Topotecan Use for Second-Line Treatment in Patients with Recurrent or Metastatic Cervical Cancer at Brazilian National Cancer Institute (INCA)

doi:10.4236/jct.2013.46126

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Journal of Cancer Therapy, 2013, 4, 1095-1099

http://dx.doi.org/10.4236/jct.2013.46126 Published Online August 2013 (http://www.scirp.org/journal/jct) 1095

Topotecan Use for Second-Line Treatment in Patients with

Recurrent or Metastatic Cervical Cancer at Brazilian

National Cancer Institute (INCA)*

Leandro Nascimento de Oliveira#, Flávia Vieira Guerra Alves, Paulo Alexandre Ribeiro Mora,

Claudio Calazan do Carmo, Angélica Nogueira-Rodrigues, Alvaro Henrique Ingles Garces†,

Andréia Cristina de Melo

Instituto Nacional do Câncer, Hospital do Câncer II, Rio de Janeiro-RJ, Brazil.

Email: †[email protected]

Received March 17th, 2013; revised April 20th, 2013; accepted April 30th, 2013

tribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is prop-

erly cited.

ABSTRACT

Objective: Cervical cancer represents the third most commonly diagnosed cancer and is an important cause of death for

women suffering with malignancies. Patients who are refractory or progressed after first-line palliative treatment have a

dismal prognosis and no secon d-line chemotherapy is con sidered standard so far. Several agents h ave been investigated

in this setting and topotecan is one of the most characterized. The objectiv e of this study was to evaluate response rate

(RR), progression-free survival (PFS), overall survival (OS) and toxicity of topotecan in second palliative line for cer-

vical cancer. Methods: An analysis was performed of all patients with recurrent or metastatic cervical cancer treated

with topotecan in second palliative line at Brazilian National Canc er Institute, between 2008 and 2010. Results: A to tal

of 73 courses of topotecan were given in the current study (median: 3.5 cycles; range 1 - 6). Anemia was the most fre-

quent adverse event (grade 2:35%; grade 3:30%). Of the 20 patients evaluable, there were 2 partial responders to the

treatment. The overall response rate (ORR) was 10%; 3 patients (15%) had stable disease as maximum response. The

median PFS for the entire group was 2.93 months (95% CI 2.41 - 3.45) and OS was 4.66 months (95% CI 1.21 - 8.11).

Conclusion: The limited activity of topotecan schemas in second-line treatment of cervical cancer and the associated

overall toxicity may not justify their use in this setting. Patients who progress after first-line treatment may be offered

participation in clinical trials, other second-line agents or best supportive care measures.

Keywords: Topotecan; Cervical Cancer; Palliative Treatment

1. Introduction

Cervical cancer represents the third most commonly di-

agnosed cancer [1] and is an important cause of death for

women suffering with malignancies; one-third of patients

initially treated for early and locally advanced cervical

cancer will die due to local or systemic relapse [2]. The

5-year survival rates for patients with locally advanced or

distant cervical cancer are 49% and 15% respectively [3]

and in accordance to literature the mortality rate in those pa-

tients has re mained u nch anged o ver the past 25 years [4].

Palliative systemic chemotherapy, usually including

platinum-based regimens, is the best option for patients

who have relapsed after primary surgery or cisplatin-

based chemoradiation, not amenable for curative treat-

ment, and for those staging IVB at the initial diagnosis;

however, the results for the majority of them are disap-

pointing. Patients who are refractory or progressed after

first-line palliative treatment have a dismal prognosis

with infrequent responses and no second-line chemo-

therapy is considered standard so far. The treatment usu-

ally focuses on symptoms palliation and g ains in survival

when feasible.

*Authors’ disclosures of potential conflicts of interest: The authors in-

dicated no potential conflicts of interest.

#in memor ian.

†Corresponding a uthor.

Several agents have been investigated in this setting

and topotecan is one of the most characterized. In vitro

experiments have shown significant antineoplasic activ-

Topotecan Use for Second-Line Treatment in Patients with Recurrent or Metastatic

Cervical Cancer at Brazilian National Cancer Institute (INCA)

1096

ity in squamous cell lines of cervical cancer with topo-

tecan alone as well as an increase in cytotoxicity when

used in combination with cisplatin [5].

To date, the use of topotecan as second-line or third-

line therapy in patients with cervical cancer has been

studied in five phase II trials.

The first study [6] administered intravenously topo-

tecan at a dose of 1.2 mg/m2 per day during 5 consecu-

tive days, on a 28-day cycle and included 22 patients

with squamous cell carcinoma (SCC) or adenocarcinoma

who had received prior chemotherapy (1 or 2 regimens).

Eighteen patients were evaluated for efficacy with partial

response (PR) in 16.6 % and stable disease (SD) in 33.3%

of the patients. All 3 PR cases were diagnosed as SCC.

The second trial, GOG 127-F [7 ], was restricted to pa-

tients with advanced, recurrent or metastatic squamous

cell carcinomas; one prior chemotherapy, usually plati-

num-based, was allowed for metastatic disease. Patients

received topotecan at 1.5 mg/m2 per day for 5 days on

21-day cycle. Thirty-four out of 45 patients who were

included had received prior chemotherapy. Forty patients

were evaluable for response-complete response (CR) in

2.5%, PR in 10% and SD in 37.5%. The median progres-

sion-free interval (PFI) was 2.1 months with a median

overall survival (OS) of 6.6 months.

The third study [8] employed topotecan at a regimen

of 1.0 mg/m2 per day during 5 consecutive days, every

21 days. Twelve patients with SCC or adenocarcinoma

were treated, 7 of them received topotecan as second-line

chemot h er ap y treatment. The re w er e 2 P R ( 16.7%).

The fourth phase II [2] trial have demonstrated that an

alternative schedule of weekly topotecan at 3.0 mg/m2

(maximum 5.0 mg/dose) administered at days 1, 8 and 15

on 28-day cycles as second or third-line treatment in pa-

tients with recurrent or metastatic cervical cancer is safe

and well tolerated. Twenty-two patients entered this study

and 18 were evaluable for response; no CR or PR were

observed and 27.7% of patients exhibited SD as the best

response. Median PFI was 3.5 months and median OS

was 7.0 months.

Finally, the fifth was the GOG 127-U trial [4] evaluat-

ing weekly topotecan as a single agent in second-line

therapy in persistent or recurrent cervical carcinoma.

Topotecan was administered at a dose 3.0 mg/m2, re-

peated every 7 days for 21 days followed by a seven-day

recovery, cycles were defined as a 28-day period. Twenty-

five patients were evaluable and none responded to the

treatment, 40% had SD. The median progression-free

survival (PFS) was 2 .4 months.

The main toxicity related to topotecan treatment is

myelosuppresion with high incidence of grade 3 and 4

hematologic events and weekly schemes have remarka-

bly proven to ameliorate hematologic toxicity. Nonhe-

matologic toxicity is manageable, generally mild, not dose-

limiting and does not present a dominant pattern.

Herein, the experience of topotecan use for second-line

treatment in patients with recurrent or metastatic cervical

cancer at Brazilian National Cancer Institute is reported.

2. Material and Methods

2.1. Patient Selection and Data Collection

This study was approved by the Ethics in Human Re-

search Committee of the Brazilian National Cancer In-

stitute (INCA), Rio de Janeiro, Brazil and conducted in

accordance with the Declaration of Helsinki and Good

Clinical Practice guidelines.

In order to evaluate RR, PFS, OS and toxicity, an

analysis of all cervical cancer patients treated with topo-

tecan in second palliative line at INCA, between 2008

and 2010, was performed. Patients were identified through

internal database and must have received one previous

chemotherapy line for the treatment of incurable disease.

Clinical data including demographics, stage, histology,

previous th erapies and the toxicity related with topotecan

therapy were retrospectively collected by medical re-

cords review.

Response was determined by physical examination

and predominantly by repeated imaging studies. Re-

sponse was defined as follows: complete response (CR),

partial response (PR), progressive disease (PD) and sta-

ble disease (SD). The radiological evaluation was based

on the Response Evaluation Criteria in Solid Tumors

(RECIST) v ersion 1.0.

Adverse events were supposed to be assessed every

cycle using the National Cancer Institute Common Tox-

icity Criteria (NCI CTCAE), version 3.0.

Before the first cycle of topotecan, patients had a com-

plete medical history and physical examination, docu-

mentation of disease progression after or during the first

palliative line and laboratory assessment. Prior to each

cycle patients had a medical evaluation including adverse

events, complete blood count and chemistry panel. Im-

aging studies were performed in a frequency according to

physicians’ dis c ret i on.

2.2. Treatment

A variety of topotecan schedules were prescribed (0.75

mg/ m2 per day during 5 consecutive days to 2.0 mg/m2

per day during 3 consecutive days, every 21 days or

weekly topotecan at 3.0 mg/m2 administered at days 1, 8

and 15 on 28-day cycles) in an outpatient setting with

cycles repeated until disease progression, prohibitive

toxicity or patient refusal for further therapy. Premedica-

tion and discharge prescription were in accordance to the

guidelines of the Institution. Regimen selection, dose

Topotecan Use for Second-Line Treatment in Patients with Recurrent or Metastatic

Cervical Cancer at Brazilian National Cancer Institute (INCA) 1097

adjustments and delays in subsequent cycles were deter-

mined by the assistant physician, according to clinical

evaluation and presented toxicities. History, physical

examination and laboratory evaluations were obtained

prior to each treatment cycle.

2.3. Statistical Analysis

OS was estimated from time of the first treatment day

until death or for living patients, the last available fol-

low-up and PFS was measured from the date of the first

palliative chemotherapy infusion to either first progres-

sion or death or the date of last contact for patients who

are alive and progression-free, in both cases using the

Kaplan-Meier method. All analyses were performed with

the SPSS software, version 18.0.

3. Results

From January 2008 to December 2010, 21 patients were

treated at INCA with some topotecan scheme in sec-

ond-line setting for recurrent or metastatic cervical can-

cer.

The patient characteristics are described in Table 1.

The median age at progression to first palliative line

therapy was 50.97 years (range 32 - 63). At diagnosis, 1

patient had early stage, 16 had locally advanced tumors

and 4 metastatic disease; the most frequent histology was

squamous cell carcinoma (90.5%). As first approach and

with curative intent, the major ity of patients (80.9%) had

Table 1. Patient Characteristics.

n %

Age (years)#

Median 50.97

Range 32 - 63

Histology SCC 19 90.5

ADC 2 9.5

Stage at disease presentation (FIGO)

IB1 1 4.7

IB2, II, III and IVA 16 76.2

IVB 4 19.1

Prior isolated radiotherapy 2 9.5

Prior chemo-radiation 15 71.4

Number of cycles

Median 3.5

Range 01 (one) - 06 (six)

#At progression to first palliative line therapy. Abbreviations: SCC: squam-

ous cell carcinoma; ADC: adenocarcinoma.

received pelvic radiation and 71.4% concurrent chemo

therapy with cisplatin as a radiosensitizing treatment.

The first palliative line regimens included most fre-

quently carboplatin and paclitaxel in 90.5%, fo llowed by

single agent cisplatin or carboplatin in the rest of the

cases. The median number of delivered first line chemo-

therapy was 6 cycles (range 2 - 8).

Considering one loss of follow-up, a total of 73 cour-

ses of topotecan where given in the current study (a me-

dian of 3.5 cycles; range 1 - 6).

Taking into acount the possible bias of retrospective

assessments and the lack of information regarding toxici-

ties in one treated patient, the main evaluable toxicities

which occurred during the entire therapy are summarized

in Table 2. Anemia was the most frequent adverse event;

grade 2 and 3 anemia were seen in 35% and 30% resp ec-

tively. Hematologic toxicity was not cumulative and pa-

tients could receive further cycles of chemotherapy after

the initial dose was reduced according to the physician’s

discretion. There were no treatment-related death s. Over-

all, the incidence of non-hematologic toxicity was not se-

rious. Other less common grade 3 events included creat-

inine elevation in 2 cases and transaminases increasing in

one case.

Of the 20 patients evaluable, there were 2 partial re-

sponders to the treatment. The overall response rate

(ORR) was 10%, 3 patients (15%) had stable disease as

maximum response. Response was not assessed in one

patient due to loss of follow-up .

Table 2. Prevalence and grade of adverse effects (%)*.

Grade

Adverse event0 1 2 3 4

Anemia 10.0 25.0 35.0 30.0 0.0

Thrombocytopenia95.0 5.0 0.0 0.0 0.0

Neutropenia 75.0 0.0 10.0 15.0 0.0

Nausea 55.0 20.0 15.0 10.0 0.0

Vomiting 95.0 5.0 0.0 0.0 0.0

Constipation 70.0 15.0 15.0 0.0 0.0

Diarrhea 90.0 5.0 0.0 5.0 0.0

Mucositis 80.0 20.0 0.0 0.0 0.0

Muscle pain 80.0 0.0 20.0 0.0 0.0

Fatigue 80.0 5.0 15.0 0.0 0.0

Anorexia 95.0 0.0 5.0 0.0 0.0

Fever 90.0 10.0 0.0 0.0 0.0

Renal toxicity 90.0 0.0 0.0 10.0 0.0

Alopecia 75.0 25.0 0.0 NA NA

*Considerin g valid information. NA = not applicable.

Topotecan Use for Second-Line Treatment in Patients with Recurrent or Metastatic

Cervical Cancer at Brazilian National Cancer Institute (INCA)

1098

The median PFS for the entire group was 2.93 months

(95% CI 2.41 - 3.45) and OS was 4.66 months (95% CI

1.21 - 8.11).

4. Discussion

The combination of paclitaxel and cisplatin (or carbo-

platin alternatively) is a worldwide current first choice

for systemic treatment in advanced and persistent/recur-

rent cervical cancer not amenable to curative therapy

with an overall response rate of 36% [9]. Patients who

have progressed after platinum-based therapy may be

treated with second-line schemas, included in clinical

studies or receive best supportive care measures.

A variety of second-line agents have been tested in this

scenario [10-12] and the efficacy is rather modest. Topo-

tecan is one of the cytotoxic options that had been inves-

tigated for antineoplastic activity in a small number of

trials. The heterogeneity of patients accrued in these

studies render it impossible to compare results among

them. It seems that topotecan, as a single agent or in

combination, exihibits only modest activity in a popula-

tion of previously treated patients with cervical cancer

albeit at a cost of substantial hematologic toxicity [11].

There is clearly an unmet need for active new thera-

pies in the management of advanced cervical cancer. The

poor outcome for these patients warrants the develop-

ment of novel therapeutic strategies that exploit abnormal

tumor biology.

Some targeted drugs modulating different signal trans-

duction pathways are currently under clinical develop-

ment inhibiting angiogenesis, targeting epidermal gro wth

factor receptor (EGFR), cell cycle, matrix metallopro-

teinases, cyclooxygenase-2, mammalian target of rapa-

mycin (mTOR) or proteasome, evaluating efficacy and

safety [11-13]. However, no phase III trials have been

published and consequently no molecularly targeted agents

have been approved for use in clinical practice.

The limited activity of topotecan schemas in second-

line treatment of cervical cancer and the associated over-

all toxicity as shown in this retrospective study may not

justify their use in this settin g. Patients who progress after

first-line treatment may be offered participation in clini-

cal trials, other second-line agents or best supportive care

measures.

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