Commentary

Adjuvant and systemic therapy for rare tumors of the uterus and cervix

Editor’s Note: This column is a three-part series offering oncologists practical advice on the treatment of rare gynecologic malignancies. Part 1, published in the Feb. 25 issue, presented advances in surgical management. Part 2, published in the March 10 issue, addressed adjuvant therapy for rare ovarian tumors. Part 3, presented here, addresses rare diseases of the uterus and cervix.

Gynecologic cancers will account for an estimated 107,470 new cancer diagnoses and 31,600 deaths this year in the United States.

Rare gynecologic cancers have been variably defined, but they tend to be the histologies responsible for less than 5% to 10% of cancers in a given anatomic site.

Jubilee Brown, MD
Jubilee Brown
Erin K. Crane, MD
Erin K. Crane
R. Wendel Naumann, MD
R. Wendel Naumann

Here, we highlight advances in adjuvant and systemic therapy in the management of uncommon tumors of the uterus and cervix with emerging data and clinical applications.

Uterine malignancies

1. Malignant mixed Müllerian tumor of the uterus, or carcinosarcoma

Although the Gynecologic Oncology Group (GOG) historically pooled all histologies of endometrial cancers, research specific to carcinosarcomas has been performed.

In one trial, researchers randomly assigned 232 patients with stage I to stage IV carcinosarcoma to whole-abdominal radiotherapy or three cycles of cisplatin, ifosfamide and mesna (CIM). After adjusting for stage and age, CIM appeared associated with reductions in risk for recurrence (HR = 0.78) and death (HR = 0.71; P = 0085).

The combination of radiation therapy for local control and systemic therapy using platinum and anthracyclines for distant disease may be rational. Multiple studies have evaluated variations of this approach and demonstrated significant benefit.

The most active agents for recurrent disease are ifosfamide, cisplatin and paclitaxel — with response rates of 18% to 32% — but regimens of ifosfamide/paclitaxel/filgrastim and paclitaxel/carboplatin both demonstrate an improvement in response rate and PFS compared with single-agent therapy. A GOG comparison trial has completed accrual and results are anticipated this year.

In the second-line setting, topotecan has resulted in limited responses with severe toxicity. Sorafenib (Nexavar, Bayer) has been associated with stable disease but no responses. Claudin-3 and claudin-4 represent potential targets for investigation.

2. Serous carcinoma of the uterus

Researchers of GOG 209 randomly assigned 1,381 women to paclitaxel and carboplatin vs. paclitaxel, adriamycin and cisplatin. This study included patients with serous carcinoma.

Investigators observed no differences in outcome, eliminating adriamycin as part of the regimen for serous carcinoma of the uterus. Further data are limited to retrospective trials, but all demonstrate improved outcomes after platinum and paclitaxel compared with platinum-based chemotherapy alone, establishing paclitaxel and carboplatin with or without radiation as the standard for nearly all patients with serous carcinomas of the uterus.

The only patients who can safely forego adjuvant therapy are those with no disease remaining in the uterus at the time of hysterectomy or patients with disease confined to a polyp.

3. Leiomyosarcoma

Patients with early-stage leiomyosarcoma may benefit from adjuvant therapy. Four cycles of adjuvant gemcitabine–docetaxel showed improvement compared with historical controls, with a 2-year PFS rate of 59% and a median PFS of 39 months.

GOG 177 is evaluating observation vs. gemcitabine–docetaxel for four cycles followed by four additional cycles of doxorubicin in patients with early-stage leiomyosarcoma. GOG evaluated gemcitabine and docetaxel in the second-line setting, with a 28% response rate and disease stabilization in another 50% of patients.

Other active agents include doxorubicin, ifosfamide, single-agent gemcitabine, liposomal doxorubicin and trabectedin (Yondelis; Janssen, Pharma Mar). Temozolomide shows promise in the recurrent setting, with a response rate of 5% to 33%, and disease stabilization in 47% to 50% of patients.

Because 7% to 71% of leiomyosarcomas express ER or PR, hormonal manipulation may represent a therapeutic strategy. Aromatase inhibitors resulted in responses in some ER–positive patients. Thalidomide (Thalomid, Celgene), sunitinib (Sutent, Pfizer), and the addition of bevacizumab (Avastin, Genentech) to gemcitabine and docetaxel all are inactive.

4. Low-grade endometrial stromal sarcoma

Hormonal therapy with progestational agents (eg, megestrol acetate) and aromatase inhibitors is the adjuvant treatment of choice for low-grade endometrial stromal sarcoma, as most patients respond.

Cervical cancer

There will be an estimated 12,820 new cases of cervical cancer this year in the United States, and 4,210 women will die of the disease. The majority of cases are HPV related.

HPV vaccination provides immunity against the most common oncogenic subtypes and resultant dysplasia and cancer.

Surgery often is curative in early-stage disease, although for certain subsets of patients with comorbidities or high-risk features, chemoradiation may achieve cure, as well. For patients with early-stage disease who desire fertility preservation, new and more conservative surgical approaches — including radical trachelectomy and conization — are under investigation.

In advanced-stage disease, chemoradiation is employed rather than surgery, and prognosis depends on stage.

Recurrent cervical cancer typically is incurable. However, GOG 240 demonstrated that the addition of bevacizumab to chemotherapy doublets — either paclitaxel/cisplatin or paclitaxel/topotecan — yielded a 3.7-month improvement in OS in patients with recurrent disease. This now represents the standard of care for patients with recurrent cervical cancer.

Additional areas of progress include activity of veliparib (ABT-888, AbbVie) — a PARP inhibitor — as well as immunotherapy and PD-1 inhibitors.

Although adenocarcinomas and squamous cell carcinomas comprise the majority of cervical cancers, rare subtypes exist.

Verrucous and warty carcinomas may be mistaken for benign condylomatous lesions and pose a diagnostic challenge. Warty carcinoma and adenoid basal cell carcinoma can behave in a more indolent fashion than the more common adenocarcinomas and squamous cell carcinomas, and they may often be cured with surgery alone. Conversely, adenoid cystic carcinoma and small cell carcinoma are more aggressive with poor outcomes despite multimodal treatment.

Although treatment for rare subtypes usually mirrors the more common histologies, small cell carcinoma is treated differently. This aggressive neoplasm constitutes 3% of cervical cancers and is characterized by early nodal metastases, lymphovascular spread and a high relapse rate. Even in early-stage disease, adjuvant treatment with cisplatin and etoposide and radiation is recommended.

One series showed improvement in PFS among patients with recurrent small cell neuroendocrine carcinoma of the cervix who received combination therapy with topotecan, paclitaxel and bevacizumab. Despite aggressive treatment, 5-year survival is low (37%) for stage I to stage IIa disease. Patients with cervical lymphomas are often treated with chemotherapy alone.

Conclusion

Treatment of cervical cancer depends on stage of disease. Surgery is typically curative for patients with early-stage disease, whereas chemoradiation is favored in advanced stages. Recurrent disease is treated with chemotherapy doublets in addition to bevacizumab.

Histologies of rarer subtypes vary in prognosis but generally are treated with the same principles as adenocarcinomas and squamous cell carcinomas. For malignant mixed Müllerian tumor, or carcinosarcoma, adjuvant multiagent chemotherapy or combined chemoradiation is preferable to whole-abdominal radiation. For the treatment of serous carcinoma, adjuvant paclitaxel and carboplatin — with or without radiotherapy — is preferred for most patients.

Active agents for leiomyosarcoma include gemcitabine with docetaxel, doxorubicin, ifosfamide and trabectedin. Progestational agents and aromatase inhibitors are active for low-grade endometrial stromal sarcoma.

For cervical cancer, the addition of bevacizumab to adjuvant paclitaxel/cisplatin or paclitaxel/topotecan yields an OS advantage and is the preferred regimen for recurrent disease.

References:

Cohen JG, et al. Am J Obstet Gynecol. 2010;doi:10.1016/j.ajog.2010.04.019.

Dahhan T, et al. Eur J Obstet Gynecol Reprod Biol. 2009;doi:10.1016/j.ejogrb.2009.02.005.

Fader AN, et al. Cancer. 2009;doi:10.1002/cncr.24247.

Ferriss JS, et al. Int J Gynecol Cancer. 2010;doi:10.1111/IGC.0b013e3181c7fe53.

Frumovitz M, et al. Gynecol Oncol. 2017;doi:10.1016/j.ygyno.2016.10.040.

Hensley ML, et al. Gynecol Oncol. 2008;doi:10.1016/j.ygyno.2008.03.010.

Hensley ML, et al. Gynecol Oncol. 2009;doi:10.1016/j.ygyno.2008.11.027.

Homesley HD, et al. J Clin Oncol. 2007;25:526-531.

Kunos C, et al. Int J Gynecol Cancer. 2015;doi:10.1097/IGC.0000000000000380.’

Manolitsas TP, et al. Cancer. 2001;91:1437-1443.

Miller D, et al. Gynecol Oncol. 2012;125:771-773.

Ng WK, et al. Acta Cytol. 2003;47:159-166.

O’Cearbhaill R, et al. Gynecol Oncol. 2010;doi:10.1016/j.ygyno.2009.10.064.

Pautier P, et al. Int J Gynecol Cancer. 2004;14:1112-1117.

Siegel RL, et al. CA Cancer J Clin. 2016;doi:10.3322/caac.21332.

Tewari KS, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1309748.

Viswanathan AN, et al. Gynecol Oncol. 2004;93:27-33.

Wolfson AH, et al. Gynecol Oncol. 2007;107:177-85.

For more information:

Jubilee Brown, MD, is professor and associate director in the division of gynecologic oncology at Levine Cancer Institute at Carolinas HealthCare System. She can be reached at 1021 Morehead Medical Drive, Suite 2100, Charlotte, NC 28204; email: jubilee.brown@carolinashealthcare.org.

Erin K. Crane, MD, is a gynecologic oncologist at Levine Cancer Institute at Carolinas HealthCare System. She can be reached at erin.crane@carolinashealthcare.org.

R. Wendel Naumann, MD, is a gynecologic oncologist at Levine Cancer Institute at Carolinas HealthCare System. He can be reached at wnaumann@mac.com.

Disclosure: Brown, Crane and Naumann report no relevant financial disclosures.

Editor’s Note: This column is a three-part series offering oncologists practical advice on the treatment of rare gynecologic malignancies. Part 1, published in the Feb. 25 issue, presented advances in surgical management. Part 2, published in the March 10 issue, addressed adjuvant therapy for rare ovarian tumors. Part 3, presented here, addresses rare diseases of the uterus and cervix.

Gynecologic cancers will account for an estimated 107,470 new cancer diagnoses and 31,600 deaths this year in the United States.

Rare gynecologic cancers have been variably defined, but they tend to be the histologies responsible for less than 5% to 10% of cancers in a given anatomic site.

Jubilee Brown, MD
Jubilee Brown
Erin K. Crane, MD
Erin K. Crane
R. Wendel Naumann, MD
R. Wendel Naumann

Here, we highlight advances in adjuvant and systemic therapy in the management of uncommon tumors of the uterus and cervix with emerging data and clinical applications.

Uterine malignancies

1. Malignant mixed Müllerian tumor of the uterus, or carcinosarcoma

Although the Gynecologic Oncology Group (GOG) historically pooled all histologies of endometrial cancers, research specific to carcinosarcomas has been performed.

In one trial, researchers randomly assigned 232 patients with stage I to stage IV carcinosarcoma to whole-abdominal radiotherapy or three cycles of cisplatin, ifosfamide and mesna (CIM). After adjusting for stage and age, CIM appeared associated with reductions in risk for recurrence (HR = 0.78) and death (HR = 0.71; P = 0085).

The combination of radiation therapy for local control and systemic therapy using platinum and anthracyclines for distant disease may be rational. Multiple studies have evaluated variations of this approach and demonstrated significant benefit.

The most active agents for recurrent disease are ifosfamide, cisplatin and paclitaxel — with response rates of 18% to 32% — but regimens of ifosfamide/paclitaxel/filgrastim and paclitaxel/carboplatin both demonstrate an improvement in response rate and PFS compared with single-agent therapy. A GOG comparison trial has completed accrual and results are anticipated this year.

In the second-line setting, topotecan has resulted in limited responses with severe toxicity. Sorafenib (Nexavar, Bayer) has been associated with stable disease but no responses. Claudin-3 and claudin-4 represent potential targets for investigation.

2. Serous carcinoma of the uterus

Researchers of GOG 209 randomly assigned 1,381 women to paclitaxel and carboplatin vs. paclitaxel, adriamycin and cisplatin. This study included patients with serous carcinoma.

Investigators observed no differences in outcome, eliminating adriamycin as part of the regimen for serous carcinoma of the uterus. Further data are limited to retrospective trials, but all demonstrate improved outcomes after platinum and paclitaxel compared with platinum-based chemotherapy alone, establishing paclitaxel and carboplatin with or without radiation as the standard for nearly all patients with serous carcinomas of the uterus.

PAGE BREAK

The only patients who can safely forego adjuvant therapy are those with no disease remaining in the uterus at the time of hysterectomy or patients with disease confined to a polyp.

3. Leiomyosarcoma

Patients with early-stage leiomyosarcoma may benefit from adjuvant therapy. Four cycles of adjuvant gemcitabine–docetaxel showed improvement compared with historical controls, with a 2-year PFS rate of 59% and a median PFS of 39 months.

GOG 177 is evaluating observation vs. gemcitabine–docetaxel for four cycles followed by four additional cycles of doxorubicin in patients with early-stage leiomyosarcoma. GOG evaluated gemcitabine and docetaxel in the second-line setting, with a 28% response rate and disease stabilization in another 50% of patients.

Other active agents include doxorubicin, ifosfamide, single-agent gemcitabine, liposomal doxorubicin and trabectedin (Yondelis; Janssen, Pharma Mar). Temozolomide shows promise in the recurrent setting, with a response rate of 5% to 33%, and disease stabilization in 47% to 50% of patients.

Because 7% to 71% of leiomyosarcomas express ER or PR, hormonal manipulation may represent a therapeutic strategy. Aromatase inhibitors resulted in responses in some ER–positive patients. Thalidomide (Thalomid, Celgene), sunitinib (Sutent, Pfizer), and the addition of bevacizumab (Avastin, Genentech) to gemcitabine and docetaxel all are inactive.

4. Low-grade endometrial stromal sarcoma

Hormonal therapy with progestational agents (eg, megestrol acetate) and aromatase inhibitors is the adjuvant treatment of choice for low-grade endometrial stromal sarcoma, as most patients respond.

Cervical cancer

There will be an estimated 12,820 new cases of cervical cancer this year in the United States, and 4,210 women will die of the disease. The majority of cases are HPV related.

HPV vaccination provides immunity against the most common oncogenic subtypes and resultant dysplasia and cancer.

Surgery often is curative in early-stage disease, although for certain subsets of patients with comorbidities or high-risk features, chemoradiation may achieve cure, as well. For patients with early-stage disease who desire fertility preservation, new and more conservative surgical approaches — including radical trachelectomy and conization — are under investigation.

In advanced-stage disease, chemoradiation is employed rather than surgery, and prognosis depends on stage.

Recurrent cervical cancer typically is incurable. However, GOG 240 demonstrated that the addition of bevacizumab to chemotherapy doublets — either paclitaxel/cisplatin or paclitaxel/topotecan — yielded a 3.7-month improvement in OS in patients with recurrent disease. This now represents the standard of care for patients with recurrent cervical cancer.

Additional areas of progress include activity of veliparib (ABT-888, AbbVie) — a PARP inhibitor — as well as immunotherapy and PD-1 inhibitors.

Although adenocarcinomas and squamous cell carcinomas comprise the majority of cervical cancers, rare subtypes exist.

PAGE BREAK

Verrucous and warty carcinomas may be mistaken for benign condylomatous lesions and pose a diagnostic challenge. Warty carcinoma and adenoid basal cell carcinoma can behave in a more indolent fashion than the more common adenocarcinomas and squamous cell carcinomas, and they may often be cured with surgery alone. Conversely, adenoid cystic carcinoma and small cell carcinoma are more aggressive with poor outcomes despite multimodal treatment.

Although treatment for rare subtypes usually mirrors the more common histologies, small cell carcinoma is treated differently. This aggressive neoplasm constitutes 3% of cervical cancers and is characterized by early nodal metastases, lymphovascular spread and a high relapse rate. Even in early-stage disease, adjuvant treatment with cisplatin and etoposide and radiation is recommended.

One series showed improvement in PFS among patients with recurrent small cell neuroendocrine carcinoma of the cervix who received combination therapy with topotecan, paclitaxel and bevacizumab. Despite aggressive treatment, 5-year survival is low (37%) for stage I to stage IIa disease. Patients with cervical lymphomas are often treated with chemotherapy alone.

Conclusion

Treatment of cervical cancer depends on stage of disease. Surgery is typically curative for patients with early-stage disease, whereas chemoradiation is favored in advanced stages. Recurrent disease is treated with chemotherapy doublets in addition to bevacizumab.

Histologies of rarer subtypes vary in prognosis but generally are treated with the same principles as adenocarcinomas and squamous cell carcinomas. For malignant mixed Müllerian tumor, or carcinosarcoma, adjuvant multiagent chemotherapy or combined chemoradiation is preferable to whole-abdominal radiation. For the treatment of serous carcinoma, adjuvant paclitaxel and carboplatin — with or without radiotherapy — is preferred for most patients.

Active agents for leiomyosarcoma include gemcitabine with docetaxel, doxorubicin, ifosfamide and trabectedin. Progestational agents and aromatase inhibitors are active for low-grade endometrial stromal sarcoma.

For cervical cancer, the addition of bevacizumab to adjuvant paclitaxel/cisplatin or paclitaxel/topotecan yields an OS advantage and is the preferred regimen for recurrent disease.

References:

Cohen JG, et al. Am J Obstet Gynecol. 2010;doi:10.1016/j.ajog.2010.04.019.

Dahhan T, et al. Eur J Obstet Gynecol Reprod Biol. 2009;doi:10.1016/j.ejogrb.2009.02.005.

Fader AN, et al. Cancer. 2009;doi:10.1002/cncr.24247.

Ferriss JS, et al. Int J Gynecol Cancer. 2010;doi:10.1111/IGC.0b013e3181c7fe53.

Frumovitz M, et al. Gynecol Oncol. 2017;doi:10.1016/j.ygyno.2016.10.040.

Hensley ML, et al. Gynecol Oncol. 2008;doi:10.1016/j.ygyno.2008.03.010.

Hensley ML, et al. Gynecol Oncol. 2009;doi:10.1016/j.ygyno.2008.11.027.

Homesley HD, et al. J Clin Oncol. 2007;25:526-531.

Kunos C, et al. Int J Gynecol Cancer. 2015;doi:10.1097/IGC.0000000000000380.’

Manolitsas TP, et al. Cancer. 2001;91:1437-1443.

Miller D, et al. Gynecol Oncol. 2012;125:771-773.

Ng WK, et al. Acta Cytol. 2003;47:159-166.

O’Cearbhaill R, et al. Gynecol Oncol. 2010;doi:10.1016/j.ygyno.2009.10.064.

Pautier P, et al. Int J Gynecol Cancer. 2004;14:1112-1117.

PAGE BREAK

Siegel RL, et al. CA Cancer J Clin. 2016;doi:10.3322/caac.21332.

Tewari KS, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1309748.

Viswanathan AN, et al. Gynecol Oncol. 2004;93:27-33.

Wolfson AH, et al. Gynecol Oncol. 2007;107:177-85.

For more information:

Jubilee Brown, MD, is professor and associate director in the division of gynecologic oncology at Levine Cancer Institute at Carolinas HealthCare System. She can be reached at 1021 Morehead Medical Drive, Suite 2100, Charlotte, NC 28204; email: jubilee.brown@carolinashealthcare.org.

Erin K. Crane, MD, is a gynecologic oncologist at Levine Cancer Institute at Carolinas HealthCare System. She can be reached at erin.crane@carolinashealthcare.org.

R. Wendel Naumann, MD, is a gynecologic oncologist at Levine Cancer Institute at Carolinas HealthCare System. He can be reached at wnaumann@mac.com.

Disclosure: Brown, Crane and Naumann report no relevant financial disclosures.