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Clinical Practice Guidelines

Clinical Practice Guidelines for Gynecologic Cancers

H. Lee Moffitt Cancer Center & Research Institute
Developed by James V. Fiorica, MD; William S. Roberts, MD;
Mitchel S. Hoffman, MD; and Denis Cavanagh, MD
Department of Obstetrics and Gynecology
University of South Florida, Tampa, Fla

Carcinoma of the Cervix

The size and the extent of the primary tumor are the major factors that dictate therapeutic decisions in cervical cancer. Cancers of the cervix generally remain locoregionally confined until late in the course of the disease. Once the diagnosis is established by punch or cone biopsy, the appropriate workup is guided by the size and extent of the primary tumor. Patients with microinvasive cancer require no additional tests prior to therapy, and those with more than microinvasive disease confined to the cervix (less than or equal to 4 cm in diameter) on physical examination require only routine blood studies, urinalysis, chest radiograph, and intravenous pyelogram. Cystoscopy, proctoscopy, and computed tomography scan of the abdomen and pelvis need not be performed. Patients with primary tumors larger than 4 cm in diameter receive computed tomography scan of the abdomen and pelvis to evaluate for pelvic and periaortic lymphadenopathy. Lymphangiography and magnetic resonance imaging are of uncertain value.

Microinvasive cancer is defined as a squamous cancer that invades no more than 3 mm below the basement membrane and is no more than 7 mm in diameter with no lymph-vascular involvement on cone biopsy. Patients with this diagnosis are effectively treated with simple hysterectomy. In nulliparous patients, a cone biopsy with negative margins is reasonable therapy until childbearing is complete.[1]

Patients with more than microinvasive cancer but with a lesion less than or equal to 4 cm in diameter confined to the cervix can be given the choice of either radical hysterectomy with bilateral pelvic lymphadenectomy or standard pelvic radiation. This approach includes patients with FIGO stage IA2 (depth of invasion of 3 to 5 mm). We exclude these patients from the microinvasive category because they may metastasize to pelvic lymph nodes.[2] Retrospective evidence suggests that the survival in this group of patients is the same whether radical hysterectomy or pelvic radiation is chosen.

Patients who are treated with radical hysterectomy and bilateral pelvic lymphadenectomy may be at either high risk or low risk. High-risk features include involved pelvic lymph nodes, positive or close surgical margins, parametrial involvement, extensive lymph-vascular space involvement, or deep cervical stromal invasion (75% or more of cervical depth). These patients are treated with postoperative pelvic radiation, although the efficacy of this treatment has not been demonstrated in a prospective, randomized trial. Retrospective data suggest that pelvic radiation offers no survival benefit but may result in superior local control. In our experience, 90% of high-risk patients who receive pelvic radiation survive.[3] The possibility that chemotherapy may be of value in this circumstance is being explored.[4]

Most patients with tumors greater than 4 cm that are confined to the cervix can be treated with pelvic radiation alone or modified radiation with an adjunctive extrafascial hysterectomy. Retrospective studies comparing these two treatment methods have been conflicting.[5,6] Radical hysterectomy has been advocated by some, but concern for surgical margins limits its use. Neoadjuvant chemotherapy followed by radical hysterectomy may show promise.[7]

Patients with disease extending into the parametrial tissues usually are treated with pelvic radiation. Because of a high rate of local failure in patients with lesions equal to or greater than 6 cm, there has been interest in radiosensitization with chemotherapy.[8]

The prognosis for patients with distant metastatic disease is poor. Symptomatic relief is of paramount importance. Bleeding and pain from the primary tumor is best addressed with pelvic radiation if not given previously. Chemotherapy is minimally effective with a relatively low response rate.[9]

Follow-up of cervical cancer patients treated with curative intent has not been studied with regard to cost effectiveness. Low-risk patients are followed periodically with physical examination and Papanicolaou smear to detect local recurrences that are potentially curable. High-risk patients can be similarly followed with the addition of serum tumor markers (squamous cell antigen, CA-125), which are reasonably sensitive and specific in this setting. Expensive imaging tests are reserved for symptomatic patients or patients with suspicious physical findings.

References

  1. Morris M, Mitchell MF, Silva EG, et al. Cervical conization as definitive therapy for early invasive squamous carcinoma of the cervix. Gynecol Oncol. 1993;51:193-196.
  2. Maiman MA, Fruchter RG, DiMaio TM, et al. Superficially invasive squamous cell carcinoma of the cervix. Obstet Gynecol. 1988;72:399-403.
  3. Fiorica JV, Roberts WS, Greenberg H, et al. Morbidity and survival patterns in patients after radical hysterectomy and postoperative adjuvant pelvic radiotherapy. Gynecol Oncol. 1990;36:343-347.
  4. Curtin JP, Hoskins WJ, Venkatraman ES, et al. Adjuvant chemotherapy versus chemotherapy plus pelvic irradiation for high-risk cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RH-PLND): a randomized phase III trial. Gynecol Oncol. 1996;61:3-10.
  5. Gallion HH, van Nagell JR Jr, Donaldson ES. Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel-shaped cervical cancer. Cancer. 1985;56:262-265.
  6. Mendenhall WM, McCarty PJ, Morgan LS, et al. Stage IB or IIA-B carcinoma of the intact uterine cervix greater than or equal to 6 cm in diameter: is adjuvant extrafascial hysterectomy beneficial? Int J Radiat Oncol Biol Phys. 1991;21:899-904.
  7. Sardi J. Sananes C, Giaroli A, et al. Results of a prospective randomized trial with neoadjuvant chemotherapy in stage IB, bulky, squamous carcinoma of the cervix. Gynecol Oncol. 1993;49:156-165.
  8. Hreschyshyn MM, Aron BS, Boronow RC, et al. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys. 1979;5:317.
  9. Omura GA, Blessing J, Vaccarello L, et al. A randomized trial of cisplatin (C) versus C + mitolactol (CM) versus C + ifosfamide (CIFX) in advanced squamous carcinoma of the cervix (SCC) by the Gynecologic Oncology Group (GOG). Proc Annu Meet Am Soc Clin Oncol. 1995; 14: A736.

Summary Algorithm for Management of Carcinoma of the Cervix

Carcinoma of the Endometrium

Endometrial cancer is diagnosed by endometrial biopsy that should be accompanied with an endocervical curettage to differentiate concomitant endocervical tumor extension. Due to the false-negative rate of 10% from office endometrial biopsies, high-risk patients or those with an insufficient tissue sample should undergo a full dilatation and curettage.

Diagnosed patients receive a laparotomy, peritoneal lavage for cytologic analysis, and a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Since lymph node sampling provides staging and prognostic information, bilateral pelvic and periaortic lymph node sampling is performed when it can be accomplished safely. Radical hysterectomy with complete bilateral pelvic lymphadenectomy is recommended when invasive endocervical stromal penetration occurs. Brachytherapy followed by total abdominal hysterectomy with lymphadenectomy is a reasonable alternative for patients with cervical extension. Full pelvic teletherapy combined with brachytherapy is an acceptable alternative for patients with surgical contraindications.

Adverse prognostic factors include poor histologic grade, deep myometrial penetration, nonadenomatous histologic cell types, lymph node metastasis, malignant cells in peritoneal washings, lymph-vascular invasion, cervical invasion, intraperitoneal and/or adnexal spread, and negative estrogen and progesterone receptors.

No additional therapy is needed for 50% to 60% of patients with endometrial cancer after the primary surgery is completed. The modalities available for patients who are at high risk for recurrence include radiation therapy, chemotherapy, and hormonal therapy. Chemotherapy and hormonal therapy are used for advanced disease, and radiation therapy is used as an adjuvant in selected high-risk patients in order to achieve local control.

Since patients at intermediate risk are difficult to define, recommendation of adjuvant treatment is challenging. These patients can be entered on multicenter cooperative group clinical trials.

Since 90% of recurrences develop within the first five years and one third within the first year, follow-up is tailored to these time frames. Fifty percent of recurrences are local, 29% are distant, and 21% are simultaneously local and distant. The median time to recur is 14 months.[1] The most common site for local recurrence is the upper vagina, which can be detected by a Papanicolaou smear and digital pelvic examination. The most common distant recurrent site is the lung, which is easily seen on chest radiographs. CA-125 titers often are elevated in patients with recurrent disease. Expensive imaging tests (eg, computed tomography scan and magnetic resonance imaging) are reserved for symptomatic patients or patients with suspicious physical findings.

References

  1. Aalders JG, Abeler V, Kolstad P. Recurrent adenocarcinoma of the endometrium: a clinical and histopathological study of 379 patients. Gynecol Oncol. 1984;17:85-103.

Summary Algorithm for Management of Carcinoma of the Endometrium

Epithelial Carcinoma of the Ovary

Choice of therapy and accurate assignment of prognosis for epithelial carcinoma of the ovary are dependent on accurate surgical staging.[1] In patients with advanced disease, aggressive cytoreductive surgery is performed.[2] A large body of retrospective evidence supports the value of primary cytoreductive surgery.[3]

Most patients with epithelial ovarian cancer require additional therapy following surgery. Those with epithelial cancers of low malignant potential do not require postoperative therapy. Therapy is reserved for clear evidence of progression or symptomatology. Patients with histologic grade 1 or 2 disease confined to the ovary have a cure rate of at least 90% and do not require adjuvant therapy.[4] Those with grade 3 cancers confined to the ovary or with disease beyond the ovary but confined to the pelvis are at high risk for recurrence and should receive adjuvant therapy.

It is unclear whether any therapy for high-risk, early-stage epithelial ovarian cancer is superior to no therapy.[5] Intraperitoneal P32, whole abdominopelvic radiation, and systemic chemotherapy have been used. Our bias is to use intravenous cisplatin and paclitaxel.

Patients with advanced epithelial ovarian cancer receive systemic chemotherapy after surgery. Few are cured, but most respond and live longer. Patients with suboptimal residual disease are best treated with intravenous cisplatin and a 24-hour infusion of paclitaxel.[6] Interval cytoreductive surgery in suboptimal patients may be reasonable.[7]

The therapy of choice for patients with optimal residual disease is unclear. We presently use intravenous paclitaxel given over 24 hours and intraperitoneal cisplatin.[8]

Initial therapy of metastatic carcinoma of the ovary is rapidly evolving in the areas of high-dose chemotherapy with stem cell rescue, intraperitoneal paclitaxel, and new drugs and biologics. Once patients with advanced epithelial ovarian cancer complete therapy and appear to be disease free, a "second-look" laparotomy to assess response and to detect small-volume residual disease may be used in a research setting or when a reasonable second-line therapy is available if persistent disease is found.[9]

References

  1. Piver MS, Barlow JJ, Lele SB. Incidence of subclinical metastasis in stage I and II ovarian carcinoma. Obstet Gynecol. 1978;52:100-104.
  2. Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol. 1994;170:974-980.
  3. Roberts WS. Cytoreductive surgery in ovarian cancer: why, when, and how? Cancer Control: JMCC. 1996;3:130-136.
  4. Young RC, Walton LA, Ellenberg SS, et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med. 1990;322:1021-1027.
  5. Colombo N, Chiari S, Maggioni A, et al. Controversial issues in the management of early epithelial ovarian cancer: conservative surgery and role of adjuvant therapy. Gynecol Oncol. 1994;55:S47-S51.
  6. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1-6.
  7. van der Burg ME, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer: Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med. 1995;332:629-634.
  8. Alberts DS, Liu PY, Hannigan EV, et al. Phase III study of intraperitoneal (ip) cisplatin (CDDP)/intravenous (iv) cyclophosphamide (CPA) vs iv CDDP/iv CPA in patients (pts) with optimal disease stage III ovarian cancer: a SWOG-GOG-ECOG intergroup study (INT 0051). Proc Annu Meet Am Soc Clin Oncol. 1995;14:A760.
  9. Hoskins WJ, Rubin SC, Dulaney E, et al. Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian cancer. Gynecol Oncol. 1989;34:365-371.

Summary Algorithm for Management of Epithelial Carcinoma of the Ovary

Carcinoma of the Vulva

Carcinoma of the vulva is predominantly a locoregional illness. Imaging studies such as computed tomography scans are not helpful (except in advanced disease), since the staging and treatment are primarily surgical, based on the initial size, location, and local spread of the tumor. Radical vulvectomy is the treatment of choice for vulvar cancer. Since squamous cancers are often unilateral, the surgery may be tailored to include a radical wide excision of the area (modified radical vulvectomy) in order to optimally remove the tumor with cancer-free surgical margins of resection. A bilateral inguino-femoral lymphadenectomy is required for any cancers with a depth of invasion greater than 1 mm, since the incidence of lymph node metastasis increases at this depth. A small unilateral vulvar lesion may need only a radical wide excision with removal of the ipsilateral lymph nodes. Most vulvar cancers occuring near the midline require a bilateral groin node dissection. Surgical removal of the deep pelvic nodes is not recommended.

Wound breakdown occurs in 50% of patients. Separate surgical incisions, closed suction draws, and immobilization of skin flaps can reduce this complication rate.[1]

Prognostic factors include size, location, lymph node metastasis, and status of surgical margins. Patients with metastatic inguinal nodes are best treated with radiotherapy to the inguino-femoral and pelvic lymph nodes.[2] Close surgical margins place a patient at high risk for local recurrences, and the patient must be followed carefully. These high-risk patients may be eligible for a randomized trial to quantitate the benefits and risks of adjuvant radiotherapy and/or chemotherapy.

Patients with advanced disease benefit from radical pelvic surgery including a radical vulvectomy and pelvic exenteration with inguino-femoral lymphadenectomy.[3] Recent attempts to control advanced disease have used concomitant chemotherapy and radiotherapy followed by radical surgery.

Over 80% of recurrences develop in the first two years and 95% within five years. Fifty percent of the recurrences are local and appear near the site of the initial tumor. Careful inspection and palpation of the area and regional nodes are the most cost-effective ways to follow these patients. A serum squamous cell antigen level can be of value in detecting recurrences in more advanced cases.

References

  1. Cavanagh D, Fiorica JV, Hoffman MS, et al. Invasive carcinoma of the vulva: changing trends in surgical management. Am J Obstet Gynecol. 1990;163:1007-1015.
  2. Homesley HD, Bundy BN, Sedlis A, et al. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol. 1986;68:733-740.
  3. Cavanagh D, Shepherd JH. The place of pelvic exenteration in the primary management of advanced carcinoma of the vulva. Gynecol Oncol. 1982;13:318-322.

Summary Algorithm for Management of Carcinoma of the Vulva


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