The overall incidence of invasive cervical carcinoma has declined steadily since the mid-1940s. Of the predominant gynecologic cancers, cervical cancer is the least common, with only 12,900 new cases anticipated in the United States in the year 2001. Nevertheless, approximately 4,400 women die of invasive cervical carcinoma annually in the United States.
Age The peak age of developing cervical cancer is 47 years. Approximately 47% of women with invasive cervical cancer are < 35 years old at diagnosis. Older women (> 65 years) account for another 10% of patients with cervical cancer. Although these older patients represent only 10% of all cases, they are more likely to die of the disease due to their more advanced stage at diagnosis.
Socioeconomic class Carcinoma of the uterine cervix primarily affects women from the lower socioeconomic class and those with poor access to routine medical care.
Geography Although invasive cervical carcinoma is relatively uncommon in the United States compared to the more common cancers in women (breast, endometrial, and ovarian cancers), it remains a significant health problem for women worldwide. In many developing countries, not only is cervical carcinoma the most frequently occurring cancer among middle-aged women, but also it is a leading cause of death. This is due, in part, to poor access to medical care and the unavailability of routine screening in many of these countries.
Sexual activity Invasive cervical carcinoma can be viewed as a sexually transmitted disease. If a woman is never sexually active, it is extremely unlikely that she will ever develop this cancer. Conversely, any woman who has been sexually active is at risk for invasive cervical carcinoma.
Human papillomavirus An important cofactor in the etiology of invasive cervical carcinoma is the human papillomavirus (HPV). Worldwide, it is estimated that approximately 90%-100% of all invasive cervical carcinomas are related to HPV infection. Of the wide variety of HPV subtypes, several (ie, subtypes 16, 18, 31, 33, and 35) are associated with invasive carcinoma.
Age of onset of sexual activity Population studies of women with invasive cervical carcinoma have demonstrated that early age of onset of sexual activity also plays a role in the later development of the cancer. It is postulated that during the time of menarche in early reproductive life, the transformation zone of the cervix is more susceptible to oncogenic agents, such as HPV. Women who begin sexual activity before 16 years of age or who are sexually active within 1 year of beginning menses are at a particularly high risk of developing invasive cervical carcinoma .
Other risk factors include multiple sexual partners and a history of genital warts.
Cigarette smoking has been identified as a significant risk factor for cervical carcinoma. The mechanism may be related to diminished immune function secondary to a systemic effect of cigarette smoke and its by-products or a local effect of tobacco-specific carcinogens.
Oral contraceptives may also play a role in the development of invasive cervical carcinoma, although this theory is more controversial. Given that most women who use oral contraceptives are more sexually active than women who do not use oral contraceptives, this may represent a confounding factor rather than a true independent risk factor. The exception may be adenocarcinoma of the cervix. This relatively uncommon histologic subtype may be related to previous oral contraceptive use.
Immune system alterations In recent years, alterations in the immune system have been associated with an increased risk of invasive cervical carcinoma, as exemplified by the fact that patients who are infected with the human immunodeficiency virus (HIV) have increased rates of both preinvasive and invasive cervical carcinoma. These patients also are at risk for other types of carcinoma, including Kaposi’s sarcoma, lymphomas, and other squamous cell carcinomas of the head and neck and the anogenital region. (For further discussion of AIDS-related malignancies, see chapter 29.)
Data suggest that patients who are immunocompromised due to immunosuppressive medications also are at risk for both preinvasive and invasive cervical carcinoma. This association is probably due to the suppression of the normal immune response to HPV, which makes patients more susceptible to malignant transformation.
Common symptoms The classic symptom of cervical carcinoma is intermenstrual bleeding in a premenopausal patient. Other commonly reported symptoms include heavier menstrual flows and metrorrhagia. The patient may also complain of postcoital bleeding.
Less common presentations Less commonly, patients present with signs of advanced disease, such as bowel obstruction and renal failure due to urinary tract obstruction. Only rarely are asymptomatic patients (normal screening Pap smear) found to have a lesion on the cervix, which leads to a diagnosis of invasive cervical carcinoma.
Screening
Pap smear The paradigm for a cost-effective, easy-to-use, reliable screening test is the cervical cytology screen, or Pap smear. In every population studied, the introduction of the Pap smear has resulted in a significant reduction in the incidence of invasive cervical carcinoma, as well as a shift toward earlier-stage disease at the time of diagnosis. The success of cervical cytology, as measured by the lowered incidence of cervical cancer, ironically has led to some controversy regarding the most effective application of this screening tool. With the marked reduction in the incidence of cervical carcinoma, more patients are screened and greater costs incurred in order to detect each additional case of cervical carcinoma.
Current screening recommendations The current recommendation of the American College of Obstetricians and Gynecologists (ACOG) is that all women who are 18 years of age or older and are sexually active be screened. If the patient has three consecutive annual cervical cytology smears that are normal, she may be safely screened at a less frequent interval of perhaps 2-3 years. There are no data to support screening patients on a less frequent basis. Any patient who has a history of cervical dysplasia should be screened, at a minimum, on a yearly basis.
Three new techniques designed to improve the sensitivity of the Pap smear (Thin Prep system, Autopap, and Papnet) were recently approved by FDA. However, no large, population-based, prospective studies have been completed to determine whether any of these techniques lowers the incidence of invasive cervical cancer or improves the survival rate. Consequently, in a committee opinion, ACOG has stated that the appropriate use of these techniques requires further investigation and that "they currently are not the standard of care."
Diagnosis
The diagnosis of invasive cervical carcinoma can be suggested by either an abnormal Pap smear or an abnormal physical finding.
Colposcopy In the patient who has an abnormal Pap smear but normal physical findings, colposcopy is indicated. Colposcopic findings consistent with invasive cervical carcinoma include dense white epithelium covering the ectocervix, punctation, mosaicism, and, especially, an atypical blood vessel pattern.
Biopsy If the colposcopic findings are suggestive of invasion, biopsies are obtained from the ectocervix and endocervix. If these biopsies demonstrate only precancerous changes but not an invasive carcinoma, the patient should undergo an excisional biopsy of the cervix. In most current clinical settings, the loop electrosurgical excision procedure (LEEP) is the most expedient method for performing an excisional biopsy. This can be easily accomplished in the office under local anesthesia and provides adequate tissue for diagnosis. Once the diagnosis of either a microinvasive or an invasive carcinoma has been established, the patient can be triaged accordingly.
Patients with signs/symptoms of advanced disease The patient with signs/symptoms of advanced invasive cervical carcinoma requires a cervical biopsy for diagnosis and treatment planning. In this setting, a Pap smear is superfluous and may be misleading.
Squamous cell carcinoma The most common histology associated with invasive cervical carcinoma is squamous cell carcinoma, which accounts for approximately 80% of all carcinomas of the uterine cervix. For the most part, the decline in the annual incidence of invasive cervical carcinoma has been seen primarily among patients with this subtype.
Adenocarcinoma In the past, adenocarcinoma was relatively uncommon as a primary histology of cervical cancer. As a result of the decrease in the overall incidence of invasive squamous cell cancer and, probably, an increase in the baseline incidence of adenocarcinoma of the uterine cervix, this histology now accounts for approximately 20% of all cervical cancers.
There is controversy over whether patients with adenocarcinoma of the cervix have a worse prognosis than those with the more common squamous cell histology. The poorer prognosis associated with adenocarcinoma may be due to the relatively higher frequency of late stage at the time of diagnosis among patients with this histologic type. In several series in which patients were stratified by stage and tumor size, the outcome of cervical adenocarcinoma appeared to be similar to that of squamous lesions of the cervix.
Aggressive subtypes Among the various subtypes of adenocarcinoma, certain types are particularly aggressive and are associated with a poor prognosis. Among these are the small neuroendocrine tumors, which have a poor prognosis even when diagnosed at an early stage.
Rare tumor types More rare lesions of the cervix include lymphoma, sarcoma, and melanoma. These histologic subtypes account for < 1% of all cervical cancers.
Clinical staging
The widely accepted standard for staging of cervical carcinoma is the staging system outlined by the International Federation of Gynecology and Obstetrics (FIGO). This is primarily a clinical staging system based on histology for the earlier stage I cancers and tumor size . For the more advanced tumors, staging is based on extension of the disease in the pelvis.
Radiographic examination allowed under the FIGO staging system includes chest x-ray and barium enema, as well as IV pyelography. However, where available, CT scanning or MRI is the preferred diagnostic study. MRI is superior to the CT scan in evaluating extent of disease in the pelvis. Lymphangiography may be helpful in evaluating the pelvic and para-aortic lymph nodes. In the United States, barium enema and IV pyelography are rarely indicated. For advanced disease, cystoscopy and/or sigmoidoscopy may be indicated. Additional clinical information can be gathered by pelvic examination under anesthesia.
A recent modification of the FIGO system has clarified the description of patients with microinvasive cervical carcinoma. This better differentiation between stages IA1 and IA2 followed the lead established by the Society of Gynecologic Oncologists (SGO) in their staging of microinvasive carcinoma.
In addition, the modified FIGO system now stages patients with lesions that are clinically confined to the cervix (stage IB) according to the size of the primary tumor.
Surgical staging
Clinical staging of cervical carcinoma, although widely utilized, is not without controversy. When compared to surgical staging carried out by large cooperative groups, clinical staging is frequently inaccurate in predicting locoregional spread. For many cooperative groups, including the Gynecologic Oncology Group (GOG), surgical staging may be required for patients who are entering prospective, randomized clinical protocols.
The most common method used to stage patients with advanced disease is extraperitoneal sampling of the pelvic and aortic lymph nodes. This approach minimizes the risk of subsequent radiation injury to the small bowel due to surgical adhesions and, in patients with advanced disease, allows for individualized treatment planning.
Work-up for advanced disease The standard work-up of a patient with advanced cervical carcinoma who is not considered a candidate for radical surgery includes an abdominopelvic CT scan with both renal and GI contrast. If there is evidence of aortic lymph node metastases, the patient should undergo fine-needle aspiration (FNA) of these enlarged lymph nodes. If the FNA confirms that there is aortic lymph node metastasis, treatment should be individualized and extended-field radiation should be considered as part of the primary treatment regimen.
If the scalene lymph nodes are negative on clinical examination and the patient is known to have positive metastatic disease to the aortic lymph nodes, consideration can be given to performing a scalene lymph node biopsy; the incidence of positive scalene nodes when aortic lymph nodes are known to be positive ranges from 0.0% to 17%. The rationale for biopsying the scalene nodes is that if there is disease outside of the radiation therapy field, chemotherapy is appropriate.
If the fine-needle aspirate is negative, or if the abdominopelvic CT scan does not demonstrate enlarged aortic lymph nodes, the patient can be considered for surgical staging.
Pros and cons of surgical staging The advantage of surgical staging is that patients with microscopic disease in the aortic lymph nodes can be treated with extended-field radiation therapy and, possibly, chemotherapy and potentially benefit in terms of long-term survival. The controversy regarding surgical staging stems from the fact that a very small number of patients will actually benefit from the procedure; the majority of patients who undergo it either will be found not to have metastatic disease and will receive the same treatment as planned prior to surgical staging or, if they are found to have metastatic disease, will be unlikely to benefit from extended-field radiation therapy. Because of this controversy, the GOG considers surgical staging to be optional for patients with advanced-stage cervical cancer.
Laparoscopic surgery In more recent years, the introduction of minimal-access surgery has allowed surgeons to accurately stage patients via the laparoscope prior to initiation of radiation therapy. However, the safety and efficacy of laparoscopic surgical staging are areas of ongoing investigation. Therefore, at present, its use should be reserved for clinical trials.
Work-up for early-stage disease For patients who have early-stage disease for which surgery is contemplated, only a minimal diagnostic work-up is indicated prior to surgery. At most institutions, this would include a two-view chest x-ray. Patients who have stage IA cervical carcinoma (microinvasive carcinoma) do not require preoperative CT scanning prior to hysterectomy. For patients with a small IB carcinoma of the cervix, a CT scan of the abdomen and pelvis has a low yield and is unlikely to change the treatment plan.
Prognostic factors
Clinical stage The most important determinant of prognosis remains clinical stage. The overall 5-year survival rate ranges from 95% to 100% for patients with stage IA cancer and from 75% to 90% for those with stage IB disease. Patients with stage IV disease have a ?/font> 5% chance of surviving 5 years after diagnosis.
Patients with early disease For patients with early invasive carcinoma (stage IB), the size of the lesion, percentage of cervical stromal invasion, histology, tumor grade, and lymphovascular space involvement are important local factors that predict prognosis. In general, good prognostic signs are lesions that are ?/font> 2 cm in diameter, superficially invasive, and well differentiated with no lymphovascular space involvement.
For patients who have undergone a radical hysterectomy for early cervical carcinoma, poor prognostic factors, in addition to the local factors mentioned above, include positive vaginal or parametrial margins and metastasis to the pelvic lymph nodes. For stage IB patients with positive pelvic nodes, the 5-year survival rate drops from approximately 75%-85% to 50%.
Patients with advanced disease For patients with advanced-stage disease (stages II through IV), the primary determinants of prognosis are histology and size of the primary lesion. Survival is significantly higher for patients with small stage IIB cervical carcinomas and minimal parametrial involvement than for patients with large bulky tumors and bilateral parametrial involvement. Disease extension beyond the pelvis to the aortic nodes is associated with a significant decrease in overall survival rate. With regard to histology, a better prognosis is associated with a large-cell nonkeratinizing squamous cell cancer of the cervix, as opposed to a poorly differentiated adenocarcinoma.
Other prognostic factors Other factors that may predict outcome include the patient’s general medical and nutritional status. Patients who are anemic may respond poorly to radiation therapy, as compared with those with normal hemoglobin levels. Patients with significant alterations in their immune system may not respond as well; this is becoming increasingly apparent with regard to patients who are HIV-seropositive.
SURGICAL TREATMENT OF EARLY-STAGE DISEASE
The standard management of patients with early cervical carcinoma is surgical removal of the cervix. The extent of resection of surrounding tissue depends on the size of the lesion and depth of invasion.
Stage IA1 disease
Simple hysterectomy Patients who have a microinvasive squamous carcinoma of the cervix with < 3 mm of invasion, < 7 mm of lateral extent, and no lymphovascular space involvement (stage IA1) can be treated with a simple hysterectomy. Vaginal and abdominal hysterectomy are equally effective.
Cone biopsy Although simple hysterectomy is considered the standard therapy for patients with microinvasive cervical carcinoma, there are some patients in whom preservation of future fertility is a strong consideration. A cone biopsy entails removal of the cervical transformation zone. Provided that the biopsy margins are free of dysplasia and microinvasive carcinoma, cone biopsy is probably a safe treatment for such patients who meet the criteria of having superficial invasion < 3 mm, minimal lateral extension, and no lymphovascular space involvement.
Since there is a small risk of recurrence among this population of patients treated by cone biopsy alone, they should be followed closely. Follow-up includes a Pap smear every 3 months for 2 years and then twice a year. An abnormal Pap smear is an indication for a repeat colposcopy. If such a patient is successful in achieving pregnancy and has no evidence of recurrent squamous cell carcinoma, there is no need to proceed with hysterectomy at the completion of her planned childbearing.
Stages IA2, IB1, and nonbulky IIA disease
Radical hysterectomy A standard treatment for patients with small cervical carcinomas (tumor ?/font> 4 cm) confined to the uterine cervix or with minimal involvement of the vagina (stage IIA) is radical hysterectomy (removal of the uterus, cervix, and parametrial tissue), pelvic lymphadenectomy, and aortic lymph node sampling. The overall success of this treatment is similar to that of radiation therapy, and for patients with early lesions, radical hysterectomy may provide an improved quality of life. The benefits of surgical excision include rapid treatment, less time away from normal activities, and preservation of normal ovarian and vaginal function.
A recent randomized trial for patients with early stage cervix cancer, reported no difference in survival between radical hysterectomy and definitive radiation. Because a significant percentage of patients following radical hysterectomy required postoperative pelvic radiotherapy, the morbidity was increased in the surgery arm. Therefore, patients selected for radical hysterectomy should have small-volume disease so adjuvant pelvic radiation is unnecessary.
Currently, there are no specific contraindications to radical hysterectomy. Several studies have demonstrated that patients ?/font> 65 years old tolerate this procedure well, and age alone should not be considered a contraindication. Obesity also is not a contraindication to radical hysterectomy.
Alternatives to radical hysterectomy Recent reports have described the use of laparoscopically assisted radical vaginal hysterectomy and laparoscopic abdominal radical hysterectomy as less invasive alternatives to traditional radical hysterectomy. The use of fertility-preserving surgery by means of laparoscopic pelvic lymphadenectomy followed by radical vaginal trachelectomy (removal of the uterine cervix) has also been evaluated. Successful pregnancies after this procedure have been reported. However, until further data accumulate, these procedures should be considered strictly investigational.
Complications Due to improved surgical techniques, as well as the use of prophylactic antibiotics and prophylaxis against deep-vein thrombosis, the morbidity and mortality associated with radical hysterectomy have declined significantly over the past several decades. The currently accepted complication rate for radical hysterectomy includes approximately a 0.5%-1.0% incidence of urinary tract injury, a 0.5%-1.0% incidence of deep-vein thrombosis, and an overall mortality of < 1.0%.
The increased awareness of the risks associated with blood transfusion is reflected in the fact that, in many cases, no transfusions are administered. The need for heterologous blood transfusion also can be decreased by encouraging autologous blood donation prior to radical hysterectomy or by using intraoperative hemodilution.
The average hospital stay for patients undergoing a radical hysterectomy is between 4 and 7 days. Follow-up should include a vaginal Pap smear every 3 months for 2 years, twice a year for 3 years, and yearly thereafter.
Stages IB2 and bulky IIA disease
Numerous studies have demonstrated that patients with early-stage "bulky" lesions (tumor > 4 cm) have a worse prognosis than those with nonbulky tumors. Therefore, patients who have undergone radical hysterectomy and pelvic lymphadenectomy for early-stage bulky cervical cancer have traditionally received postoperative adjuvant pelvic radiation therapy. However, a recent randomized trial from Italy demonstrated that radical hysterectomy plus radiotherapy does not improve overall or disease-free survival in patients with early-stage bulky tumors, as compared with radiation therapy alone, but does significantly increase morbidity.
Furthermore, a recent GOG trial demonstrated the benefit of the addition of cisplatin (Platinol) chemotherapy to pelvic radiation followed by extrafascial hysterectomy in this group of patients (Figure 1). Therefore, many experts feel that patients with stage IB2 and bulky IIA cervical cancer should be treated initially with chemoradiation followed by adjuvant extrafascial hysterectomy.
RADIATION THERAPY FOR STAGES I-IV DISEASE
The role of curative surgery diminishes once cervical cancer has spread beyond the confines of the cervix and vaginal fornices. Intracavitary radiation for central pelvic disease and external-beam radiation therapy for lateral parametrial and pelvic nodal disease are typically combined to encompass the known patterns of disease spread with an appropriate radiation dose while sparing the bladder and rectum from receiving full doses. The addition of intracavitary radiation to external-beam radiation is associated with improved pelvic control and survival over external radiation alone, as the combination can achieve high central doses of radiation.
Radiation techniques
Intracavitary brachytherapy Radioactive isotopes, such as cesium-137, can be introduced directly into the uterine cavity and vaginal fornices with special applicators. The most commonly used applicator is the Fletcher-Suit intrauterine tandem and vaginal ovoids.
Calculating dose rates With the advent of computerized dosimetry, the dose rate to a number of points from a particular source arrangement can be calculated. Adjustments in the strength or positioning of the sources can then be made to yield a selected dose rate to one or more points.
Points of interest usually include the maximum rectal and bladder dose, as well as the dose to three standard pelvic points: A, B, and P (see Figure 2). Point A is located 2 cm cephalad from the cervical os and 2 cm lateral to the uterine canal. Anatomically, it represents the medial parametrium/lateral cervix, the approximate point at which the ureter and uterine artery cross. Point B is 5 cm lateral to the center of the pelvis at the same level as point A and approximates the region of the obturator nodes or lateral parametrium. Point P is located along the bony pelvic sidewall at its most lateral point and represents the minimum dose to the external iliac lymph nodes.
LDR vs HDR brachytherapy Standard dose rates at point A are typically 50-70 cGy/h; this is considered low-dose-rate (LDR) brachytherapy. The applicator is placed into the uterus while the patient is under anesthesia in the operating room, and the patient must stay in bed in the hospital for 2-3 days during the implant. One or two implants are usually placed. Despite the fact that two insertions may allow time for regression of disease between placements, there are no data indicating that two insertions improve pelvic control or survival rates over one insertion.
Whereas LDR brachytherapy has been used successfully for decades in the treatment of carcinoma of the cervix, the use of high-dose-rate (HDR) brachytherapy has been increasing in the United States over the last decade. Dose rates are typically 200-300 cGy/min, with short treatment times allowing for stable position of the applicator.
The major benefit of HDR brachytherapy is that the procedure can be performed on an outpatient basis with less radiation exposure to personnel. The major disadvantage is biological: large single fractions of radiation (5-10 Gy) are used with 3-10 insertions per patient, which may increase the rate of late complications.
Several series have cited comparable disease control and complication rates with HDR and LDR brachytherapy. HDR brachytherapy is an alternative to LDR brachytherapy in the current GOG advanced cervical cancer trial.
External-beam pelvic radiation therapy is used in conjunction with intracavitary radiotherapy for stages IA2 disease and above when the risk of pelvic lymph node involvement is significant. The amount of external-beam radiation delivered and the timing of its administration relative to intracavitary radiation is individualized. For example, the presence of a large exophytic cancer that distorts the cervix would initially preclude successful placement of intracavitary brachytherapy. External-beam radiotherapy would be administered first, and after significant regression of disease, could be followed by intracavitary radiotherapy.
Advanced tumors require relatively more external radiation due to the inability of central radioisotope sources to effectively irradiate disease in the lateral parametrium. Typically, external pelvic doses of 4,000-5,000 cGy are followed by 4,000-5,000 cGy to point A with intracavitary brachytherapy, for a total dose of 8,000-9,000 cGy to point A. A parametrial boost completes treatment to the lateral pelvis, for a total dose to point B or P of 6,000 cGy from external-beam radiation and brachytherapy, depending on the extent of disease.
External-beam para-aortic radiation therapy may be used in addition to external-beam pelvic radiation when para-aortic disease is confirmed or suspected. A Radiation Therapy Oncology Group (RTOG) trial found that external-beam para-aortic radiation conferred a survival benefit in patients with advanced cervical cancer (stage IB > 4 cm, stage IIA, and stage IIB) over external-beam pelvic therapy alone. Although external-beam radiation therapy can successfully sterilize microscopic disease, its value in the treatment of gross para-aortic disease is limited, as the tolerance of surrounding organs (bowel, kidney, spinal cord) precludes the delivery of sufficiently high doses to the para-aortic region.
In multivariate analysis, treatment factors associated with improved pelvic control for cervical cancer include the use of intracavitary brachytherapy, total point A dose > 8,500 cGy (stage III only), and overall treatment time < 8 weeks.
Definitive radiation therapy
CIS, stage IA disease Carcinoma in situ (CIS) and microinvasive cervical cancer (stage IA) are not associated with lymph node metastases. Therefore, intracavitary brachytherapy alone, delivering approximately 5,500 cGy to point A, can control 100% of CIS and stage IA disease and is an acceptable alternative to surgery for patients who cannot undergo surgery due to their medical condition.
Stage IB disease The most important prognostic factor associated with pelvic tumor control and survival following radiation therapy for stage IB cervical cancer is tumor size. The central pelvic control rate with radiotherapy alone is excellent for tumors < 8 cm (97%), with total pelvic control and survival rates of 93% and 82%, respectively. Therefore, many experts have argued that adjuvant hysterectomy is unnecessary for cervical cancer < 8 cm. For bulky cervical cancers ?/font> 8 cm, pelvic control and survival rates decrease to 57% and 40%, respectively, with irradiation alone, and adjuvant hysterectomy may potentially improve local control and survival rates (Table 3).
A recently completed RTOG trial (RTOG 9001) for advanced cervical cancer (stage IB or IIA with tumor ?/font> 5 cm or with biopsy-proven pelvic lymph node involvement and stage IIB-IVA) compared external-beam pelvic radiation plus concurrent fluorouracil (5-FU) and cisplatin with external-beam pelvic and para-aortic radiation; in both arms, these therapies were followed by intracavitary radiation. The addition of chemotherapy to radiation improved 5-year survival from 58% to 73% and disease-free survival from 40% to 67% by reducing rates of both local recurrence and distant metastases (Figures 1 and 3).
A previous trial by the GOG attempted to define the best local therapy (radiation therapy alone or radiation followed by extrafascial hysterectomy) in bulky stage IB2 cervical disease (defined as > 4 cm). The results of this trial suggested that adjuvant hysterectomy reduces the risk of recurrence but does not affect overall survival.
A recently reported GOG trial (GOG 123) randomized similar patients to either local treatment alone (external and intracavitary radiation followed by hysterectomy) or local therapy plus weekly cisplatin. The combination of concurrent weekly cisplatin and radiation significantly reduced the relapse rate and improved survival by 50%. The 3-year survival rate was significantly improved from 74% to 83% with the use of chemotherapy; this was primarily due to a reduced risk of local recurrence (21% vs 9%) (Figures 1 and 4).
Current treatment recommendations Concurrent radiotherapy and chemotherapy (cisplatin-based) with or without adjuvant hysterectomy are standard treatments for bulky IB2 cervical cancer.
The use of adjuvant hysterectomy is controversial for small (< 8 cm) stage IB2 cervical cancer, since dose-intense external pelvic and intracavitary radiation plus chemotherapy may obviate the need for adjuvant surgery. The GOG trial suggests that adjuvant hysterectomy reduces the recurrence rate but does not affect survival.
The use of weekly cisplatin ?6 cycles or 5-FU and cisplatin every 3 weeks ?2 cycles concurrent with radiotherapy is the standard treatment approach for bulky IB cervical cancer.
Stage IIA-IVA disease The most important prognostic factor associated with pelvic tumor control and survival is the bulk of pelvic disease within each stage. For stage IIB, bulky disease is variously defined as bilateral or lateral parametrial infiltration or central bulky disease > 5 cm in diameter. For stage IIIB, bulky disease is defined as bilateral sidewall involvement, lower third vaginal involvement, or hydronephrosis.
In the previous GOG experience, in which para-aortic lymph node staging had been mandated, multivariate analysis testing revealed para-aortic lymph node involvement to be the most powerful negative prognostic factor, followed by pelvic lymph node involvement, larger tumor diameter, young age, advanced stage, and lower performance status for patients with negative para-aortic lymph nodes. Five-year survival rates for radiotherapy alone vary from 80% for stage I, 60% for stage II, and 35% for stage III disease, with corresponding pelvic control rates of 90%, 80%, and 50%, respectively.
Chemoradiation Attempts by cooperative groups to improve upon these results have generally included concurrent chemotherapy with standard radiation therapy. The GOG has completed a phase III trial (GOG 85) randomizing stage IIB-IVA patients with pathologically negative para-aortic lymph nodes to pelvic external-beam radiation plus hydroxyurea (Hydrea) vs pelvic external-beam radiation plus 5-FU and cisplatin followed, in both arms, by intracavitary radiotherapy. Compared with hydroxyurea, the use of 5-FU and cisplatin was associated with a significant improvement in survival, as well as a decrease in relapse (Figure 1).
A recently completed GOG phase III trial (GOG 120) compared standard pelvic external-beam radiation/intracavitary brachytherapy plus hydroxyurea vs weekly cisplatin vs hydroxyurea, 5-FU, and cisplatin. Both the weekly cisplatin and the 5-FU-cisplatin-hydroxyurea arms produced significantly improved survival and relapse rates compared to hydroxyurea alone. Two-year progression-free survival rates were significantly improved from 47% to 67% and 64% with weekly cisplatin-radiation and 5-FU-cisplatin-hydroxyurea-radiation compared with hydroxyurea and radiotherapy (Figures 1 and 5). The improved outcome was due to reduced rates of pelvic failure and lung metastases. Because of an improved therapeutic ratio, weekly cisplatin is the favored regimen.
A recently completed GOG trial (GOG 165) compared standard radiation therapy plus concurrent weekly cisplatin vs concurrent protracted venous infusion 5-FU (225 mg/m2/d over 5 weeks) as radiation sensitizers. In this study, the dose of radiation to point A had been increased by 500 cGy, and the pelvic fields redefined to improve the dose intensity and accuracy of radiotherapy.
As mentioned above, the recently completed RTOG study (RTOG 9001) of advanced cervical cancer compared pelvic and para-aortic external-beam radiotherapy to pelvic radiation plus 5-FU/cisplatin-based chemotherapy, both followed by intracavitary radiation.
In contrast to the above positive results with concurrent cisplatin-based chemotherapy regimens and radiotherapy, the Toronto group found no significant benefit to infusional 5-FU (1 g/m2/d) administered during the first and last 4 days of pelvic radiotherapy.
Current treatment recommendations For patients without para-aortic lymph node metastases, pelvic external radiation (4,000-5,000 cGy) should be used, followed by intracavitary brachytherapy (4,000-5,000 cGy) to point A, for a total dose of 8,000-9,000 cGy to point A.
In view of the multiple randomized trials documenting a survival benefit with concurrent chemoradiation, the use of concurrent weekly cisplatin or cisplatin-5-FU every 3 weeks with radiation is standard therapy for stages IB2-IVA cervical cancer (Figure 1). Determination of the benefit of protracted infusional 5-FU administered concurrently with radiotherapy awaits analysis of the recently closed GOG trial.
Adjuvant radiotherapy following radical hysterectomy
Node-negative patients Local failure rates approach 20% following radical hysterectomy and pelvic lymphadenectomy when pelvic lymph nodes are not involved but the primary tumor has high-risk characteristics (primary tumor > 4 cm, outer third cervical stromal invasion, and capillary-lymphatic space invasion). A recently completed GOG trial randomized these intermediate-risk, node-negative patients to receive pelvic external-beam radiation therapy (5,100 cGy/30 fractions) or no further therapy following radical hysterectomy-pelvic lymphadenectomy. Postoperative radiation produced a significant 44% reduction in recurrence; the recurrence-free rate at 2 years was 88% with radiation vs 79% without it. Survival analysis awaits further follow-up.
Node-positive patients For patients with positive pelvic lymph nodes following radical hysterectomy–pelvic lymphadenectomy, pelvic radiotherapy reduces the pelvic failure rate from approximately 50% to 25% but does not affect survival since distant metastases are still seen in 30% of patients. A recently reported GOG/Southwest Oncology Group (SWOG 8797) trial randomized these high-risk, node-positive patients (or patients with positive surgical margins) to pelvic external-beam radiation (4,930 cGy/29 fractions) vs pelvic external-beam radiation plus concurrent 5-FU and cisplatin for 4 cycles following radical hysterectomy–pelvic lymphadenectomy. A significant improvement in progression-free and overall survival was seen for concurrent 5-FU-cisplatin and radiation therapy compared with radiation therapy alone (4-year survival, 81% vs 71%) (Figures 1 and 6).
Current treatment recommendations At present, the use of adjuvant pelvic radiotherapy should be considered for patients with negative nodes who are at risk for pelvic failure, and remains the standard postoperative treatment for patients with positive lymph nodes. Treatment consists of external pelvic radiation (45-50 Gy), with specific sites boosted with further external-beam or intracavitary radiation as needed.
Since the combination of radical surgery and irradiation has greater morbidity than either modality alone, complete preoperative assessment is crucial to minimize the need for both.
Since concurrent chemoradiation following radical hysterectomy provides a significant benefit in node-positive high-risk cervical cancer, it should be part of the postoperative treatment plan.
SURGICAL MANAGEMENT OF RECURRENT OR METASTATIC DISEASE
Recurrent advanced disease
Pelvic exenteration For patients whose disease fails to respond to primary radiation therapy or those with early invasive cervical carcinoma whose disease recurs after surgery or radiation therapy, pelvic exenteration offers the possibility of cure. Patients should be considered for pelvic exenteration only if they have locoregional disease that can be completely removed by this radical surgical procedure. In most cases, patients will require surgical removal of the bladder, uterus, cervix, vagina, and rectum.
Of all patients who are considered candidates for pelvic exenteration, only about half will be found to have resectable disease at the time of exploratory laparotomy. For patients who successfully undergo pelvic exenteration, 5-year survival rates range from 25% to 50%.
When the patient has a central recurrence of squamous cell or adenocarcinoma of the cervix, the initial evaluation includes a complete physical examination, as well as an abdominopelvic CT or MRI scan and, usually, a chest CT scan. Evidence of extrapelvic disease is a contraindication to pelvic exenteration. If no evidence of disease beyond the pelvis is found, the patient can be prepared for pelvic exenteration.
Preparation for exenteration includes complete bowel preparation, a visit with the stoma therapy nurse, and counseling regarding the radical nature of the surgery and the anticipated changes in body image after the operation. In most cases, we counsel the patient that vaginal reconstruction should be done at the time of pelvic exenteration, both for maintenance of body image and improved healing.
Surgical procedure During surgery, a careful exploration is carried out to confirm that there is no evidence of unresectable disease beyond the pelvis. The pelvic sidewall spaces are opened and resectability is determined. An en bloc resection is usually carried out; in some cases, especially when the recurrent tumor involves the lower vagina, a two-team approach can expedite the procedure. The actual exenterative portion of the procedure may take several hours and is usually accompanied by significant blood loss.
Reconstruction Following the exenterative procedure, the reconstructive portion of the procedure begins. We currently recommend to nearly all patients that they consider a continent urinary diversion using the Miami pouch technique. While this may add approximately ?1 hour to the surgical procedure, the improvement in quality of life is significant.
In patients who have undergone a supralevator pelvic exenteration, we frequently attempt a stapled reanastomosis of the colon. Unless there is excessive tension on the anastomosis or other problems, a diverting colostomy is not routinely indicated. About one-third of these patients suffer anastomotic breakdown in the postoperative period. At that time, a diverting colostomy can be performed. Unfortunately, Hatch et al found no benefit to the earlier use of colostomy.
Lung metastasis
For the rare patient who presents with a single isolated lung metastasis after treatment of invasive cervical carcinoma, pulmonary resection may offer the possibility of long-term disease-free survival or even cure in selected cases. For patients who have multiple lung metastases or unresectable pelvic disease, surgery offers little or no hope and produces significant morbidity and mortality.
RADIATION THERAPY FOR RECURRENT OR METASTATIC DISEASE
Local recurrence after radical hysterectomy
Local recurrence confined to the pelvis and para-aortic lymph nodes following radical hysterectomy for cervical cancer can be treated with radiotherapy with curative intent. An experience with 5-FU-based chemotherapy and concurrent pelvic external-beam radiation resulted in a 58% complete response rate and a 45% no-evidence-of-disease rate at a median follow-up of 57 months. The total pelvic external-beam dose was 5,280 cGy plus a boost to sites of recurrence with twice-daily 160-cGy fractions during the 5-FU infusion. Therefore, radiotherapy, with or without chemotherapy, can provide durable local control, with better results attainable for small, central recurrences, for which brachytherapy is possible.
Local recurrence after definitive radiation
Local recurrence confined to the pelvis following definitive radiation therapy rarely can be cured with exenteration. In a series of patients treated with definitive radiotherapy, 21% (80/376) of recurrences were isolated to the pelvis. Only 29% (23/80) of these localized pelvic recurrences were explored for curative exenteration, and for the 43% (10/23) of patients deemed operable, the 5-year survival rate was 16%.
Palliation of metastatic disease
Palliative radiation therapy to sites of metastatic cervical cancer is effective. The most common sites of metastasis are distant lymph nodes, bone, and lung. Reirradiation of the pelvis is possible in selected patients to control local symptoms, such as bleeding, but carries an increased risk of bowel complications. For previously unirradiated sites of metastatic disease, 3,000 cGy in 10 fractions provides palliation of symptoms in the majority of patients.
CHEMOTHERAPY FOR ADVANCED/RECURRENT DISEASE
Chemotherapy has traditionally been used for the palliative management of advanced or recurrent disease that can no longer be managed by surgery or radiation therapy. Various factors complicate the use of chemotherapy in such patients, however. Prior radiation treatment can affect the blood supply to the involved field, which may result in decreased drug delivery to the tumor site. Pelvic irradiation also reduces bone marrow reserve, thus limiting the tolerable doses of most chemotherapeutic agents. Moreover, radiation may produce its cytotoxic effect, in part, through a mechanism similar to that of alkylating agents; thus, it is thought to be cross-resistant with some chemotherapeutic agents. A significant number of patients with advanced disease may also have impaired renal function, further limiting the use of certain chemotherapeutic regimens.
Single agents
Among the chemotherapeutic agents used for cervical cancer, cisplatin and ifosfamide (Ifex) have shown the most consistent activity as single agents (Table 4). The duration of response with any single agent is brief, ranging from 4 to 6 months, with survival ranging from 6 to 9 months.
Cisplatin has been the most extensively evaluated single agent for cervical carcinoma. A dose of l00 mg/m2 was shown to have a higher response rate than a dose of 50 mg/m2 (31% vs 21%), but the higher dose was associated with increased toxicity, and overall survival did not differ significantly between the two groups. A 24-hour infusion of cisplatin was tolerated better than a 2-hour infusion, with no difference in therapeutic efficacy.
Ifosfamide produces response rates ranging from 33% to 50% in various dose schedules. A dose of 1.5 g/m2 over 30 minutes for 5 days (with mesna [Mesnex]) produced an overall response rate of 40% and a 20% complete response rate.
Lower response rates are generally seen in patients who have had prior chemotherapy. Responses also are decreased in previously irradiated sites.
Taxanes Paclitaxel (Taxol) and docetaxel (Taxotere) have been reported to have activity in cervical cancer. A study of paclitaxel (170 mg/m2 over 24 hours) showed an objective response rate of 17%, and another study of paclitaxel (250 mg/m2 over 3 hours) demonstrated an objective response rate of 27%. Docetaxel (100 mg/m2 over 1 hour) has yielded a response rate of 15%.
Camptothecins Irinotecan (CPT-11 [Camptosar]), and topotecan (Hycamptin) semisynthetic camptothecins, have shown activity in patients with cervical cancer, even in patients who did not respond to prior chemotherapy and prior radiation therapy. The reported objective response rates were 21% and 19%, respectively.
Combination regimens
Various combination chemotherapy regimens have been evaluated in phase II trials, and high response rates (> 50%) were noted even in patients who had received prior radiation therapy. The results of some of these trials are summarized in Table 5. In one study, a subset analysis showed a response rate of 72% with the combination of bleomycin, ifosfamide, and cisplatin as treatment for tumors located in previously irradiated sites. However, no adequate phase III trial has yet determined whether polychemotherapy regimens offer a survival benefit over single-agent cisplatin.
NEOADJUVANT CHEMOTHERAPY
The use of chemotherapy in the neoadjuvant (primary) setting has also been investigated. Four randomized trials in which patients with stages IIB-IVA disease were treated either with various cisplatin-based combination chemotherapy regimens followed by radiation therapy or with radiation therapy alone failed to show any survival benefit of neoadjuvant chemotherapy. In fact, one of these studies showed increased toxicity and decreased survival in the patients given neoadjuvant therapy. Another trial also reported significantly inferior local disease control and survival rates in the patients randomized to receive primary chemotherapy compared to those who received radiotherapy alone.
Theoretically, increased toxicity with neoadjuvant chemotherapy may prevent delivery of adequate radiation doses. As mentioned above, there also is the issue of cross-resistance between these two modalities.
Neoadjuvant chemotherapy combined with surgery may decrease lymph node involvement, as compared with historical controls. However, a randomized trial of patients with stage IB bulky disease failed to show any benefit in overall survival for patients receiving neoadjuvant cisplatin, vincristine, and bleomycin, when compared to patients receiving surgery and postoperative radiation therapy alone.
ADJUVANT CHEMOTHERAPY AFTER RADICAL HYSTERECTOMY
Adjuvant chemotherapy has shown no benefit in patients found to have pelvic lymph node involvement after a radical hysterectomy. A randomized trial failed to demonstrate any improvement in survival and relapse rates when this group of patients was treated with adjuvant cisplatin, vinblastine, and bleomycin.
INTRA-ARTERIAL CHEMOTHERAPY
The use of intra-arterial chemotherapy offers the theoretical advantage of increased drug concentration at the tumor site, as well as the possibility of decreased systemic drug delivery. Most response rates obtained with various intra-arterially administered regimens have not been superior to rates achieved with IV chemotherapy, however. Furthermore, significant drug- and catheter-related toxicity has been seen with intra-arterial chemotherapy.
BIOLOGICAL AGENTS
Retinoids and interferon The combination of 13-cis-retinoic acid and interferon-alfa 2a (IFN-a-2a [Roferon-A]) produced an overall response rate of 50% (12% complete response rate) in 32 previously untreated patients who had locally advanced squamous cell carcinoma of the cervix. The drugs were administered daily for at least 2 months at doses of 1 mg/kg PO for 13-cis-retinoic acid and 6 million units SC for IFN-a-2a. After a median response duration of 3 months, 9 of the 16 responders eventually progressed. Only minimal toxicity was seen with this regimen.
Both interferons and retinoids have antiviral as well as immunoregulatory properties, and they also modulate malignant cell differentiation and proliferation. Furthermore, they are known to inhibit angiogenesis, and serial biopsies of the responders in the study described above showed a significant reduction in the number of blood vessels.
Preliminary data from an ongoing trial of an induction regimen of 13-cis-retinoic acid and IFN-a-2a followed by concomitant radiobiotherapy in patients with > stage II active cervical cancer showed this regimen to be tolerable; 70% of patients treated with this regimen were free of disease at 1 year.
Angiogenesis inhibitors Angiogenesis inhibition is a novel approach to cancer treatment. TNP-470, a fumagillin analog that inhibits angiogenesis, is being evaluated in cervical cancer. In a phase I study, a patient with metastatic disease treated with this agent has maintained a complete response for over 2 years, and three other patients have stabilization of progressive disease. A phase II study did not demonstrate activity of TNP-470 in cervical cancer.
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