This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Papadimitriou, C. A. Articles by Dimopoulos, M. A. Search for Related Content PubMed PubMed Citation Articles by Papadimitriou, C. A. Articles by Dimopoulos, M. A. Social Bookmarking                            What's this?

Phase II Trial of Paclitaxel and Cisplatin in Metastatic and Recurrent Carcinoma of the Uterine Cervix

From the Departments of Clinical Therapeutics, Gynecology, Radiation Oncology, and Radiology, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece; and Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Address reprint requests to Meletios A. Dimopoulos, MD, 227 Kifissias Ave, 14561 Kifissia, Athens, Greece.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent cancer of the cervix, and the combination of these two agents has shown activity and possible synergism in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent cervical cancer to evaluate its activity.

PATIENTS AND METHODS: Thirty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m² administered intravenously over a 3-hour period followed by cisplatin 75 mg/m² administered intravenously with granulocyte colony-stimulating factor support. The chemotherapy was administered every 3 weeks for a maximum of six courses.

RESULTS: Sixteen patients (47%; 95% confidence interval, 30% to 65%) achieved an objective response, including five complete responses and 11 partial responses. Responses occurred in 28% of patients with disease within the radiation field only and in 57% of patients with disease involving other sites. The median duration of response was 5.5 months, and the median times to progression and survival for all patients were 5 and 9 months, respectively. Grade 3 or 4 toxicities included anemia in 18% of patients and granulocytopenia in 15% of patients. Fifty-three percent of patients developed some degree of neurotoxicity; 21% of cases were grade 2 or worse.

CONCLUSION: The combination of paclitaxel with cisplatin seems relatively well tolerated and moderately active in patients with metastatic or recurrent cervical cancer. The significant incidence of neurotoxicity is of concern, and alternative methods of administration of the two agents could be evaluated. Then, further study of this combination, alone or with the addition of other active agents, is warranted.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CARCINOMA OF THE UTERINE cervix is one of the most common malignant neoplasms among women and remains the leading female malignancy in populations with a low socioeconomic level.¹ The disease is usually radioresponsive and highly curable in the early stages. Either surgery or radiotherapy alone for stage IB and IIA tumors has resulted in 5-year survival rates of 75% to 90%. Nevertheless, for patients who present with stage IV disease or for those with recurrent disease after radiotherapy, no consistent improvement in survival has been observed during the last 30 years.² For patients who have advanced or recurrent disease that is not curable by surgery or irradiation, treatment with cytotoxic agents, alone or in combination, can be considered. Response rates of the most active single agents vary between 20% and 30%, with a median response duration of 3 to 6 months and a 5- to 9-month survival rate.^2-5 A number of combination regimens have also been explored during the last two decades, most in uncontrolled trials. Although high response rates have been reported in some of these studies, it is difficult to interpret the relative merits of the combination regimens in these selected patient populations.^6-9 At this point, no agent or multiagent regimen has been shown to be significantly more efficacious in terms of survival than single-agent cisplatin.¹⁰ Therefore, identification of new agents or new drug combinations with activity in carcinoma of the uterine cervix is highly desirable.

Recently, paclitaxel has shown activity in squamous cell carcinoma of the uterine cervix.^11,12 The apparent clinical non–cross-resistance between paclitaxel and cisplatin in other neoplasms (for example, in ovarian carcinoma¹³) and the moderate activity of these two agents in carcinoma of the uterine cervix provided the basis for a phase II trial using the combination of paclitaxel and cisplatin in patients with primary stage IV or recurrent carcinoma of the uterine cervix.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients were eligible for the study if they had documented primary stage IV or recurrent carcinoma of the uterine cervix, were no longer candidates for curative surgery or radiation therapy, and had not received chemotherapy for advanced disease. Prior neoadjuvant chemotherapy or chemotherapy given as radiation sensitizer was allowed, provided that tumor recurrence occurred at least 6 months after completion of this treatment. Other eligibility requirements included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3, one or more lesions measurable in perpendicular diameters by physical examination or imaging modalities, granulocyte count more than or equal to 1,500/µL, platelet count more than or equal to 100,000/µL, serum creatinine concentration less than or equal to 1.5 mg/dL, serum bilirubin less than 2.0 mg/dL, 3 weeks from prior surgery, and 4 weeks from radiation. Our study was approved by the Hospital Ethics Committee, and informed consent was obtained from all patients before study entry.

Patients were excluded if they had brain metastases, active infection, serious concurrent medical illnesses, and preexisting clinically significant peripheral neuropathy.

Evaluation
Before study entry, all patients underwent a complete physical and gynecologic examination, assessment of performance and pain status, complete blood cell (CBC) count and differential, liver and kidney function tests, urinalysis, ECG, pelvic and abdominal computed tomography, and chest x-ray with computed tomography of the chest in cases of lung or mediastinal metastases. Imaging of the brain and the bones was performed when clinically indicated. During treatment, CBC counts were repeated weekly. Physical and gynecologic examination, urinalysis, creatinine and liver function tests, performance status, and pain and toxicity evaluations were conducted before each cycle. Response to treatment was assessed every other cycle by repeating all abnormal imaging modalities. All imaging studies were reviewed by two clinicians (C.A.P., M.A.D.) and reviewed independently by the same radiologist (L.A.M.), who was blinded to the patients' clinical outcome.

Treatment Plan
All patients underwent a pretreatment regimen designed to abrogate allergic reactions that consisted of dexamethasone 20 mg administered 12 and 6 hours before paclitaxel, and diphenhydramine 25 mg and ranitidine 50 mg administered by intravenous injection 30 minutes before paclitaxel. The chemotherapy was administered on an outpatient basis and consisted of paclitaxel 175 mg/m² administered as a continuous intravenous (IV) infusion in 500 mL of dextrose over a 3-hour period. Subsequently, the patients received 900 mL of 0.9% NaCl with mannitol 100 mL IV over a 1-hour period followed by cisplatin 75 mg/m² in 1,000 mL 0.9% NaCl IV over a 2-hour period. After completion of cisplatin, the patients received an additional 2 L of 0.9% NaCl that contained potassium and magnesium. Appropriate antiemetics were used before and after the administration of chemotherapy. Courses of paclitaxel and cisplatin were given every 21 days for a maximum of six cycles. Chemotherapy was discontinued in cases of progressive disease or unacceptable toxicity.

Because most of our patients were expected to have received pelvic radiation, and because the combination of paclitaxel and cisplatin has been associated with significant neutropenia even in nonirradiated patients,¹³ we decided to administer a hematopoietic growth factor to avoid dose reductions because of neutropenia. Granulocyte colony-stimulating factor (G-CSF) 5 µg/kg was administered subcutaneously daily from day 5 until the total WBC count exceeded 10,000/µL. The dose of paclitaxel was reduced by 20% if febrile neutropenia occurred, but the dose of cisplatin was not changed. In case of neurotoxicity or fatigue higher than grade 2 (World Health Organization [WHO] criteria), treatment was delayed by 1 or 2 weeks and both drugs were reduced by 20%. Cisplatin was reduced by 50% for a creatinine level more than 2 times baseline and withheld for a creatinine level more than 3 times baseline. If treatment was delayed by 3 weeks, for any reason, the patient was taken off the study.

Definition of Response and Toxicity
WHO criteria for response and toxicity were used.¹⁴ One dose of therapy was considered adequate for response and toxicity assessment, and patients experiencing toxic death were rated as nonresponders. A complete response (CR) required disappearance of all clinically detectable disease for at least 4 weeks. A partial response (PR) required more than a 50% reduction in the sum of the products of the two largest perpendicular dimensions of bidimensionally measurable lesions for at least 4 weeks. Stable disease was defined as regression not meeting the aforementioned criteria for objective response, with no progression for at least 3 months. All other cases were considered to have progressive disease. At each visit, performance status and pain were scored by the patient's physician. Improvement or deterioration of performance status required a decrease or an increase, respectively, of at least one point on the ECOG scale. Improvement of pain required discontinuation of opioid analgesics or substitution by nonsteroidal anti-inflammatory drugs (NSAIDs). Deterioration of pain required initiation of any type of pain treatment or addition of opioid analgesics to prior treatment with NSAIDs. This was not a validated instrument and was devised in particular for our study. No formal quality-of-life assessment was made.

Dose-Delivery Analysis
Dose intensity is a measurement of the dose received as a function of time. We used the method described by Hryniuk and Goodyear.¹⁵ A value for received dose intensity was calculated by dividing the cumulative dose treatment given to each patient. One dose interval was added to the treatment period of each patient to adjust for methodologic problems in dealing with those patients who received fewer than six cycles.¹⁶ The received dose intensity was calculated from the beginning of chemotherapy.

Statistical Analysis
The study was a nonrandomized, phase II study in which an objective response rate (CR + PR) of at least 40% would be clinically significant; thus, a sample size of 33 patients would provide an adequate precision (95% confidence interval [CI], 23% to 58%). An early stopping rule was in place according to Simon's two-stage "minimax" design,¹⁷ for type 1 and type 2 error levels of 5% and 20%, respectively. At least five responses in the first 18 patients were required to conclude that the true response rate is more than 20% and to proceed to the next stage. At the second stage, if at least 11 responses were observed in the 33 patients, we would be able to reject the hypothesis that the response rate is less than 40%.

Response duration was defined as the time from PR or CR to the appearance of progressive disease. Time to progression was measured from the time of initiation of treatment to the time of last patient contact or documented progressive disease. Survival was measured from the time of initiation of therapy to the last patient contact or death. Time to progression and survival curves were constructed using the Kaplan-Meier product-limit method.¹⁸ Differences in survival were compared with the log-rank statistical test using a microcomputer-assisted program.¹⁹ Statistical analyses of frequency data were performed with the ² test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between February 1996 and July 1997, 34 patients with cervical carcinoma were accrued to this study. Data analysis was performed in July 1998, 12 months after the accrual of the last patient. All patients were considered eligible for evaluation of response and toxicity. The main characteristics of the patients are summarized in Table 1. Forty-five percent of patients initially presented with an advanced FIGO (International Federation of Gynecology and Obstetrics staging system) stage (III or IV), 76% of patients had received pelvic irradiation, 30% of patients had tumors with histology other than pure squamous cell carcinoma, and in 53% of patients, the tumors were poorly differentiated.

Response
A total of 167 paclitaxel and cisplatin cycles (median, six cycles; range, one to six cycles) were administered. Sixteen patients (47%) achieved objective clinical response (95% CI, 30% to 65%), including five CRs (15%) and 11 PRs (32%) (Table 2). Based on the analysis of Brader et al,²⁰ we divided our patients into two groups by site of disease: patients with disease in a previously irradiated site and patients with disease outside of a previously irradiated field, regardless of whether they also had disease within the irradiated field (Table 2). When these two groups were analyzed with regard to response, a trend for higher response rate was observed for patients with disease outside a radiation field (57% v 28%; P = .1). All CRs occurred in sites outside of radiation fields. We observed responses in most metastatic sites outside of a previously irradiated field, but none of the patients with liver metastases responded to treatment. Complete responses occurred in patients with assessable primary tumors and with lymph node metastases. Several other variables were assessed for their possible prognostic value for objective response, such as age, performance status, hemoglobin, histology, tumor grade, mode of primary treatment, time from primary diagnosis to disease recurrence, and recurrent versus primary metastatic disease at the time of study entry. None of these variables was a statistically significant predictor of response. We observed responses in 42% of patients with pure squamous cell carcinoma and in 60% of patients with other histologies. Patients with performance status of 0 or 1 on the ECOG scale had a tendency for a higher response rate than did patients with more impaired performance (60% v 28%; P = .07).

Survival
The median time to progression for all patients was 5 months (range, 0.5 to 23.5+ months). The median time to progression of responders was 7.1 months (range, 2 to 22.5+ months) and the median response duration was 5.5 months (range, 2 to 20.5+ months). The median overall survival for all patients was 9 months (range, 0.5 to 22.5+ months). Several parameters were analyzed for their possible association with survival. Age, tumor histology, tumor differentiation, and prior treatment with radiation did not correlate with survival. The median survival of the patients with performance status of 0 or 1 before chemotherapy was 11.6 months, whereas the median survival of patients with more impaired performance was 6.2 months (P = .045).

Symptoms
Twenty-nine patients had impaired performance status before treatment (Table 1). The performance status improved in 13 patients, seven patients maintained their pretreatment performance status, and the performance status deteriorated in nine patients. Before treatment, 22 patients were complaining of moderate or severe pain and were taking regularly opioid analgesics. After treatment, pain improved in 10 patients: seven patients were not taking any pain treatment, and three patients were taking NSAIDs only. The pain remained stable in five patients and became worse in eight patients.

Toxicity
Detailed toxicity data according to the WHO scale were available for all cycles (Table 3). Toxic nonhematologic reactions consisted primarily of grade 2 or 3 nausea and emesis in 53% of patients and alopecia in 94% of patients. Renal toxicity grade 1 and 2 occurred in six patients (18%) but was completely reversible without discontinuing the treatment. Forty-four percent of patients had grade 1 and 2 neuropathy, but three patients developed debilitating grade 3 peripheral neuropathy. Generalized fatigue occurred in nine patients (26%), because of which patients were temporarily unable to perform normal activities and were confined to bed for 50% or more of the day. We did not observe any incident of significant mucositis or diarrhea. Grade 3 or 4 granulocytopenia occurred in 15% of patients, four episodes of neutropenic fever were documented, and a 70-year-old patient presenting with liver metastases, ascites, and severely impaired performance status died of neutropenic sepsis after the first course of treatment. To achieve recovery to a total WBC count of 10,000/µL, a median of 5 days of G-CSF was required (range, 3 to 10 days). Grade 3 or 4 anemia occurred in 18% of patients, but significant thrombocytopenia was rare.

Dose Intensity
The relative dose intensities are shown in Table 4. For paclitaxel, 91% of patients had a dose intensity of more than 80% of the intended dose. For cisplatin, this figure was 86%. The percentage of optimal dose delivered was 93% for paclitaxel and 92% for cisplatin.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The prognosis of patients who have recurrent or metastatic cervical cancer that is not treatable with curative surgery or radiation therapy is dismal. Systemic chemotherapy is frequently administered to such patients in an attempt to improve symptoms and to possibly prolong survival. Among several chemotherapeutic agents that have been used, cisplatin and ifosfamide have a reproducible activity in at least 20% of patients.¹⁹ Several combination chemotherapy regimens that contain cisplatin, with or without ifosfamide, have been tested in phase II studies. Objective responses have been documented in 30% to 70% of patients, the median overall survival ranged between 7 and 12 months, and occasional patients have survived for more than 2 years.^6-9 It is difficult to compare the results of these phase II studies because of their relatively small number of patients and the bias of patient selection. A large, prospective, randomized trial recently reported by the Gynecologic Oncology Group (GOG) indicated that the combination of cisplatin and ifosfamide had a higher response rate and a longer progression-free survival time compared with cisplatin alone. However, the combination chemotherapy regimen was more toxic, and there was no difference in overall survival, which was about 8 months in both groups.¹⁰ Thus, there is a need to identify new agents that have activity in these patients.

During the last 3 years, several new chemotherapeutic agents—including paclitaxel, irinotecan, and vinorelbine—have been shown to have some single-agent activity in the treatment of patients with metastatic or recurrent carcinoma of the uterine cervix.^11,12,21-23 The GOG administered single-agent paclitaxel at a dose of 170 mg/m² IV over a 24-hour period to 52 patients with squamous cervical cancer. Objective responses occurred in 17% of patients, with a median duration of response of 3.4 months.¹¹ In another phase II study, from the M.D. Anderson Cancer Center, 32 patients were treated with paclitaxel at the dose of 250 mg/m² IV over a 3-hour period. The final analysis reported a 25% response rate, with an overall median survival of 7.3 months.¹² The moderate activity of paclitaxel in squamous cell cervical cancer prompted us to combine this agent with cisplatin, another agent with reproducible moderate activity in this disease. Furthermore, this combination has been used in the treatment of several solid tumors, including ovarian cancer, and the doses and side effects have been adequately defined.

We administered the combination of paclitaxel at a dose of 175 mg/m² IV over a 3-hour period followed by cisplatin 75 mg/m² IV, because there is evidence of additive or even synergistic effects when paclitaxel is followed by cisplatin.²⁴ We treated 34 consecutive patients referred to two departments of medical oncology during a relatively short period of 18 months. We included patients with metastatic or recurrent cervical cancer, regardless of histology. We observed objective responses in 47% of patients, including complete responses in 15% of patients. The response rate in our patient population was similar to the 44% response rate reported in the preliminary analysis of the GOG study that used paclitaxel 135 mg/m² infused over a 24-hour period followed by cisplatin 75 mg/m².²⁵ The relatively small number of patients included in our study did not allow us to perform a formal analysis of possible prognostic factors affecting response. There was a tendency for higher response rates in sites outside of an irradiated field and in patients with better performance status; these findings are consistent with previous reports.^20,26,27 Responses were observed in all metastatic sites, with the exception of the liver. Complete responses occurred in nonirradiated lymph nodes and in the primary tumor. One-fifth of our patients had no prior therapy because they presented with metastatic disease. This figure might have introduced a bias in our study, because there is evidence of higher response rates to chemotherapy in patients without any type of prior therapy when compared with those patients who failed radiation therapy. Among seven patients presenting with de novo metastatic disease, we observed two CRs and one PR, a figure similar to that reported by Costa et al,²⁸ who observed responses in 50% of patients with locally advanced cervical cancer receiving neoadjuvant chemotherapy with paclitaxel and cisplatin. Among the remaining 23 patients, three CRs and 10 PRs were documented. Furthermore, only three PRs were noted in the 11 patients who had disease recurrence only within the radiation field. In our study, we also included patients with nonsquamous histologies and observed responses in six of 10 such patients.

The median times to progression and overall survival for all patients were 5 and 9 months, respectively; these figures are similar to those reported in previous phase II studies and in the GOG randomized trial.¹⁰ Patients with good performance status survived longer. Given the relatively small number of patients, we were not able to identify other variables that favorably affected patients' survival.

We were able to administer the chemotherapy on an outpatient basis, and the treatment was relatively well tolerated. The percentage of optimal dose delivered was 93% for paclitaxel and 92% for cisplatin. There were no incidents of significant renal impairment. With the routine administration of G-CSF for a median of 5 days, the incidence of significant neutropenia was 15%. There was, however, one death caused by neutropenic sepsis. The routine use of G-CSF in chemotherapy trials of cervical cancer, a disease that predominantly affects women from a lower socioeconomic background and from developing countries, significantly increases the cost of the treatment. We have no proof that G-CSF was necessary in all of our patients, and its use could have been restricted to patients who had previously experienced neutropenic fever or to those with protracted neutropenia necessitating a delay in the administration of chemotherapy. The more common side effects were alopecia, nausea and emesis, and fatigue. These side effects were manageable and reversible in most patients.

Fifty-three percent of our patients developed some degree of neurotoxicity, including grade 3 neurotoxicity in 9%. The regimen of 3-hour paclitaxel and cisplatin has been used in prior studies and is associated with a higher incidence of neurotoxicity compared with the 24-hour dosing schedule of paclitaxel combined with cisplatin. Connelly et al²⁹ reported a 71% incidence of neurotoxicity, 20% of which was grade 3 or 4. Other studies have reported grade 3 neurotoxicity rates of 8% to 16%.^30,31 It seems that the incidence and severity of neurotoxicity is the result of the high peak levels of paclitaxel achieved in the systemic compartment during and after the 3-hour infusion at the same time that cisplatin, a known neurotoxic agent, is administered.^32-34 Thus, before adopting our current regimen, alternative treatment strategies such as the delivery of paclitaxel at lower doses on a weekly basis or the separation of paclitaxel and cisplatin administration by at least 24 hours could be considered to prevent the concomitant high concentration of both neurotoxic agents.²⁹ The final analysis of the GOG study that uses the 24-hour dosing schedule of paclitaxel combined with cisplatin²⁵ will indicate whether the latter regimen is preferred in terms of response toxicity, particularly neurotoxicity.

In summary, our combination of 3-hour paclitaxel and cisplatin, administered to outpatients, was relatively well tolerated. Objective responses were noted in almost one-half of the treated patients, and several patients had improvement of their symptoms. However, the proportion of complete responses remained low and there was no obvious improvement in the patients' long-term outcome. Further evaluation of the combination of paclitaxel and cisplatin, alone or with the addition of other agents, is warranted to define the least toxic method of administration and the patients more likely to benefit.  

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Thigpen T, Vance R, Khansur T: Carcinoma of the uterine cervix: Current status and future directions. Semin Oncol 21:43-56, 1994

2. Thigpen T, Vance RB, Khansur T: The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Semin Oncol 22:67-75, 1995 (suppl 12) [Medline]

3. Park RC, Thigpen T: Chemotherapy in advanced and recurrent cervical cancer. Cancer 71:1446-1450, 1993[Medline]

4. Vermorken JB: The role of chemotherapy in squamous cell carcinoma of the uterine cervix: A review. Int J Gynecol Cancer 3:129-142, 1993[Medline]

5. Omura GA: Chemotherapy for cervix cancer. Semin Oncol 21:54-62, 1994

6. Buxton EJ, Meanwell CA, Hilton C, et al: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81:359-361, 1989[Abstract/Free Full Text]

7. Murad AM, Triginelli SA, Ribalta JCL: Phase II trial of bleomycin, ifosfamide, and carboplatin in metastatic cervical cancer. J Clin Oncol 12:55-59, 1994[Abstract]

8. Long HJ, Cross WG, Wieand HS, et al: Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in advanced/recurrent carcinoma of the uterine cervix and vagina. Gynecol Oncol 57:235-239, 1995[Medline]

9. Papadimitriou CA, Dimopoulos MA, Giannakoulis N, et al: A phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in the treatment of metastatic carcinoma of the uterine cervix. Cancer 79:2391-2395, 1997[Medline]

10. Omura GA, Blessing JA, Vaccarello L, et al: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 15:165-171, 1997[Abstract/Free Full Text]

11. McGuire WP, Blessing JA, Moore D, et al: Paclitaxel has moderate activity in squamous cervix cancer: A Gynecologic Oncology Group study. J Clin Oncol 14:792-795, 1996[Abstract/Free Full Text]

12. Kudelka AP, Winn R, Edwards CL, et al: An update of a phase II study of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Anticancer Drugs 8:657-661, 1997[Medline]

13. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996[Abstract/Free Full Text]

14. Miller AB: Reporting results of cancer treatment. Cancer 47:207-214, 1981[Medline]

15. Hryniuk KWM, Goodyear M: The calculation of received dose intensity. J Clin Oncol 8:1935-1937, 1990[Medline]

16. Coppin CM: The description of chemotherapy delivery options and pitfalls. Semin Oncol 14:32-42, 1987 (suppl 14) [Medline]

17. Simon R: Optimal two-stage designs for phase II clinical trials. Controlled Clin Trials 10:1-10, 1989[Medline]

18. Kaplan E, Meier F: Nonparametric estimation from incomplete observations. J Am Stat Assoc 58:457-481, 1958

19. Campos-Filho N, Franco ELF: Micro-computer-assisted univariate survival data analysis using Kaplan-Meier life table estimators. Comput Methods Programs Biomed 27:223-228, 1988[Medline]

20. Brader KR, Morris M, Levenback C, et al: Chemotherapy for cervical carcinoma: Factors determining response and implications for clinical trial design. J Clin Oncol 16:1879-1884, 1998[Abstract]

21. Thigpen T, Vance R, Khansur T, et al: The role of paclitaxel in the management of patients with carcinoma of the cervix. Semin Oncol 24:41-46, 1997 (suppl 2)

22. Verschaegen C, Levy T, Kudelka AP, et al: Phase II study of irinotecan in prior chemotherapy treated squamous cell carcinoma of the cervix. J Clin Oncol 15:625-631, 1997[Abstract/Free Full Text]

23. Morris M, Brader KR, Levenback C, et al: Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix. J Clin Oncol 16:1094-1098, 1998[Abstract]

24. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequences of Taxol and Cisplatin: A phase I and pharmacologic study. J Clin Oncol 9:1962-1703, 1991[Abstract/Free Full Text]

25. Rose PG, Blessing JA, Gershenson DM: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: A Gynecologic Oncology Group (GOG) study. Proc Am Soc Clin Oncol 16:363a, 1997 (abstr)

26. Potter MA, Hatch KD, Potter MY, et al: Factors affecting response of recurrent squamous cell carcinoma of the cervix to cisplatin. Cancer 63:1283-1286, 1989[Medline]

27. Zanetta G, Torri W, Bocciolone L, et al: Factors predicting response to chemotherapy and survival in patients with metastatic or recurrent squamous cell cervical carcinoma: A multivariate analysis. Gynecol Oncol 58:58-63, 1995[Medline]

28. Costa MA, Rocha JCC, Araujo CM, et al: Paclitaxel and cisplatin as primary medical treatment in locally advanced cervical cancer. Proc Am Soc Clin Oncol 16:368a, 1997 (abstr)

29. Connelly E, Markman M, Kennedy A, et al: Paclitaxel delivered as a 3-hour infusion with cisplatin in patients with gynecologic cancers: Unexpected incidence of neurotoxicity. Gynecol Oncol 62:166-168, 1996[Medline]

30. Piccart MJ, Bertelsen G, Stuart G, et al: Is cisplatin-paclitaxel (P-T) the standard in first-line treatment of advanced ovarian cancer (Ov Ca)? The EORTC-GCCG, NOCOVA, NCIC and Scottish intergroup experience. Proc Am Soc Clin Oncol 16:352a, 1997 (abstr)

31. du Bois A, Richter B, Warm M, et al: Cisplatin/paclitaxel vs carboplatin/paclitaxel as first-line treatment in ovarian cancer. Proc Am Soc Clin Oncol 17:316a, 1998 (abstr)

32. Rowinsky EK, Chaudhry V, Forastiere A, et al: Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: Neuromuscular toxicity is dose-limiting. J Clin Oncol 11:2010-2020, 1993[Abstract/Free Full Text]

33. Chaudhry V, Rowinsky EK, Sartorius et al: Peripheral neuropathy from Taxol and cisplatin combination chemotherapy: Clinical and electrophysiological studies. Ann Neurol 35:304-311, 1994[Medline]

34. Warner E: Neurotoxicity of cisplatin and Taxol. Int J Gynecol Cancer 5:161-169, 1995[Medline]

Submitted August 20, 1998; accepted November 24, 1998.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				G. Mountzios, M. A. Dimopoulos, A. Bamias, G. Vourli, H. Kalofonos, G. Aravantinos, G. Fountzilas, and C. A. Papadimitriou Randomized multicenter phase II trial of cisplatin and ifosfamide with or without paclitaxel in recurrent or metastatic carcinoma of the uterine cervix: a Hellenic Cooperative Oncology Group (HeCOG) study Ann. Onc., August 1, 2009; 20(8): 1362 - 1368. [Abstract] [Full Text] [PDF]

				H. J. Long III Management of Metastatic Cervical Cancer: Review of the Literature J. Clin. Oncol., July 10, 2007; 25(20): 2966 - 2974. [Abstract] [Full Text] [PDF]

				D. H. Moore, J. A. Blessing, R. P. McQuellon, H. T. Thaler, D. Cella, J. Benda, D. S. Miller, G. Olt, S. King, J. F. Boggess, et al. Phase III Study of Cisplatin With or Without Paclitaxel in Stage IVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study J. Clin. Oncol., August 1, 2004; 22(15): 3113 - 3119. [Abstract] [Full Text] [PDF]

				A. Duenas-Gonzalez, C. Lopez-Graniel, A. Gonzalez-Enciso, L. Cetina, L. Rivera, I. Mariscal, G. Montalvo, E. Gomez, J. de la Garza, G. Chanona, et al. A phase II study of multimodality treatment for locally advanced cervical cancer: neoadjuvant carboplatin and paclitaxel followed by radical hysterectomy and adjuvant cisplatin chemoradiation Ann. Onc., August 1, 2003; 14(8): 1278 - 1284. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Papadimitriou, C. A. Articles by Dimopoulos, M. A. Search for Related Content PubMed PubMed Citation Articles by Papadimitriou, C. A. Articles by Dimopoulos, M. A. Social Bookmarking                            What's this?