chemotherapy for the treatment of lymph node and distant metastases. Therefore, to improve response rate and survival time, a combination of intravenous and intraarterial chemotherapy then would be the therapy of the choice for patients who have advanced cervical carcinoma.

Nedaplatin, a new analog of cisplatin, has been reported to achieve a very high response rate (46%) in patients with cervical carcinoma22 as compared with cisplatin (35%).23 Hirabayashi et al. reported that intravenous chemotherapy with nedaplatin, ifosphamide, and peplomycin achieved a high response rate in patients with cervical carcinoma.24 However, intraarterial chemotherapy with nedaplatin alone is not associated with better survival rates than with radiotherapy alone.11 We speculated that this was due to pharmacologic differences between cisplatin and nedaplatin. Nedaplatin does not bind to protein or create tumor DNA adducts as rapidly as cisplatin and thus is not appropriate for local administration.

Combination chemotherapy with cisplatin and carboplatin has been applied to some malignancies based on the finding that these agents have shown partial non–cross-resistance and a synergic effect in vitro.25 This combination chemotherapy has been reported to have high efficacy in patients with advanced ovarian carcinoma26 and nonsmall cell lung carcinoma.27 Shida et al. reported a higher synergic effect of nedaplatin and cisplatin when compared with cisplatin and mitomycin, bleomycin, or irinotecan.10 We therefore decided to use nedaplatin in combination with intraarterial cisplatin.

In this study, we obtained a high response rate (100%) and a high pathologic CR rate (25%) in patients with squamous cell carcinoma. This is therefore a very effective combination chemotherapy for squamous cell carcinoma of the uterine cervix over the short term, but long term efficacy still needs to be assessed. We also need to find a different combination chemotherapy to obtain pathologic CR for adenocarcinoma of the cervix.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Gregory H. Smith for helping in the preparation of this article.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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