l.Lay Summary: Single agents are the best choice for 2nd line chemotherapy of cervical cancer.

Treatment is only palliative in patients with stage IVB disease, especially 2nd line, so quality of life and toxicity profiles must influence the choice of treatment. The only RCT to identify a chemotherapy regimen that gave these patients an overall survival advantage and that included quality of life measurements compared cisplatin with cisplatin plus topotecan. Progression free survival and overall survival favoured combination chemotherapy, but toxicity was more common, although it did not significantly reduce quality of life.

NCCN lists: 5fu and mitomycin as single agents, also docetaxel, ifosfomide, irinotecan, vinorelbine and epirubicin.

Treatment is only palliative in patients with stage IVB disease, especially 2nd line, so quality of life and toxicity profiles must influence the choice of treatment. The only RCT to identify a chemotherapy regimen that gave these patients an overall survival advantage and that included quality of life measurements compared cisplatin with cisplatin plus topotecan. Progression free survival and overall survival favoured combination chemotherapy, but toxicity was more common, although it did not significantly reduce quality of life.

NCCN lists: 5fu and mitomycin as single agents, also docetaxel, ifosfomide, irinotecan, vinorelbine and epirubicin. The proposed therapy is in a clinical trial that incldues an non-FDA approved drug, pralatrexate. I was not able to find this trial on the clinicaltrials.gov site.

Regarding Tarceva(erlotinib): Twenty-eight patients with squamous cell carcinoma were enrolled by Schilder. Twenty-five patients were evaluable. There were no objective responses with four (16%) achieving stable disease; only one patient had a PFS ≥ 6 months (4%). The one-sided 90% confidence interval (CI) for response was 0.0%–8.8%. The two-sided 90% CI for the proportion of patients surviving progression-free for at least 6 months is 0.2%–17.6%. Erlotinib was well tolerated with the most common drug-related adverse events being gastrointestinal toxicities, fatigue and rash.

 Russell J. Schilder et al,A PHASE II TRIAL OF ERLOTINIB IN RECURRENT SQUAMOUS CELL CARCINOMA OF THE CERVIX: A GYNECOLOGIC ONCOLOGY GROUP STUDY Int J Gynecol Cancer. 2009 July; 19(5): 929–933.

 Monk BJ, Huang HQ, Cella D, Long HJ III. Quality of life outcomes from a randomized phase III trial of cisplatin with or without topotecan in advanced carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 2005;23:4617-25

nccn.org, cervical

Lay Summary: I review otions for metastatic cervical cancer with the focus on the TPF regimen.

Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease is still problematic, and there are relatively few randomized trials to guide treatment decisions. There are a large number of chemotherapeutic agents with “activity” in metastatic cervical cancer. Cisplatin is the single most active agent to treat cervical cancer. In the Gynecologic Oncology Group (GOG) studies, involving approximately 800 patients, cisplatin was associated with a response rate of 29%. The response rate was greater at 31% with 100 mg/m2 compared with 21% at 50 mg/m2, but this was not associated with any significant improvement in progression-free or overall survival. The response rate of other platinum compounds, such as carboplatin, is possibly lower (15%), but the two agents have not been compared in a randomized trial. Cisplatin is associated with response rates of 20%-30% and a median survival of about 7 months. The impact of chemotherapy on palliation and survival is unclear. There have not been any randomized studies comparing chemotherapy with best supportive care or studies that have specifically investigated the impact of chemotherapy on symptom control and quality of life. One study demonstrated that the combination of cisplatin and methotrexate was associated with a significant increase in survival compared with a single inactive agent, hydroxyurea. In another relatively small study of cisplatin-based chemotherapy, it was demonstrated that, while only 30% of patients had an objective response to treatment, 67% had palliation of their pain.

A number of new agents (e.g., paclitaxel, vinorelbine, irinotecan, and gemcitabine) have been combined with cisplatin in phase II studies in patients with either locally advanced and/or recurrent cervical cancer . High response rates have been observed (40%-66%), particularly among patients with locally advanced disease. Similar findings have been observed with older cisplatin-based combinations, and randomized trials are essential before adopting such combinations for routine use outside clinical trials. The preliminary results of a large GOG study comparing cisplatin alone (50 mg/m2) with cisplatin (50 mg/m2) plus paclitaxel (135 mg/m2 over 24 hours) in 280 patients with recurrent or stage IV B squamous cell carcinoma of the cervix were presented at the American Society of Clinical Oncology meeting in May 2001.The combination produced a significantly higher response rate compared with cisplatin alone (36.2% versus 19.4%, p = 0.002). The combination regimen also was associated with higher rates of complete response (20% versus 8%) and partial response (27% versus 18%). These higher response rates translated into a significantly longer progression-free survival (p = 0.001) but no significant difference in overall survival (median 9.7 versus 8.8 months). Interim results suggested that the combination also improved various health-related quality-of-life parameters, but the quality-of-life data were incomplete at the time of presentation. IV carboplatin, Taxol and 5FU (TPF) is a combination used successfully in head and neck squamous cell cancer but there is little support for its use for metastatic cervical cancer. Carboplatin with Taxol is listed by NCCN but not TPF.

Michael Friedlander, Michelle Grogan Guidelines for the Treatment of Recurrent and Metastatic Cervical Cancer The Oncologist, Vol. 7, No. 4, 342–347, August 2002
:10.1136/bmj.39337.615197.80

Patrick Petignat Diagnosis and management of cervical cancer
Clinical Review BMJ  2007;335:765-768 (13 October)

Dreyer G, Snyman LC, Mouton A, Lindeque BG. Management of recurrent cervical cancer. Best Pract Res Clin Obstet Gynaecol 2005;19:631-44

nccn.org, cervical

The Axxent® Electronic Brachytherapy System® utilizes a miniaturized high dose rate  X-ray source to apply radiation directly to the cancerous tumor bed. It was cleared for marketing by the FDA in December 2005. Unlike traditional high dose rate brachytherapy technologies, this form of brachytherapy is claimed not to require radioactive isotopes, heavy shielding, or major capital equipment. A number of posters and presentations, most of it in breast cancer, presented this new technology over the past three years. Five research studies were accepted for presentation at the 2008 World Congress of Brachytherapy hosted by the American Brachytherapy Society (ABS).  One of them was about the use of the Axxent System for treatment of cervical cancer, subsequently published,  and another about endometrial cancer.

Dickler A, Kirk MC, Griem K, Dowlatshahi K, Francescatti D, Abrams RA. A dosimetric comparison of MammoSite high-dose-rate brachytherapy and Xoft Axxent electronic brachytherapy. Brachytherapy 2007;6:164-168.

K. Huber, J. Hiatt, M. Puthawala, D. Wazer Dose modeling of the Xoft electronic brachytherapy source for tandem and ovoid applications in patients with cervical cancer
Brachytherapy, Volume 7, Issue 2, Pages 155-155

TEC, Accelerated Partial Breast Irradiation as Sole Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer
Assessment Program Volume 22, No. 4 September 2007

The standard of care now is chemoradiation with cisplatin alone in stage IIA cervical cancer. The value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Over the last 20 years, a number of trials testing concurrent chemoradiation were performed in an attempt to improve treatment results. Despite this, in 1996 a National Institutes of Health Consensus Statement on cervical cancer stated that there was no evidence that hydroxyurea or any other concomitant chemotherapeutic agent should be added to pelvic irradiation and incorporated into standard practice. It was not until 1999 that five randomized studies including nearly 2,000 patients were published, demonstrating that survival rate with concomitant chemotherapy (RT/CT) based on cisplatin was superior than that obtained with radiation alone. Afterwards, a meta-analysis based on 19 trials published and two unpublished) including 4,580 patients corroborated these findings, confirming that chemoradiation offers an absolute survival benefit of 12% at 5 years. Thus, cisplatin-based chemoradiation was largely accepted as the standard of care for patients with cervical cancer whose treatment required radiation, except for patients with co-morbidities who are radiated for stage IB1 or less. An update of the aforementioned meta-analysis that includes 24 trials (21 published, three unpublished) and 4,921 patients strongly suggests that chemoradiation improves overall survival and progression-free survival, whether or not platinum was used, with absolute benefits of 10 and 13%, respectively. There was, however, statistical heterogeneity for these outcomes. There was some evidence that the effect was greater in trials including a high proportion of stage I and II patients. Chemoradiation also showed significant benefit for local recurrence and the suggestion of a benefit for distant recurrence. Acute hematological and gastrointestinal toxicity was significantly higher in the concomitant chemoradiation group. Treatment-related deaths were rare, but late effects of treatment were not well-reported; thus, the impact of chemoradiation.

Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL, Walker JL, Gersell D: A comparison of weekly cisplatin during radiation therapy versus irradiation alone each followed by adjuvant hysterectomy in bulky stage IB cervical carcinoma: a randomized trial of the Gynecology Oncology Group. New Engl J Med 1999, 340:1154-1161.

Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalacos S: Concurrent cisplatin-based chemoradiation improves progression-free survival in advanced cervical cancer: results of a randomized Gynecologic Oncology Group study. New Engl J Med 1999, 340:1144-1153.

Green JA, Kirwan JM, Tierney JF: Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001, 358:781-786.

Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, Williams C, Collingwood M: Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2005

Small cell carcinoma of the cervix is a rare cancer, comprising less than 3% of all cervical neoplasms. It uniformly has a poor prognosis, and has a high mortality even with early stage disease. It can metastasise rapidly and metastatic sites include lung, liver, brain, bone, pancreas and lymph nodes. The largest retrospective review was form Korea and published in 2007. It concluded that : “results indicate primary radical surgery followed by adjuvant chemotherapy is the preferred treatment modality for patients with early stage SCNEC disease.” Although this study was retrospective in design, with a limited number of patients, it is one of the largest series reported to date. Favorable results have been reported for patients with SCNCC who received concurrent chemoradiation followed by several additional cycles of chemotherapy, while other studies have reported that radical surgery is an important component in the multimodal treatment of SCNCC.

Lee JM, Lee KB, Nam JH, Ryu SY, Bae DS, Park JT, Kim SC, Cha SD, Kim KR, Song SY, Kang SB : Prognostic factors in FIGO stage IB-IIA small cell neuroendocrine carcinoma of the uterine cervix treated surgically: results of a multi-center retrospective Korean study.Ann Oncol 19(2): 321-326, 2008

G. BIFULCO, V. D. MANDATO, P. GIAMPAOLINO, R. PICCOLI, L. INSABATO, N. DE ROSA, and C. NAPPI
Small Cell Neuroendocrine Cervical Carcinoma with 1-Year Follow-up: Case Report and Review
Anticancer Res, February 1, 2009; 29(2): 477 – 484.

Metastatic cervical cancer responds moderately to chemotherapy and it can provide palliation. One guideline writes: “It is recommended that all patients, particularly those who have been previously treated with cisplatin as a radiosensitizer, be offered the opportunity to participate in randomized trials, if available, that evaluate the efficacy and toxicity of other single-agent or combination chemotherapy regimens.
Until further evidence becomes available, it is recommended that cisplatin in combination with topotecan should be offered to patients on the basis of improvements in response and survival outcomes when compared with single-agent cisplatin alone.” However NCCN is more liberal, listing in addition carboplatin and cisplatin/paclitaxel, cisplatin/gemcitabine and a variety of single agents.

There was a recent study of single agent Avastin. To evaluate Avastin in the treatment of recurrent squamous cell carcinoma of the cervix, researchers conducted a Phase II clinical trial among 46 women. Study participants received intravenous Avastin every three weeks until cancer progression or the development of severe side effects.

24% of patients survived progression-free for at least six months.
11% of patients had a partial response.
Median response duration was 6.2 months.
Median overall survival was 7.3 months.
Median progression-free survival was 3.4 months.
There was one infection-related death that was possibly due to treatment.
Side effects included hypertension and thromboembolism

These researchers concluded that Avastin was generally well tolerated and appeared to have anticancer activity in women with previously treated recurrent cervical cancer. They note that the role of Avastin in this population merits further study in Phase III clinical trials. A combination phase II trial with topotecan reported as an abstract concluded: “Combination bevacizumab and topotecan administered in a weekly fashion demonstrate good activity in platinum refractory OC with acceptable toxicity.”  There were also trials with 5FU or capecitbine.

For second line therapy, NCCN on page Papillae CER V – be recommence Avastin, docetaxel, 5-FU, gemcitabine, ifosfamide, irinotecan, mitomycin, topotecan. This is a category 2B recmmendation. Premetrexed and vinorelbine are recommended as category 3.

There are no FDA approved chemotherapy drugs specifically for cervical cancer.

For second line therapy, NCCN on page CER V –recommended Avastin, docetaxel, 5-FU, gemcitabine, ifosfamide, irinotecan, mitomycin, topotecan. There are no recommendations after line 2. This is a category 2B recmmendation. Premetrexed and vinorelbine are recommended as category 3. The most recent 2016 review says the following: Additional treatment options outside of platinum-based therapy are limited. Ifosfamide, paclitaxel, topotecan, irinotecan, capecitabine, pemetrexed, vinorelbine, and nab-paclitaxel are among the most active single agents, while docetaxel, gemcit abine, and ixabepilone were found to have minimal activity -

 

Hirte H, Strychowsky J, Oliver T, Fung-Kee-Fung M, Elit L, Oza A, Gynecology Cancer Disease Site Group. Chemotherapy for recurrent, metastatic, or persistent cervical cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Jul 5. 21 p. (Evidence-based series; no. 4-20). [27 references]

nccn.org, cervical cancer, CERV-B 2016

K. F. McGonigle, H. G. Muntz, J. L. Vuky, P. J. Paley, D. S. Veljovich, H. J. Gray, T. W. Malpass Phase II prospective study of weekly topotecan and bevacizumab in platinum refractory ovarian cancer or peritoneal cancer (OC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 5551)

Alejandra Fuentes, MD, and Agustin A. Garcia, MD, Advancements in Cervical Cancer Prevention and Management of Persistent, Recurrent, and Metastatic Disease: 2016 Update. AJHO. 2