Review

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Management of advanced or recurrent cervical cancer: chemotherapy and beyond Expert Rev. Anticancer Ther. 14(3), 319–332 (2014)

Laurie M Elit1* and Hal Hirte2 1 Department of Obstetrics and Gynecology, 699 Concession Street, McMaster University, Hamilton, ON, L9G 2Z8 Canada 2 Department of Oncology, McMaster University, 699 Concession Street, Hamilton, ON, Canada *Author for correspondence: Tel.: +1 905 389 5688 Fax: +1 905 575 6343 [email protected]

Metastatic or recurrent cervical cancer has a survival duration of approximately 12 months. Thus, we review the outcomes of chemotherapy and/or novel agents for women who present in this situation. Included were studies in women with advanced or recurrent cervical cancer where at least response rate, survival or toxicity were reported. Platinum alone chemotherapy at 50 mg/m2 is superior to other single-agent platinum or nonplatinum regimens in terms of efficacy and toxicity profile. Platinum with either paclitaxel, gemcitibine, topotecan or vinorelbine has equivalent efficacy but differ with respect to toxicity profile and convenience of treatment regimen. Bevacizumab in addition to combination chemotherapy provides a duration of survival that is 3.7 months longer than that provided by combination chemotherapy alone. EGF receptor (EGFR) tyrosine kinase inhibitor agents did not provide promising efficacy. Bevacizumab in addition to combination chemotherapy provides superior efficacy with acceptable toxicity. Evaluation of other novel targeted antiangiogenic agents, either alone or in combination with chemotherapy is ongoing. KEYWORDS: antiangiogenic agents • cervical cancer

In 2010, 530,000 women globally were diagnosed with cervical cancer, and 250,000 women died of the disease [1]. This is a tragedy given that vaccination and/or screening can prevent cervical cancer. Vaccines can prevent 70% of the cervical cancers; however, it will take several generations to see an impact on cervical cancer incidence [2]. Cervical cancer screening has resulted in a 70% drop in cervical cancer rates globally [3,4]. The problem with implementing cervical cancer screening in low and middle resource setting is related to the complex infrastructure required to provide cervical cancer screening with cytology. There is promising work using visual inspection with acetic acid as the screening test in such settings [4]. When cervical cancer is identified and confined to the cervix (early-stage disease), this can be cured through radical surgery. Locally advanced disease (stage 1b2 through 4a) is treated with moderate cure rates using chemoradiation [5]. In contrast, metastatic or recurrent disease has a 25% response rate (RR) even with aggressive treatment and only a 12-month median survival from the date of recurrence. Unfortunately, 75% of women

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10.1586/14737140.2014.866041

with cervical cancer who live in low resource settings present with locally advanced disease. In this paper, we will review the outcomes of systemic therapy options for metastatic, relapsed or recurrent cervical cancer. We will discuss evolving data concerning novel agents. Methods

A literature search using Medline (2005– 2013), National Guidelines Clearinghouse, Clinicaltrials.gov was conducted using the search terms: disease-specific terms (‘cervical cancer,’ ‘cervical neoplasm’ and ‘metastatic’ or ‘recurrent’ or ‘advanced’); and treatment terms (‘chemotherapy,’ ‘biologic or noncytotoxic agents’). Included were Phase I, II or III studies in women with advanced, recurrent or persistent cervical cancer, respectively, where the authors reported at least one of the following outcomes: RR, survival or toxicity. Where novel agents were concerned, we included results where the novel agent was used alone or in combination with chemotherapy (concurrently or sequentially). Excluded were nonEnglish publications and publications where radiation was included in the treatment

Ó 2014 Informa UK Ltd

ISSN 1473-7140

319

Review

Elit & Hirte

strategy. We purposely do not discuss high-risk histologies like neuroendocrine, clear cell or papillary serous cervical cancers. Relevant articles and abstracts were selected and reviewed, and the reference lists from these sources and review articles were searched for additional trials. Results

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Chemotherapy

Most cervical cancers are squamous histology (80%) with a smaller proportion being adenocarcinoma. It is not known whether the squamous cell and adenocarcinomas behave in a similar or different manner when exposed to chemotherapy. Single-agent chemotherapy Phase II trials with single agents

Several agents have been explored in Phase II trial designs with women who have metastatic, persistent or recurrent cervical cancer. In the original Phase II Gynecologic Oncology Group (GOG) study with cisplatin, the RR was 50% in 22 women who had not received prior chemotherapy and 17% in 12 patients who received prior treatment [6,7]. Other agents that were found to be active included paclitaxel [8–10], topotecan [11–13], ifosfamide [14–18] and vinorelbine [19–22]. RRs with these agents were in the range of 20% with an overall duration of survival of 9–11months. Performance of other single agents like teniposide [23], mitomycin C [24], 5FU [25], pemetrexed [26,27], mitolactol [28], gemcitabine [29,30], docetaxel [31], irinotecan [32] and pegylated liposomal doxorubicin [33] were lower. It is difficult to compare results across studies as the degree of pretreatment varies as well as the histologic type of disease (i.e., some studies include only women with squamous histology, while other studies include women with squamous, adenocarcinoma and adenosquamous histologies). Other chemotherapy agents undergoing Phase II evaluation include eribulin mesylate (E7389), which is a novel inhibitor of microtubule dynamics (ClinicalTrials.gov identifier: NCT 016768218), and ixabepilone (BMS 247550), which is in the epithilone class of agents (ClinicalTrials.gov identifier: NCT 00924066). Phase III trials Phase III trials with one arm as cisplatin alone

The single cisplatin arm of 50 mg/m2 consistently provided a 20% RR in numerous studies [34–38]. Rapid versus slow infusion of cisplatin did not affect RR (18%) or rate of side effects [39]. Platinum-based treatment has shown RRs of 20–30% regardless of the dose (i.e., 50 mg/m2 or 100 mg/m2 q3wk) [40] or schedule (1 days q3weekly vs daily for 5 days q3weekly) [40]. The progression-free survival (PFS) or overall survival (OS) was similar between arms, and higher doses were associated with greater nephrotoxicity and myelosuppression. Doses lower than 50 mg/ m2 did not appear to be as effective (i.e., 37.5 mg/m2 [32]

after failing these agents, those who received subsequent cisplatin had a surprisingly high RR (18%) [41]. With carboplatin, there was minimal nephrotoxicity and neurotoxicity, and outpatient administration was possible without prehydration [41]. Studies by Lira-Puerta [42] and Thomsen [44] did show a 26 and 33% RR, respectively, with carboplatin 400 mg/m2. Within-study assessments showed no superiority of iproplatin [42] or teniposide [44] over carboplatin. PFSs were in the order of 3–4.6 months and overall survivals of 5.5–9.5 months [42,44]. Phase III trials with nonplatinum agent(s)

A Phase III study where one arm was bleomycin alone [45] or hydroxyurea alone [46] had no responses. Phase III studies with doxorubicin showed RRs in the 20% range with PFS of 3.5 months and overall survival of 5.5–7.3 months [46–48]. A Phase III study with irinotecan showed a low RR of 13% [35]. Combination agent chemotherapy Phase II trials

The purpose for Phase II studies with combination agents is to identify if there is activity over and above the standard (which in this case is platinum alone) and to determine whether the side effect profile was acceptable. Platinum doublets

Combinations that did not appear to have a benefit over and above cisplatin alone included the combinations of cisplatin and 5FU [48], or with mitomycin C [7] or with tirapazamine [49] or with methotrexate, vinblastine and bleomycin [7]. Cisplatin and paclitaxel [9,50,51] had good activity with 32% grades 3–4 neutropenia and 32% grades 3–4 anemia [51]. Carboplatinum and paclitaxel had good activity, but 61.4% had grade 4 neutropenia and 27.7% neutropenic sepsis resulting in 4.5% deaths [50]. Gemcitabine and cisplatin had modest activity [52–56] with low toxicity (i. e., 2.4% grade 4 neutropenia, 1.2% grade 4 anemia [52] and 20% grade 4 neutropenia, 10% grade 4 anemia [53]). Topotecan and cisplatin also had modest activity with 30% grades 3–4 neutropenia and 10% thrombocytopenia [57]. Cisplatin and vinorelbine had modest activity with 67% grade 4 neutropenia [58]. Methotrexate, vinblastine, doxorubicin and cisplatin had high RR (51–66%), but toxicity was significant [59–61]. Phase II trials with nonplatinum doublets

The paclitaxel and topotecan combination had a good RR with an acceptable side effect profile (47% grades 3–4 anemia, 27% leucopenia, 13% thrombocytopenia, 13% neurotoxicity) [62]. The Scottish trial with docetaxel and gemcitibine had modest activity, but the toxicity was so high that Day 8 gemcitabine had to be omitted in 41% of the cycles [63]. Phase III trials

Phase III trials with other platinum agents given as monotherapy

Other platinum agents like carboplatin [41], iproplatin [41,42,201] and oxaliplatin [43] did not perform as well as cisplatin. In fact, 320

Phase III trials are conducted to determine either superiority or noninferiority of an agent or combination of agents compared with the standard of care. Expert Rev. Anticancer Ther. 14(3), (2014)

Management of advanced or recurrent cervical cancer

Phase III trials involving cisplatin

shows that cisplatin alone at 50 mg/m2 q3weeks was superior to combinations with methotrexate, vinblastine and bleomycin [7] or mitomycin C [7]. Combination chemotherapy arms that showed superiority over either a concurrent arm of single-agent cisplatin or historical rates for cisplatin included ifosphamide and cisplatin [34] (improved RR and PFS but not OS), 5FU–ifosfamide–cisplatin [35] (improved RR), irinotecan with cisplatin [36], paclitaxel with cisplatin [37] (improved RR and PFS but not OS), BEMP (bleomycin, etoposide, mitomycin, cisplatin) [38] and topotecan and cisplatin [64]. GOG 179 was the first GOG randomized study to show a combination regimen (cisplatin and topotecan) that had a superior OS. What GOG 169 [27] and GOG 179 [64] also showed was that women who had not received prior cisplatin had superior outcomes compared with those who had (i.e., PFS were HR: 0.50 vs 0.87; OS were HR: 0.63 vs 0.78). In terms of toxicity, the combination arms had higher toxicities. Omura et al. showed that peripheral and central neurotoxicity (i.e., somnolence, coma, seizures) were more frequent and severe in the ifosfamide with cisplatin arm [34]. Long et al. showed 17.7% febrile neutropenia for the combination arm versus 7.5% [64] but both GOG 169 and 179 showed no change in quality of life in the combination regimen [37,64]. Lack of superiority of one combination over another was seen in cisplatin and ifosfamide versus the combination with bleomycin [65], and cisplatin with topotecan, paclitaxel, gemcitibine or vinorelbine [66]. RRs were in the range of 22–29%, median PFS was 4–6 months and median OS 11–13 months. Performance status was the greatest predictor for response to treatment. Measurable disease in the radiated field was associated with 41% greater risk of death (HR: 1.41; 95% CI: 1.10– 1.81). Toxicities were similar with differential rates of alopecia, hematologic and infection [66]. The Japanese showed that carboplatin and paclitaxel were not inferior to cisplatin and paclitaxel [67,68]. However, in women who had not had prior platinum, the cisplatin and paclitaxel combination was superior with an OS of 23.2 versus 13 months (HR: 1.57; 95% CI: 1.06–2.32). When efficacy is equivalent across regimens within the same randomized trial, decision for treatment must consider the toxicity profile, patient comorbidities, convenience and cost.

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TABLE 1

Angiogenesis

Angiogenesis is the development of new blood vessels in areas of new tissue growth like wound healing, embryogenesis and tumors. As the oxygen tension in the tissue falls below the level required for oxidative metabolism, a protein is liberated known as hypoxia-inducible factor (HIF 1 alpha). HIF 1 alpha couples with HIF-1 beta and upregulates growth factors like VEGF. The VEGF family includes six related molecules with VEGF-A as the most important. VEGF causes endothelial cell proliferation with migration toward, for example, tumor cells. This leads to loop vessel and tubule formation. Ultimately neovascularization occurs. Other cells like pericytes are recruited to stabilize the new informahealthcare.com

Review

vessels. Eventually, the growth factors are no longer required; however, constant remodeling allows the tumor to grow. Angiogenesis is a key activity in cervical cancer growth and metastasis given the unique combination of human papillomavirus (HPV) infection with upregulation of E6, which is associated with VEGF secretion and hypoxia which also drives VEGF. Copper et al. showed in a 111 cervical cancer patients that tumor angiogenesis as reflected by tumor microvessel density [69], was a significant prognostic factor associated with poor locoregional control and OS. This finding has been replicated in other cervical cancer population [70–72]. Monoclonal antibodies against VEGF Bevacizumab

Bevacizumab is a monoclonal antibody, which targets VEGF especially VEGF-A. Low doses of bevacizumab decrease the microvascular density, perfusion, interstitial fluid pressure and number of circulating endothelial cells. Pruning of the neovasculature retards the shedding of metastatic cells into the circulation, improves delivery of therapeutic agents to tumors and works synergistically with both chemotherapy and/or radiation by improving oxygenation of tumor. Wright et al. conducted a retrospective study of six cervical cancer patients who had multisite metastatic disease and who had been heavily pretreated [73]. Bevacizumab was used in conjunction with 5FU (five patients) and capecitabine (one patient). Bevacizumab was given 5–15 mcg/kg q2weeks. There was one woman with a complete response 17%, one with a partial response (PR: 17%) and two with stable disease (SD) for a 33% RR. Time to progressions was 4.3 months. There was one woman who experienced neutropenic sepsis after her second dose and one woman developed hypertension. GOG conducted a Phase II multicenter trial of bevacizumab 15 mcg/kg every 3 weeks in 46 women with persistent or recurrent squamous cell carcinoma of the cervix [74,75]. Eightythree percent of the participants had received prior radiation and 1–2 prior lines of chemotherapy. RR was 10.9% (95% CI: 4.4–21.5%). Median PFS was 3.4 months (95% CI: 2.53– 4.53). Median OS was 7.29 months (9.5% CI: 6.11–10.41). Twenty four percent of the participants survived 6 months or longer without progression (90% CI: 14–37%). Severe grades 3–4 hypertension occurred in 7 (15.2%), deep venous thrombosis/pulmonary embolus in 5, gastrointestinal issues in 4 and one woman developed a fistula. It was felt that bevacizumab had modest activity in second- and third-line treatment of women with recurrent cervical comparable to rates of activity in historical GOG Phase II trials with this population. GOG conducted a Phase II trial of bevacizumab with topotecan and cisplatin (GSK 107278). Results are pending. GOG conducted a four-arm trial (2  2 factorial design) addressing the impact of a platinum combination (cisplatin and paclitaxel) compared with a nonplatinum combination (paclitaxel and topotecan) and the effect of adding in bevacizumab at 15 mcg/m2 [76] (GOG 240, ClinicalTrials.gov identifier: NCT00803062). As reported at ASCO 2013, the combination 321

322 III III

Cisplatin 50 mg/m2 day 1 Ifosfamide 5 g/m2 d1 Bleomycin 30 U q21 days

Cisplatin 50 mg/m2 d1 Ifosfamide 5 g/m2 day 1 q21 days

Cisplatin 50 mg/m2 Paclitaxel 135 mg/m2/24 h q21 days

Cisplatin 50 mg/m2 q21days

MVAC MTX 30 mg/m2 days 1, 15 and 22 Vinblastine 3 mg/m2 days 2, 15 and 22 Doxorubicin 30 mg/m2 day 2 Cisplatin 70 mg/m2 q28 days

Bloss et al. (2002); GOG 149

Bloss et al. (2002); GOG 149

Moore et al. (2004); GOG 169

Moore et al. (2004); GOG 169

Long et al. (2005); GOG 179

Squamous and nonsquamous

Squamous

63

134

130

144

143

39

19

36

32

31.2

14 p = 0.005

24

13

19

37

17.8

21.1

31.1

Response rate (%)

2.8

4.8

4.6

5.1

4.5

5.3

3.2

3.3

4.6

PFS (months)

BEMP: Bleomycin, etoposide, mitomycin, cisplatin; Chemo: Chemotherapy; MVAC: Methotrexate, vinblastine, doxorubicin and cisplatin; OS: Overall survival; PFS: Progression-free survival.

III

III

146

III

Cisplatin 50 mg/m2 q21 days

Vermorken et al. (2001)

Squamous

141

III

BEMP Bleo 15 mg in a 24 h iv. days 2–4 VP16 3 mg/m2 day 1 Cisplatin 50 mg/m2 Mitomycin 8 mg/m2 q21 days

Vermorken et al. (2001); EORTC

Squamous

III

Irinotecan

Garin et al. (2001)

31

III

Cisplatin 80 mg/m2

27

140

Garin et al. (2001)

Squamous

147

III

III

Cisplatin 50 mg/m2 q21days

Omura et al. (1997)

Squamous

151

Total

Cisplatin 80 mg/m Irinotecan

III

Cisplatin 50 mg/m2 Mitolactol 180 mg/m2 PO q21 days

Omura et al. (1997)

Squamous

Prior chemo

Garin et al. (2001)

III

Cisplatin 50 mg/m2 Ifosfamide 5 mg/m2 over 24 h q21 days

Omura et al. (1997); GOG 110

Histology

2

Phase

Agents

Study (year); group

Closed early dt 4 Tx related deaths

8.8

9.7

8.5

8.4

9.3

10.1

8.3

7.3

8.3

OS (months)

Table 1. Randomized controlled trials since 1997 where at least one arm is the combination chemotherapy for women with advanced metastatic or recurrent cervical cancer.

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[64]

[37]

[37]

[65]

[65]

[38]

[38]

[35]

[35]

[35]

[34]

[34]

[34]

Ref.

Review Elit & Hirte

Expert Rev. Anticancer Ther. 14(3), (2014)

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III

III

Cisplatin

PIF – 5FU 500 mg/m2 days 1, 2 + FA Ifosfamide 2 g/m2 days 1 , 2 + mesna Cisplatin 37.5 mg/m2 q28 days

Cisplatin 37.5 mg/m2 q28 days

Long et al. (2005)

Cadron et al. (2005)

Cadron et al. (2005)

III

III

III

III

III

III

Cisplatin 50 mg/m2 Topotecan 0.75 mg/m2 days 1,2 and 3 q21 days

Cisplatin 50 mg/m2 Gemcitabine 1,000 mg/m2 days 1 and 8 q21 days

Cisplatin 50 mg/m2 Vinorelbine 30 mg/ m2 days 1 and 8 q21 days

Cisplatin 50 mg/m2 day 2 q3wk Paclitaxel 135 mg/m2 over 24 h q21 days

Carboplatinum AUC 5 day 1 Paclitaxel 175 mg/m2 day 1 3 h q21days

Cisplatin 50 mg/m2 day 1 Paclitaxel 135–175 mg/m2 over 24 h q3wk

Monk et al. (2009)

Monk et al. (2009)

Monk et al. (2009)

Kitagawa et al. (2012); JCOG0505 Saito et al. (2010)

Kitagawa et al. (2012); JCOG0505 Saito et al. (2010)

Tenwari et al. (2013); GOG 240

Squamous and nonsquamous

Squamous and nonsquamous

Squamous and nonsquamous

Squamous and nonsquamous

Squamous and nonsquamous

squamous and nonsquamous

Histology

No

No

No

No

Prior chemo

121

123

108

112

111

103

11

10

146

147

Total

62.6

58.8

25.9

22.3

23.4

29.1

9

40

13

27

Response rate (%)

6.21

6.9

4.0

4.7

4.6

5.8

2.9

4.6

PFS (months)

BEMP: Bleomycin, etoposide, mitomycin, cisplatin; Chemo: Chemotherapy; MVAC: Methotrexate, vinblastine, doxorubicin and cisplatin; OS: Overall survival; PFS: Progression-free survival.

III

Cisplatin 50 mg/m day 2 Paclitaxel 135 mg/m2 over 24 h q21 days

Monk et al. (2009); GOG 204

2

III

Cisplatin 50 mg/m2 Topotecan 0.75 mg/m2 days 1–3 q3wk

Long et al. (2005)

III

Phase

Agents

Study (year); group

14.3

17.5

18.3

10.0

10.3

10.3

12.9

13

12.3

6.5

9.4

OS (months)

Table 1. Randomized controlled trials since 1997 where at least one arm is the combination chemotherapy for women with advanced metastatic or recurrent cervical cancer (cont.).

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[76]

[67,68]

[67,68]

[66]

[66]

[66]

[66]

[36]

[36]

[64]

[64]

Ref.

Management of advanced or recurrent cervical cancer

Review

323

[76]

[76]

17.5

16.2

III

III

III

Paclitaxel 175 mg/m2 day 1 3 h q3wk Topotecan 0.75 mg/m2 days 1, 2 and 3 q21 days

Cisplatin 50 mg/m2 day 1 Paclitaxel 135–175 mg/m2 over 24 h q3wk Bevacizumab 15 mcg/m2 3 h q21 days

Paclitaxel 175 mg/m2 day 1 3 h q3wk Topotecan 0.75 mg/m2 days 1, 2 and 3 q3wk Bevacizumab 15 mcg/m2 3 h q21 days

Tenwari et al. (2013)

Tenwari et al. (2013); GOG 240

Tenwari et al. (2013)

BEMP: Bleomycin, etoposide, mitomycin, cisplatin; Chemo: Chemotherapy; MVAC: Methotrexate, vinblastine, doxorubicin and cisplatin; OS: Overall survival; PFS: Progression-free survival.

[76]

OS (months) PFS (months) Response rate (%) Total Prior chemo Histology Phase Agents Study (year); group

Table 1. Randomized controlled trials since 1997 where at least one arm is the combination chemotherapy for women with advanced metastatic or recurrent cervical cancer (cont.).

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324

13.7

Elit & Hirte

Ref.

Review

chemotherapy-alone arms provided no difference in outcome. However, when bevacizumab was added, the median OS was 17 months compared with 13.3 months alone with a HR for death of 0.71 (97.6% CI: 0.54–0.94; p = 0.0035). This improvement in OS of 3.7 months was considered to be clinically meaningful. Median PFS was 8.2 months for the bevacizumab arms compared with 5.9 months in the chemotherapy arms for a HR 0.67 (95% CI: 0.54–0.82; p = 0.0002). RRs were 48 versus 36%, p = 0.00807 favoring the bevacizumab arms. Of interest, over 70% of the women had already had prior platinum therapy and still there was no difference in the outcome between the two chemotherapyalone arms. Subset analysis showed that bevacizumab favored women aged 48–56 years old and women with squamous cell histology. Toxicity was higher in the two arms where bevacizumab was given; for example, deep venous thrombosis/ pulmonary embolus was 8 versus 1%, grade 3 GI fistula 3 versus none, grade 3 urinary tract fistula 2% versus none, grade 2 or higher hypertension 25 versus 26%, grade 4 neutropenia 35 versus 26%. The rate of serious adverse events was below 10%. Small-molecule tyrosine kinase inhibitor of VEGFR Sunitinib malate

Sunitinib is an oral multitargeted tyrosine kinase inhibitor (TKI) of VEGF 1, 2 and 3 and PDGF receptor-A and B (R-A and B) and c-kit and PDGFR [77]. The National Cancer Institute of Canada conducted a Phase II trial in 19 women with locally advanced or metastatic cervical cancer [78]. All had had prior chemotherapy and radiation. Patients received 50 mg/day and one cycle was 6 weeks (4 weeks on followed by 2 weeks off treatment). There were no objective responses, but 84% had SD for a median duration of 4.4 months (2.3–17 months). The median time to progression was 3.5 months (2.7– 7 months). Four women developed a fistula while on study and one woman developed a fistula after discontinuing the medication. The conclusion was that sunitinib had not shown efficacy as a single agent for cervical cancer. The National Cancer Institute is conducting a Phase I study of sunitinib with hydroxychloroquine in patients with advanced solid tumors who have not responded to chemotherapy. Cervical cancer patients will be allowed to participate (ClinicalTrials. gov identifier: NCT 00813423) [78]. Pazopanib

Pazopanib is a small-molecule multikinase inhibitor targeting VEGFR (-1, -2 and -3), PDGFR and c-KIT tyrosine kinases. A three-arm multicenter randomized trial was conducted among 230 women with advanced stage 4b or recurrent or persistent cervical cancer [79]. Arm 1 was pazopanib 800 mg OD PO (n = 74). Arm 2 was lapatinib 1,500 mg OD PO (n = 78) and arm 3 was lapatinib 1,000 mg with pazopanib 800 mg PO OD (n = 64). The agent(s) were continued until disease progression or serious adverse event. The combination arm was discontinued due to a futility analysis, which included a higher Expert Rev. Anticancer Ther. 14(3), (2014)

Management of advanced or recurrent cervical cancer

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rate of serious adverse events. Pazopanib improved PFS (HR: 0.66; 90% CI: 0.48–0.91; p = 0.013) and OS (HR: 0.67; 90% CI: 0.46–0.99; p = 0.045). OS with pazopanib was 50.7 weeks compared with lapatinib that was 39.1 weeks. The main grade 3 adverse event of >10% was diarrhea (11% with pazopanib and 13% with pazopanib). Due to the absence of a standard treatment arm (i.e., platinum doublet), the impact of pazopanib is difficult to know. However, pazopanib as an oral formulation has clear antineoplastic activity with a low incidence of high-grade toxicities, so further assessment is warranted [77].

Review

of cervical cancers have EGFR-1%, 9–64% have EGFR-2, 100% have EGFR 3 and 63% have EGFR4. Presence of EGFR in histologic samples has been associated with poor prognosis [83–88]. EGFR is expressed more significantly in squamous cell carcinoma than in adenocarcinoma [83,87,89,90]. Various strategies have been developed to block EGFR function and promote cell death. These include: monoclonal antibodies that interfere with ligand binding; small-molecule kinase inhibitors that selectively block receptor activation; ligand conjugated toxins; antisense-EGFR oligonucleotides; and epidermal growth factor vaccines.

Cediranib

Cediranib is a multikinase inhibitor of VEGFR and PDGFR. Cediranib in recurrent cervical cancer is a placebo controlled randomized trial comparing cediranib versus placebo as an addition to carboplatinum and paclitaxel. It has closed to accrual (ClinicalTrials.gov identifier: NCT01229930). The primary end point is PFS with a sample size aimed to show a 50% increase compared with placebo. Secondary end points include RR, toxicity and quality of life [77]. Other-TNP-470

TNP-470 is a fumagillin analogue [80–82]. It was one of the first antiangiogenic compounds to enter clinical trials. TNP-470 was given at 60 mg/m2/h IV q2days for 4 weeks with a 2 week rest to 18 evaluable women with squamous cell carcinoma [80]. The maximum tolerated dose was 60 mg/m2. Three patients had progressive disease, which stabilized for 5, 7.7 and 19 months, respectively. One patient had grade 3 nausea. The dose-liming toxicity was neurotoxicity. EGF receptor

There has been increased understanding of the molecular and cellular processes involved in tumor progression. This has led to the identification of pathways that can be targeted and so lead to tumor stabilization or possibly regression. EGF receptor (EGFR) is a membrane tyrosine kinase expressed by most epithelial cells. EGFR is a family of four transmembrane receptors (EGFR 1, 2, 3, 4) [77,83]. EGFR 2 is also known as Her-2/neu. EGFR 1, 2 and 4 proteins are transmembrane tyrosine kinases that are autophosphorylated when engaged by their ligand. EGFR 3 does not have tyrosine kinase activity but can dimerize with other EGFR partners and lead to activation of EGFR pathway. Binding of the ligand to the receptor causes receptor dimerization, autophosphorylation and begins a cascade of downstream events, which leads to cellular proliferation, motility and resistance to apoptosis in epithelial tumor cells [83]. EGFR signaling is important for normal cell function, but inappropriate activation or overexpression can contribute to malignancy. Cervical epithelial cells secrete several EGF-like growth factors that activate the EGFR. In addition, HPV E6 causes activation of EGFR as an important step for the HPV life cycle and progression from infection to cancer. EGFR has been shown to be expressed at moderate-to-high levels in cervical dysplasia and cancer [84]. Vaidya et al. [83] showed that 54–77% informahealthcare.com

Antibody Cetuximab

Cetuximab is an antiEGFR antibody with high-affinity binding to the EGFR. Cetuximab alone or with chemotherapy

Cetuximab is a murine monoclonal antibody, which binds to EGFR extracellular domain. Binding to EGFR results in inhibiting cell proliferation and antiapoptotic effects. There are a number of Phase II studies evaluating cetuximab in cervical cancer. Cetuximab was given as a single agent at 400 mg/m2 initially followed by 250 mg/m2 weekly in GOG 277E to 38 women with squamous and nonsquamous cervical cancer of whom 35 were evaluable [91]. PFS for at least 6 months occurred in five patients (14.2%; 95% CI: 5.8–30%). Median PFS was 1.97 months and median OS 6.7 months. There were no responses. The grades 3, 4 adverse events included dermatologic (5), gastrointestinal (4), anemia (2), infection (2), pain (2), pulmonary (1) and neurologic (1). Although the drug appears to be well tolerated, it had limited activity. In GOG 76DD, Cetuximab was used as a 400 mg/m2 bolus followed by 250 mg/m2 Days 1, 8, 15 of 21 days with cisplatin (30 mg/m2 Days 1, 8) for 76 women with advanced, persistent or recurrent cervical cancer [92]. The EGFR protein was expressed in 98% of tumors. Sixty-nine women were eligible for evaluation, and the RR was only 11.6% (8/69). PFS had a HR of 1.76 (95% CI: 0.96–3.21). Adverse events included drug allergy, metabolic, vascular, dematologic, fatigue and gastrointestinal. Cetuximab was given to 19 women with cervical cancer at 400 mg/m2 iv. over 2 h as a loading dose followed by 250 mg/m2/week with cisplatin (50 mg/m2 day 1 q21days) and Topotecan (0.75 mg/m2/day for days 1, 2, 3 q21days) [93]. Granulocyte stimulating factor was used in patients who developed febrile neutropenia. RR was 32% (6/19) and 32% had SD. The study was stopped prematurely due to three treatment-related deaths. The rate of grades 3–4 neutropenia was 72%. grades 3– 5 febrile neutropenia was 39%. grades 3–4 thrombocytopenia was 61%. grades 3–4 renal toxicity was 11%. Pulmonary embolus occurred in 11% and grade 3 skin reactions occurred in 22%. MITO Cervix 2 (ClinicalTrials.gov identifier: NCT00997009) is a randomized Phase II trial of cetuximab given weekly with carboplatin every 3 weeks compared with carboplatin alone. As of May 2012, 50 of 100 women were accrued. 325

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Matuzumab/EMD 72000

Lapatinib

Matuzumab is a humanized monoclonal antibody with high specificity and affinity to EGFR-1. The antibody is able to trigger antibody-dependent cellular cytotoxicity of macrophages and lymphocytes against tumor cells overexpressing the EGFR-1 antigen. A Phase I study of 22 cases included one woman with cervix cancer. The maximum tolerated dose was 1,600 mg/week with dose-limiting toxicity of headache and fever. Two-thirds of the participants had a mild acne form rash. A Phase II trial in Europe in cervix cancer has completed accrual but not been reported [83]. Subsequent work shows high toxicity rate including gastrointestinal, hematologic and dermatologic. Drug production ceased in 2008 [94].

Lapatinib is an oral small-molecule dual TKI of EGFR and HER2/neu. Three studies suggested that lapatinib may be beneficial in patients with HER2/neu amplification [97–99]. However, the Phase III trial [79] where women were not prescreened or preselected based on EGFR expression or HER2/neu amplification did not show benefit. The mixed responses seen with antibodies to EGFR and TKI may be related to several factors. EGFRs may be present with varying degrees of expression in the cervical cancer depending on factors like histology. For example, 37% squamous cell carcinomas of the cervix express EGFR compared with 2% in adenocarcinomas [90]. EGFR amplification [90] has been shown to be associated with advanced stage, older age and poor prognosis. The EGFR does not appear to be mutated in cervical cancer. Thus, as indicated in the studies, to date, approaches to inhibiting EGFR are likely to have a therapeutic effect in cervical cancer. Lastly, KRAS is associated with resistance to EGFR-targeted treatment as is seen in colon cancer. This is unlikely to be a significant issue in cervical cancer as only 6.3% of cervical cancers are KRAS positive [100].

Small-molecular TKI of EGFR

These EGFR-targeted agents act intracellularly. They are low molecular weight TKI that compete with adenosine triphosphate at its binding site in the receptor’s kinase pocket [83]. There can be reversible or irreversible binding. Binding inhibits receptor autophosphorylation. Erlotinib

Erlotinib is a small-molecule inhibitor that competes reversibly with ATP for binding to the tyrosine kinase domain of the EGFR-1 and HER1 inhibitor. Woodworth et al. showed that erlotinib prevented immortalization of cultured human cervical epithelial cells by inducing apoptosis in cells that expressed E6/ E7 and stimulating senescence in surviving cells [95]. In mice, a single dose of erlotinib reduced the levels of EGFR autophosphorylation by 70% in 24 h. Erlotinib alone

GOG 227D [96] was a Phase II study of erlotinib (150 mg PO OD). There were no objective responses (90% CI: 0–8.8%) in the 28 study participants but one woman remained progression free for >6 months (3.6%). Four women had SD (16%). The drug was well tolerated and the most frequent adverse events were gastrointestinal, fatigue and rash. Erlotinib was considered inactive. Gefitinib

Gefitinib is a HER1/EGFR TKI. In vitro studies with cervical cancer cells show that EGF changes can be blocked by gefitinib [84]. A Phase II study of gefitinib (500 mg/day) as second- or third-line treatment for recurrent or metastatic cervical cancer was conducted in 28 patients in France. No women had a response but there was a 20% SD rate (6/28). The median duration was 111.5 days (77–188 days) [82]. PFS was 37 days (95% CI: 28–77 days). OS was 107 days (95% CI: 103–253 days). Disease response did not correlate with EGFR expression as 86.7% of biopsies expressed high levels of EGFR 2+ or 3+ and 46.7% had >80% of tumor cells expressing high levels of EGFR. Dose-limiting toxicity was diarrhea. Other toxicities included: acne, nausea and vomiting. 326

Other targets Imatinib mesylate

Imatinib mesylate is an inhibitor of tyrosine kinase as well as PDGFR and c-kit. Imatinib was used in 12 patients at 600 mg PO OD [101]. All 12 expressed PDGFR alpha and 4 expressed PDGFR beta. There were no responses. One woman had SD for 6 months; more than 50% of her malignant cells expressed PDGFR alpha and beta. There were no severe toxicities, but the bleeding from proctitis was worse in those women who had had prior pelvic radiation. As a single agent, imatinib is not active. It may move forward to be used in combination with cisplatin and gemcitabine. IGF

IGF consists of two ligands (IGF-1, IGF-2) and their associated cell surface receptors [76]. Their interactions affect downstream events via the Ras-Raf-MAPK and the PI3K-Akt pathways, which are involved in cellular proliferation, angiogenesis, invasion, metastasis and inhibiting apoptosis. There is work suggesting that IGFR-1 may have a role in combination with HPV in the development of cervical intraepithelial neoplasia (CIN) 3 and cervical cancer [102–104]. There appear to be conflicting reports as to the role IGF plays in cervical cancer. Some work has shown that elevated levels of IGFR-1 [104] or IGF-2 [105] are predictors of death and recurrence [106]. They have also been found to be higher in women with CIN and invasive cervical cancer compared with healthy controls. In contrast, others have shown lower IGF-1 [106,107] or IGF-2 levels [108] in women with CIN or invasive disease compared with controls. Figitumumab

Figitumumab is an IGFR-1 monoclonal antibody, which has been evaluated in a Phase Ib study with docetaxol for patients Expert Rev. Anticancer Ther. 14(3), (2014)

Management of advanced or recurrent cervical cancer

with solid tumors. Out of 46 patients, 1 had advanced cervical cancer and there was disease stabilization for 7 months [109]. Further evaluation of women with cervical cancer is needed.

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mTOR Inhibitors Temsirolimus

The National Cancer Institute of Canada conducted a Phase II study with weekly temsirolimus in 37 women with recurrent, locally advanced or metastatic cervical cancer [110]. Three percent had a PR and 57.6% had SD with a median duration of 6.5 months. There were 28% of women with a PFS of 6 months or longer. The toxicity profile was acceptable. Histone deacetylase & DNA methylation inhibitors

Histone proteins are a key chromatin component with their N-terminus undergoing acetylation to form a histone code that is critical to silencing tumor suppressor gene transcription [77]. Hydalazine

Hydralazine 182 mg for rapid and 83 mg for slow acetylators along with valproate 30 mg/kg was given a week prior to chemotherapy and continued until disease progression [111]. Thirty six women had a median of six cycles. There were four PRs and five SDs for a PFS of 10 months in the chemotherapy with hydralazine and valproate. There were one PR and six SDs for a PFS of 6 months in the chemotherapy with placebo group (p = 0.38). TNF-related apoptosis-inducing ligand receptor 1

Mapatumumab is a monoclonal antibody to TNF-related apoptosis-inducing ligand receptor 1 DR4 and induces cytotoxicity in multiple tumor cell lines both in vitro and in vivo. Alone this agent causes apoptosis in 51% of cells. Immunotherapy

The immune system is central to prevention of tumors as is demonstrated by the increased incidence of HPV-related cervical dysplasia and cancer in women infected by the HIV and transplant patients on long-term immunosuppressive medications. HPV infection results in expression of viral proteins on the cell surface of cervical cancer cells and invokes a cellular immune response with presence of T-cell infiltrate. The exact role of T-helper cells and cytotoxic T cells in the immune response to an HPV infection is not well understood. There are data suggesting that cytotoxic T cells may limit disease progression and regulatory T cells may create a tolerant immunologic environment contributing to viral immune evasion and persistence of HPV infection resulting in progression of disease. Ipilimumab (MDX-010, MDX-CTLA4 & BMS-734016)

Ipilimumab is a human IgG1 monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152). CTLA-4 is a negative regulator of T-cell responses following T-cell stimulation. Ipilimumab is currently being informahealthcare.com

Review

evaluated in recurrent and metastatic cervical cancer patients for whom there are limited treatment options available (NCI 9209/PHL-085). Phase I of the study involves the 3 mg/kg dose level, and Phase II of the study involves the 10 mg/kg dose level. Both toxicity and response are being assessed. Expert commentary & five-year view

In this review, we have seen that advanced or metastatic cervical cancer has a poor prognosis. Studies evaluating the role of systemic therapy have shown that as a single agent, cisplatin at 50 mg/m2 iv. every 3 weeks is superior to any other single-agent option. The combination of platinum with a taxane, gemcitibine, topotecan or vinorelbine are all equally efficacious. Management of an individual patient must take into account each combination’s side effect profile, cost, convenience and center’s experience with the regimen. One large randomized trial has shown that bevacizumab in addition to either cisplatin–paclitaxel or paclitaxel–topotecan was superior to the combination alone. Again cost, convenience and patient preference will be important factors to consider when offering this regimen to women. In addition to inhibiting VEGF patients with bevacizumab, there are also multitargeted agents for simultaneous targeting of multiple angiogenic pathways. Pazopanib has been shown to be an agent of interest. Several compounds are currently undergoing evaluation for toxicity and efficacy either alone or in combination with chemotherapy with or without radiation therapy. To date, studies evaluating EGFR TKIs have not shown them to be beneficial. This may be related to the degree of tumor EGFR expression, amplification, lack of mutation of the receptor or inhibition by other factors. In terms of the future, bevacizumab appears to be more effective and tolerable than subsequent antiangiogenic agents that have been evaluated. Studies suggest that these agents provide disease stabilization for a period of time. Given the positive results from the addition of bevacizumab to chemotherapy, the role of small-molecular weight TKIs targeting VEGFR and other angiogenic pathways, when given in combination with chemotherapy will be of great interest. Upcoming EGFRtargeted strategies that will come to the clinical trials setting include: Immunotoxin conjugates using cytotoxic single-chain fragment variable antibodies conjugated to toxins; EGF vaccines; and antisense oligonucleotides to block the translation of the ligand of the EGFR [83]. Other novel pathways that are currently being explored include: insulin growth factor and targeting mTOR inhibitors, cyclooxygenase inhibitors and histone deacetylase and DNA methylation inhibitor. Because the expression of HPV proteins on the surface of cervical cancer cells results in tumors that are immunogenic, the role of agents targeting immune checkpoint regulation, including antibodies to CTLA4, PD-1 and PD-L1, either alone or in combination with other immune approaches such as vaccines, will be of particular interest. Stepping back to ponder the big picture of cervical cancer, the greatest success we can have with respect to cervical 327

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cancer will come by eliminating this disease and that reality lies in a population-based vaccination strategy and cervical screening program using the most sensitive test available on a periodic basis for the most at-risk population (i.e., age 30 years and above). Where cervical cancer is concerned, an ounce of prevention is truly of more value than pounds spent on striving for a cure in the advanced/recurrent/persistent setting.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Key issues • As a single agent, cisplatin 50 mg/m2 is superior to any other single-agent option. • Combination chemotherapy provides a survival duration superior to single-agent chemotherapy. Platinum with a taxane, gemcitibine, topotecan or vinorelbine has equal efficacy but differ with respect to toxicity and convenience of delivering the regimen. In a different randomized trial, platinum taxane was equivalent in efficacy to taxane and topotecan. • The addition of bevacizumab to combination chemotherapy provides a superior duration of survival with a tolerable side effect profile. • Pazopanib (a small-molecule tyrosine kinase of VEGF receptor) was superior to lapatinib (a small-molecular tyrosine kinase of EGF receptor) and is of interest for further evaluation. The role of small-molecular weight tyrosine kinase inhibitors targeting VEGF receptor and other angiogenic pathways when give in combination with chemotherapy will be of interest.

Oncology Group. Cancer 48(4), 899–903 (1981).

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Expert Rev. Anticancer Ther. 14(3), (2014)

Management of advanced or recurrent cervical cancer: chemotherapy and beyond.

Metastatic or recurrent cervical cancer has a survival duration of approximately 12 months. Thus, we review the outcomes of chemotherapy and/or novel ...
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