Long follow-up of patients with locally advanced cervical cancer treated with concomitant chemobrachyradiotherapy with cisplatin and ifosfamide followed by consolidation chemotherapy.

ORIGINAL STUDY

Long Follow-up of Patients With Locally Advanced Cervical Cancer Treated With Concomitant Chemobrachyradiotherapy With Cisplatin and Ifosfamide Followed by Consolidation Chemotherapy Branka Petric Misˇe, MD,* Tihana Boraska Jelavic, MD, PhD,* Ante Strikic, MD,* Darijo Hrepic,* Kresˇimir Tomic, MD,Þ Wolfgang Hamm, MD,þ Snjezˇana Tomic, MD, PhD,§ Tomislav Prskalo, MD,* and Eduard Vrdoljak, MD, PhD*

Objectives: Locally advanced cervical cancer (LACC) is one of the leading health problems of the developing countries. We present long-term outcomes of treatment with a concomitant chemobrachyradiotherapy followed by consolidation chemotherapy regimen. Materials and Methods: We treated 118 patients with LACC (International Federation of Gynecology and Obstetrics stages IB2-IVA) with external radiotherapy (50 Gy in 25 fractions) and concomitant chemobrachyradiotherapy (low-dose rate). Chemotherapy was applied during brachyradiotherapy (cisplatin on day 1 in combination with 24-hour infusion of ifosfamide and mesna uroprotection). Four cycles of consolidation chemotherapy were given starting 4 weeks after the second concomitant chemobrachyradiotherapy cycle. Results: After median follow-up period of 99.3 months, we observed acceptable acute and late toxicity, local control rate of 97.5%, and an overall survival of 74.6% at 96 months. Conclusions: Chemobrachyradiotherapy regimen followed by consolidation chemotherapy described in this article is a valuable treatment option for LACC. Key Words: Cervical cancer, Ifosfamide, Cisplatin, Chemobrachyradiotherapy Received September 8, 2014, and in revised form October 14, 2014. Accepted for publication October 28, 2014. (Int J Gynecol Cancer 2015;25: 315Y319)

patients were diagnosed and 266,000 have I ndied2012,from528,000 cervical cancer worldwide. The lack of pre1

vention programs and consequently higher tumor stages at diagnosis in less developed countries are important reasons

*Department of Oncology, University Hospital Split, Split, Croatia; †Department of Oncology, University Hospital Mostar, Mostar, Bosnia and Herzegovina; ‡Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim am Rhein, Germany; and §Department of Pathology, University Hospital Split, Split, Croatia. Address correspondence and reprint requests to Eduard Vrdoljak, MD, PhD, University Hospital Split, Spinciceva 1, HR-21000 Split, Croatia. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000336 International Journal of Gynecological Cancer

for the high incidence and lethality. The standard treatment for locally advanced cervical cancer (LACC) is concomitant chemoradiotherapy. A paradigm change of the treatment occurred when 5 large randomized studies investigating concomitant chemoradiotherapy were published.2Y6 These studies showed a 39% risk reduction for death when radiotherapy and a cisplatin-based chemotherapy combination was compared with radiotherapy alone.5,7 Trying to improve the outcome, we designed a regimen of concomitant chemobrachyradiotherapy with cisplatin and ifosfamide followed by 4 cycles of consolidation chemotherapy.8 The concept of our regimen was based on few main principles. The first was to concomitantly apply radiotherapy with chemotherapy with known radiosensitizing properties and proven efficacy in the treatment of cervical cancer (combination of cisplatin + ifosfamide).9,10 The second principle was to apply this combination during the brachyradiotherapy insertions

& Volume 25, Number 2, February 2015

Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

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International Journal of Gynecological Cancer

exploiting 2 potential advantages: one is to deliver chemotherapy concomitantly with 30 Gy of brachyradiotherapy and to exploit the known in vitro synergistic activity of ifosfamide with low-dose rate (LDR) radiotherapy.11 Finally, we incorporated 4 cycles of consolidation chemotherapy as part of protocol knowing that adjuvant chemotherapy improved survival in many tumor types.12,13 Results of the phase II study in which we described the outcomes of 62 patients after a median follow-up of 49 months were previously published.8,14 Because of the excellent results we achieved (recurrence-free and overall survival [OS] rate of 88.7%), we adopted this study protocol as a standard approach for the treatment of LACC in our institution. Now, we present data on 118 patients treated between 1999 and 2012.

MATERIALS AND METHODS One hundred eighteen patients with LACC eligible to our regimen, that is, International Federation of Gynecology and Obstetrics stages IB2 to IVA, regardless of histology, were treated with concomitant chemobrachyradiotherapy and consolidation chemotherapy at our center. Pretreatment diagnostic evaluation consisted of a gynecological examination and a panel of laboratory and radiological tests as follows: hematology and biochemistry blood analysis, chest radiography, computed tomography (CT)/magnetic resonance scan of the abdomen and pelvis, and intravenous urography. Cystoscopy and rectoscopy were obligatory for the first 62 patients and were performed afterwards only if spread to these organs was suspected. Patients with suspected retroperitoneal lymph nodes spread according to the abdominal CT were excluded from this analysis. The minimum requirements for application of chemotherapy were a total leukocyte count greater than 3 109/L, absolute neutrophil count greater than 1.5 109/L, thrombocyte count greater than 150 109/L, and a creatinine clearance greater than 50 mL/min. Patients with obstructive uropathy underwent urinary diversion before starting treatment. External radiotherapy was conventional, based on classical 2-dimensional diascopic planning, and executed on linear accelerators with 15-MV photons in the period between 1999 and 2010. From 2011 onwards, all patients were irradiated by 3-dimensional conformal radiotherapy, on linear accelerators, with 18-MV photon beam. The standard irradiation technique was a combination of a 4-field box irradiation with posteroanterior-anteroposterior fields with portals encompassing the primary tumor volume and pelvic lymph nodes, from the level of L4 to L5 to the bottom of the obturator foramen. In the case of vaginal involvement, the inferior field border was lowered to the vaginal introitus. The external radiotherapy dose was 50 Gy in 25 fractions, with central shielding (covering the isodose line area encompassing point A) after the first brachyradiotherapy insertion, and the planned dose to be applied to point A by external radiotherapy was 25 Gy. The first brachyradiotherapy application was scheduled after 5 to 10 fractions of external radiotherapy individually for each patient based on the initial response to treatment, assessed by gynecological examination. Brachyradiotherapy was delivered with an LDR machine (90 cGy/h) with radioactive cesium (137Cs).

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Applicators consisted of tandem (intrauterine applicator) and 2 ovoids. Two intracavitary insertions were performed 3 weeks apart. Each was scheduled to deliver 30 Gy to point A, that is, the cumulative radiation dose to point A was 85 Gy. Although the current treatment standard is an imageguided high-dose rate brachyradiotherapy, at our institution and in developing countries, LDR brachyradiotherapy is still used. Chemotherapy was applied during brachyradiotherapyV cisplatin at a dose of 75 mg/m2 over a 1-hour infusion on day 1 in combination with ifosfamide at a dose of 2000 mg/m2 over a 24-hour infusion with adequate premedication, prehydration and posthydration, and with mesna uroprotection. Consolidation chemotherapy was scheduled to begin 4 weeks after the second concomitant chemobrachyradiotherapy cycle. Cisplatin was administered at the same dose on day 1 together with ifosfamide 2000 mg/m2 in a 3-hour infusion on days 1 to 3, for 4 cycles three times a week. During treatment and before each cycle, patients were evaluated by clinical assessments and complete blood counts. After the completion of the whole treatment, the disease status and the treatment-related toxic effects were evaluated by means of a history taking, a gynecological examination, a biopsy of the cervix, a CT scan of the abdomen, a complete blood count, and blood biochemistry. Thereafter, patients were evaluated three times every month by history taking, gynecological examinations, and blood counts in the first 2 years of follow-up, every 4 months in the third year, and every 6 months afterwards. Tumor response was defined as either complete response (complete pathologic, radiologic, and clinical disappearance of the tumor), partial response (950% shrinking of the tumor, no change or G50% shrinkage of the tumor size, or G25% increase in the tumor size), or progressive disease (925% increase in the tumor size or the appearance of new lesions). Toxicity was assessed at each follow-up using the World Health Organization criteria. Data on patients were analyzed using Microsoft Excel and SPSS 21.

RESULTS Between 1999 and 2012, 118 patients diagnosed with LACC who were eligible to our protocol were treated accordingly. The median follow-up is 99.3 months. Baseline characteristics of the patients are shown in Table 1. All patients received the full course of concomitant chemobrachyradiotherapy, and 91.5% of them received at least 1 cycle of consolidation chemotherapy. Nine patients did not receive consolidation chemotherapy (5 due to persisting hematological toxicity and 4 because of age and/or worsened Eastern Cooperative Oncology Group status). The radiotherapy dose delivered to point A to all patients by means of external and intracavitary brachyradiotherapy was 85 Gy. The mean duration of whole radiotherapy was 45.2 days. The average number of chemotherapy cycles was 4.7 with a median dose intensity of 98%. The median time interval between the consolidation chemotherapy cycles was 27.5 days. After the concomitant chemobrachyradiotherapy, * 2015 IGCS and ESGO




TABLE 1. Baseline patient characteristics Characteristic n Age, median (range), y ECOG 0 1 2 FIGO IB (bulky) IIA IIB IIIA IIIB IVA Tumor grade 1 2 3 Unknown Tumor histology Squamous cell carcinoma Adenocarcinoma Adenosquamous carcinoma

n

%

118 52.7 (27Y77)

100

106 11 1

89.8 9.3 0.9

13 16 65 0 21 3

11.0 13.6 55.0 0 17.8 2.6

13 77 18 10

11.0 65.2 15.2 8.6

108 8 2

91.5 6.7 1.8

ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics.

a complete clinical response was achieved in all patients (100%). All patients were assessed for acute toxicity during treatment. Chemotherapy toxicity was managed by dose delays rather than by dose reductions. The most common acute toxicity was hematological (Table 2). Approximately in 33% of the cycles, a grade 3 or 4 leukopenia was observed. Ten patients developed febrile neutropenia (8.7%). We used a granulocyte colonyYstimulating factor in cases of severe leukopenia and/or neutropenia. Anemia occurred in 85% of the cycles (69.8% grade 1 or 2). There were no treatment-related deaths. We lost 3 patients to follow-up, and 39 patients have died (18 from cervical cancer and 21 from other causes). The

Long Follow-up of Patients With LACC

Kaplan-Meier curve of OS is shown in Figure 1. We observed a 78% OS rate at 48 months and a 74.6% OS rate at 96 months of follow-up. Disease-free survival (DFS) was defined as the time from diagnosis without relapse of cervical cancer or occurrence of a new cancer or death from any other reason. Figure 2 shows the Kaplan-Meier curve of DFS. We observed a 76.5% and 72.2% DFS at 48 months and at 96 months of follow-up, respectively. Eighteen patients had documented relapse of cervical cancers. Three patients were diagnosed with new primary tumors, 2 with lung cancer and 1 with endometrial malignant mixed Mu¨llerian carcinoma. Three local recurrences occurred; 1 patient developed both local and distant recurrence. The most often first sites of distant recurrence were in the retroperitoneal lymph nodes and the lung (Table 3). The median time to recurrence was 13.8 months. During the follow-up, the patients were evaluated for late treatment-related local toxicities (Table 4). Late local toxicity occurred in 28 patients (23.9%), with some patients experiencing more than 1 toxicity. Twenty-two patients developed grade 3 or 4 late local toxicity (18.8%). The most prevalent toxicity was gastrointestinal, especially postirradiation proctitis and colitis.

DISCUSSION The cure rate of radiotherapy for LACC is approximately 50% because the doses required to treat large tumors exceed the limits of tolerability of tissues involved in the radiotherapy fields.15 Efforts to overcome this problem have resulted in the acceptance of concurrent chemoradiotherapy as a standard with 5-year OS rates of approximately 65% (55%Y73%).2,4,5 Cochrane review article suggested that chemoradiation improves OS by 31% in relative or 10% in absolute terms and progression-free survival by 34% in relative or 13% in absolute terms. The rate of local recurrence based on 14 trials enrolled in this meta-analysis was significantly reduced by the use of chemoradiation (odds ratio, 0.59; 95% confidence interval, 0.50Y0.69; P G 0.00001).16 Nevertheless, published studies show still rather high local recurrence rate (20%) when cisplatin was added to radiotherapy.6 Therefore, there is an unmet need to both improve the local control rate and lower the incidence of distant metastases.

TABLE 2. Acute toxicity occurrence Grade

0, n (%)

Leukopenia Anemia Thrombocytopenia Increase in urea and/or creatinine level Diarrhea Nausea Vomiting

102 81 353 514 463 293 339

(18.9) (15.0) (65.4) (95.2) (85.7) (54.3) (62.8)

1, n (%) 79 215 111 6 46 121 85

(14.6) (39.8) (20.6) (1.1) (8.5) (22.4) (15.7)

2, n (%) 132 173 26 2 23 106 96

(24.4) (32.0) (4.8) (0.4) (4.3) (19.6) (17.8)

3, n (%) 134 (24.8) 34 (6.3) 16 (3.0) 1 (0.2) 9 (1.7) 22 (4.1) 21 (3.9)

* 2015 IGCS and ESGO


4, n (%) 51 3 2 2 0 0 1

(9.4) (0.6) (0.4) (0.4)

(0.2)

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TABLE 3. Distribution of first sites of cervical cancer relapse Sites of Recurrence

n (%)

Median Time Until Recurrence, mo

Local (cervical or 2 (1.7) pelvic) Distant 15 (12.7) Distant and local 1 (0.8)

FIGURE 1. Kaplan-Meier analysis of OS. Potentially successful strategy to improve local control is combining chemotherapy and LDR brachyradiotherapy to improve systemic control administering consolidation therapy.8 When designing new regimens for the successful treatment of LACC, we must take into consideration their price and feasibility. We used a combination of efficient and affordable drugs and radiotherapy. As first-line therapy, ifosfamide and cisplatin showed response rates of 50% to 62% and 85%, respectively.16,17 Hence, it seemed justified to hypothesize that such approach will result in better distant and local control rates. Data on long-term follow-up results of the treatment of LACC are scarce. In this report, we present the 99.3 months median follow-up data of 118 patients. The previously observed response rate of 100% in first 62 patients has been confirmed after 118 patients. This is the highest complete clinical response rate in this setting described so far.18Y20 Some trials describe local control as complete and partial response. The highest result achieved was 95.8%, although the authors did not state the percentage of patients achieving complete response.21

50.1 15.9 13.8

In our case, with 99.3 months of median follow-up, the local control rate is 97.5%, higher than results published for similar patients.4,22 We conclude that local control is a reality for almost all patients if treated with LDR brachyradiotherapy concomitantly with ifosfamide and cisplatin. The systemic control rate is also exceptional in comparison to other results published, underlining the importance of the adequate chemotherapy (combination chemotherapy, 6 cycles) given to patients with LACC.2,3,5 The control rates resulted in excellent 4-year and 8-year DFS rates. In addition, the 4-year and 8-year OS rates are remarkable in comparison to the results from the previously mentioned studies.5 The observed acute toxicities (all grades or grade 3 or 4) were in the range or higher than similar chemotherapy or chemoradiotherapy schedules.5,23 Potentially higher rate of acute toxicities seen in our regimen is most probably due to greater number of chemotherapy cycles given in our protocol as well as the combination chemotherapy we used. No treatment-related deaths were observed. The late toxicities were also within the range of other reported results for similar patient populations.24 Our results underline the need to address the question of adjuvant or consolidation chemotherapy as well as the potential of LDR brachyradiotherapy in treating LACC. The impact of administering neoadjuvant or adjuvant therapy on OS, DFS, and safety in patients with LACC is investigated in 2 ongoing international phase III clinical trials, in which results are expected in 5 years.25,26 At last, cervical cancer occurs 3 times less frequently, but with a higher mortality rate than breast cancer (mortality rates of 50.3% vs 31.3%, respectively).1 Although the incidence of breast cancer is 3 times higher and bears a TABLE 4. Late local toxicity expressed per localization (total no. diagnosed toxicities) Toxicity

FIGURE 2. Kaplan-Meier analysis of DFS.

318

Postirradiation proctitis Postirradiation colitis Postirradiation cystitis Rectovaginal fistula Ureteral obstruction Vesicovaginal fistula Postirradiation vaginitis Subcutaneous fibrosis

Highest Grade of Toxicity n (%) 2 4 4 4 4 4 2 2

6 (5.1) 8 (6.8) 3 (2.5) 7 (5.9) 8 (6.8) 1 (0.8) 2 (1.7) 1 (0.8)





significantly better prognosis, the investments in cancer research are almost 9 times higher, according to the National Cancer Institute 2012 funding database.27 Moreover, we conduct less clinical trialsVa search at the clinicaltrials.gov Web site for the key word ‘‘breast, open studies’’ hit 2269 studies and only 143 studies when ‘‘uterine cervix, open studies’’ were searched for.28,29 Consecutively, given the mortality rates and the significance of cervical cancer, we have to do more to improve the currently available treatment options and make those improvements affordable and feasible to the less developed countries.

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