Squamous Cell Carcinoma

Several different classification systems have been suggested during the past 60 years, including the early Broders/Warren classification (based on differentiation, mitotic activity, keratinization, and pearl formation) and that of Reagan and Ng (based on size, keratinization, and nuclear pleomorphism).¹¹ In an analysis of patients entered into the Gynecologic Oncology Group (GOG) prospective treatment protocol for stage IB cervix carcinoma, none of the histologic grading systems for SCCs were found to correlate with incidence of lymph node metastasis or progression-free interval.¹²

Variants of SCC of the cervix exist, although it is unclear that any of these variations affect response to therapy. Verrucous carcinoma is a very well-differentiated carcinoma lacking cellular atypia and possessing orderly elements of maturation. It can achieve massive exophytic proportions and be extensively invasive, in contrast to the bland microscopic appearance. Verrucous carcinomas are differentiated from condylomata by the presence of invasion in addition to a lack of fibrovascular cores in the papillae, as well as by the exophytic expansion of surrounding normal tissue.^11,13 Spread to lymph nodes is quite rare. Concern is expressed by many authors that the use of radiation in these lesions may contribute to malignant degeneration, but this point is contestable.¹⁴

Papillary squamous cell differs from the verrucous form in that its cells show a high degree of nuclear atypia. Although grossly the tumor may have a warty, exophytic appearance, on microscopic examination there are found papillae with atypical immature basaloid cells reminiscent of transitional cell carcinoma of the bladder. The determination of invasion requires full-thickness biopsy, because a large exophytic component may be associated with a minimal amount of invasion.¹¹

Lymphoepithelioma-like carcinoma is characterized by solid cords of cells with minimal squamous differentiation resting like islands in a diffuse stromal chronic inflammatory reaction, with lymphocytes, plasma cells, and eosinophils. As in their counterparts in the nasopharynx, thymus, larynx, stomach, and salivary glands, well-circumscribed margins are found around nests of poorly differentiated cells with uniform vesiculated nuclei.

Adenocarcinoma

Adenocarcinomas account for 10% to 20% of cervical neoplasms in the literature.¹⁵ This appears to represent an increase from older data that showed the incidence to be in the range of 5% to 10%, possibly because of a decline in the incidence in invasive SCC secondary to effective screening programs, although the possibility remains that the incidence of adenocarcinoma is actually on the rise. The most common type, endocervical adenocarcinoma, generally is composed of mucin-producing glands of varying differentiation, within a fibrous stroma that sets it apart from normal endometrial stroma. It may be difficult to differentiate from adenocarcinoma of uterine corpus origin, increasing the necessity of a proper fractional dilatation and curettage (D&C) to establish the actual origin of the disease. It appears in an admixture with other variants in a frequent number of cases.

Minimal deviation adenocarcinoma is a variant that is an extremely well-differentiated lesion composed of endocervical glands with basal nuclei and low nuclear/cytoplasmic ratios.^16,17 The nuclei appear minimally atypical, belying the aggressive clinical nature. On extensive sampling, markedly dysplastic cells can be identified. These malignant glands can be helpful in differentiating these lesions from other benign conditions such as adenomatous hyperplasia or deep nabothian cysts. They are almost uniformly deeply invasive and are associated with a very poor prognosis. A high frequency of associated mucinous tumors of the ovary has also been reported.

Villoglandular papillary adenocarcinoma is generally found in younger women (average age 33) and consists of a surface papillary component with fibrous stroma.¹⁷ Unless there is clear evidence of vascular involvement or deep invasion, conservative management may be warranted owing to the excellent prognosis.

Endometrioid adenocarcinoma of the cervix is difficult to distinguish histologically from uterine adenocarcinoma. The clinical activity is similar to the endocervical variety.^15,18

Clear cell adenocarcinomas of the cervix, most commonly seen in young women exposed to DES in utero, are identical to the lesions that show up in the vagina, endometrium, and ovary. They can be seen in women of any age in the absence of DES exposure history. Three patterns have been described (tubulocystic, solid, and papillary), with the appearance of cells bearing a “hobnail” configuration that clearly sets them apart from other variants of adenocarcinoma.^6,8,19

Serous papillary adenocarcinoma is a rare subtype, which histologically looks similar to its namesake in the uterus and ovary.²⁰ A search must be carried out to ensure that it is not a metastatic deposit from another site in the pelvis. Too few cases have been reported to state whether or not this entity in the cervix is prone to intraperitoneal dissemination like the uterine variety. Mesonephric, signet ring cell, and intestinal-type adenocarcinomas are additional extremely rare subtypes, for which care must be taken to rule out metastases from other locations.¹⁵

Adenosquamous and Glassy Cell Carcinoma

Adenosquamous carcinomas are tumors that contain mucin or glands in an admixture with clearly recognizable squamous elements.^15,21 Any pattern of squamous cell may appear in this setting, usually in conjunction with poorly differentiated adenocarcinoma. Once again, care should be taken to establish that this is truly adenosquamous carcinoma and not two separate primary tumors of the cervix and corpus (“collision” tumors). A particularly aggressive form of poorly differentiated adenosquamous carcinoma is the glassy cell carcinoma, so called because of a ground-glass appearance to the finely granulated cytoplasm in conjunction with clearly defined cell walls and large nuclei with prominent nucleoli.^21,22 These tumors, representing approximately 1% to 2% of all cervical neoplasms, have a high mitotic rate and a particularly aggressive course.

Small Cell (Neuroendocrine) Carcinoma

Small cell carcinoma is a neuroendocrine tumor similar to small cell tumors of the lung, believed to arise from amine precursor uptake and decarboxylation cells.²³ It accounts for less than 2% of all cervical neoplasms. These lesions may have been lumped in with other small cell variants of squamous cell in the classification of Reagan mentioned earlier, giving rise to the differences seen in clinical outcome using that schema. Histologically, however, the picture seen is a sea of small monomorphous cells with a high nuclear/cytoplasmic ratio, with an occasional minimal element of glandular or squamous differentiation. Neuroendocrine granules may be identified on electron microscopy or immunohistochemical analysis. Up to one half may stain for markers such as serotonin, adrenocorticotrophic hormone, somatostatin, or gastrin, although clinical syndromes associated with the production of these markers is very unusual. A hallmark of this disease is its systemic nature early in the course of the disease. Any meaningful intervention must take into account the high propensity for early dissemination and include chemotherapeutic approaches similar to those used for oat cell carcinoma of the lung.

Other rare cervical tumors include carcinoid, adenoid basal, adenoid cystic, sarcomas (mixed müllerian, endocervical stromal), embryonal rhabdomyosarcoma, and melanoma. The interested reader is referred to the excellent review article by Clement.²⁴ Although uncommon, the cervix may also be a site of metastatic disease.

Screening

The introduction of widespread Pap staining has led to a dramatic reduction in the incidence of invasive carcinoma on a worldwide level, although a significant need remains to further extend this testing to patients of low socioeconomic status who are at high risk for dissemination of HPV, HIV, and HSV. Current recommendations for screening include annual Pap smears at the age of 18 or at initiation of sexual intercourse, whichever is younger. After three consecutive yearly normal Pap smears, the frequency of Pap smears may be reduced at the discretion of the physician, but intervals beyond 3 years are not recommended. If high-risk behavior continues, it is probably wiser to continue with yearly testing. Pap smears are currently reported using the revised Bethesda classification system. Because one-quarter of cases of invasive cervical carcinoma occur in patients older than 60 and these same patients make up 40% of the mortalities, screening with routine pelvic examinations and Pap smears should continue into the later years of life.

Colposcopy and Biopsy

In the face of a Pap smear suspicious for malignancy (HGSIL by the Bethesda classification), a search is performed to look for possible invasion. Colposcopy is performed to visibly evaluate the cervix to define the extent of any lesion and to allow directed biopsies of regions that appear abnormal. In cases in which the initial biopsies show no invasion but the transformation zone was not well-visualized, the entire lesion was not identified because of extension into the canal, or the endocervical curettage specimens are positive for dysplasia, the physician cannot be sure that the biopsied portion is representative of the entire lesion, and a conization is required to rule out invasive disease. Cone specimens should include the entire transformation zone as well as a significant portion of the endocervical canal. Techniques should be used that will allow accurate assessment of the margins of the specimen. A cone specimen with no evidence of invasion but positive margins may indicate residual disease in the endocervical canal, which may harbor invasive foci and require more extensive treatment.

Large loop electrical excision procedure (LEEP) of the transformation zone involves the use of thin wire loop electrodes to remove the transformation zones in patients with LGSIL. As opposed to ablative techniques such as cryotherapy, laser ablation, and electrocautery, LEEP produces a histologically evaluable specimen. When correctly performed, some information will be available regarding proximity of lesions to the margins. Generally these procedures are not performed if there is suspicion of invasive disease, but they occasionally provide evidence of unsuspected invasion requiring additional intervention.

Diagnostic Workup and Staging

Once a biopsy has established the presence of invasive disease, the extent of the disease must be determined. The use of a fractional D&C is useful to rule out endometrial extension, particularly in cases of adenocarcinoma in which the origination of the disease may actually be the uterine corpus with extension into the cervix.

The current FIGO staging system has evolved during the past 60 years from its initial formation in 1929 as the League of Nations Health Organization system (Table 48-4). Various changes have been made during that interval to incorporate applicable information, such as the removal of corpus extension from staging consideration (1950) and the creation of stage IA in 1962 and its later subdivision into IA1 and IA2 (1972), and IB1 and IB2 (1998). In the current system, Stage IIA is further subdivided into stage IIA1 and IIA2 (2010).

Table 48-4 Classification of Uterine Cervix Cancer

Rights were not granted to include this table in electronic media. Please refer to the printed book.

The 5-year survival rate for patients with stage IB disease can vary from less than 20% for patients with bulky disease and both pelvic and para-aortic adenopathy to greater than 90% for those with lesions less than 2 cm in maximum diameter and no involved nodes.⁵⁵ Survival rates for patients with higher staged disease also vary within each stage depending on primary tumor volume and nodal status.^37,56 In the Patterns of Care report on the uterine cervix, the differentiation between IA and IB was not found to predict for either 5-year actuarial survival or pelvic control, whereas the presence of bulky disease did correlate with a higher pelvic failure rate in stage IB disease.⁵⁶ In stage II disease, unilateral versus bilateral disease significantly affected both actuarial survival and pelvic control rates, a significance that persisted on multivariate analysis. In the analysis of stage III disease, the differentiation between unilateral or bilateral sidewall or lower-third vaginal involvement was highly significant in both actuarial survival and pelvic control results. The GOG findings regarding the great prognostic significance of para-aortic adenopathy and tumor volume also point out the shortcomings of the current system.⁴⁰

The American Joint Committee on Cancer has devised a tumor-node-metastasis system similar to the FIGO system. The FIGO staging system is most widely used (see Table 48-4), despite its shortcomings. For practical purposes of reporting, it is imperative that the clinical staging rules be adhered to in order to ensure accurate comparisons of therapeutic interventions. The rules for clinical staging according to FIGO state that staging is to be based on careful clinical examination prior to intervention, preferably an examination under anesthesia. Once established, the stage is not to be changed by later findings or therapeutic interventions. Palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and x-ray examination of the lungs and skeleton are recommended. Suspected involvement of the bladder or rectum must be documented by histology. Specifically excluded from the clinical staging system are the results of such tests as lymphangiography, fine-needle aspiration or biopsy of lymph node, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), laparoscopy, and laparotomy. These tests are not allowed to influence the clinical stage for reporting purposes but may be used for treatment planning and providing important diagnostic information.

Locally, it is important to fully describe the extent of palpable disease through the use of extensive diagrams and descriptions of the three-dimensional (3-D) characteristics of the lesion (Fig. 48-4). The degree of parametrial (medial or lateral, unilateral or bilateral) or vaginal (upper two-thirds, lower one-third) extension should be clearly defined, as should the presence or absence of hydronephrosis, rectal invasion, bladder mucosal invasion, bullous edema, uterosacral ligament involvement, or extension to the pelvic sidewall (bilateral or unilateral). The use of MRI evaluation of the pelvis is not allowed by the current staging system in determining the clinical stage but has proven to be of benefit in defining the extent of disease locally as well as regionally. It also provides information that is useful in optimizing brachytherapy planning. Cystoscopy and proctosigmoidoscopy are routinely called for by the FIGO system, but in cases of early disease in which MRI shows no suspicion of local extension, these more invasive procedures may not be necessary. On the other hand, if an MRI scan raises the question of bladder or rectal involvement, endoscopic evaluation is essential to rule out pathologic involvement of these organs. A CT scan with contrast can provide information as to the presence of hydroureterosis or hydronephrosis.

FIGURE 48-4 • An illustrative diagram of clinical findings.

Pelvic evaluation with CT or MRI, or alternatively laparoscopic nodal dissection, may provide invaluable information for radiation treatment planning. The finding of abnormal lymph nodes in the pelvis or para-aortic region on an MRI or a CT scan should be followed with a CT-guided fine needle aspiration of the suspicious nodes.

Positron emission tomography (PET) has become a useful staging modality for locally advance cervical cancer. It may be an accurate noninvasive method of evaluating nodal status, endometrial extension, tumor volume, and prognosis.^57–60 PET scan also may play an important role in post-therapy monitoring. Grigsby and associates showed that patients treated with radiotherapy who had a normal 3-month post therapy PET scan had a 5-year cause-specific survival of 80%.⁶¹ Another study shows PET scans as an effective way of detecting asymptomatic recurrence.⁶²

Further routine workup should include a complete blood count, liver function tests, renal function tests, and a chest x-ray. In patients believed to be at risk for exposure to HIV, testing for antibodies to HIV should be discussed with the patient prior to the initiation of therapy. If the patient is HIV antibody–positive, the CD4 count is currently recommended as a rough indicator of the immune status and of the patient’s likelihood to be able to tolerate therapy.⁵³ The usefulness of a bone scan is limited to patients with advanced disease with symptoms suggestive of dissemination and is not routinely obtained. In cases in which there is evidence of spread to pelvic lymph nodes on pelvic CT or MRI scan, evaluation of the abdomen to rule out higher adenopathy or liver involvement is recommended.

Blind scalene node biopsy performed in the setting of positive para-aortic lymphadenopathy has a positive rate of 0% to 35%.⁶³ In a prospective evaluation of biopsies of nonpalpable scalene nodes in 55 patients with positive para-aortic (48) or high common iliac nodes (8), only 4 were confirmed positive (14%).⁶⁴ The routine use of such biopsies is not warranted. Prior to the initiation of para-aortic radiation for patients with known retroperitoneal disease, CT scan of the chest to rule out disease missed on plain chest x-rays may be a more useful test than biopsy of clinically negative nodes.

Carcinoma In Situ and Stage IA Disease

CIS and disease with early stromal invasion isolated to buds of neoplastic cells that penetrate the basement membrane but remain immeasurable macroscopically (stage IA) have essentially a 0% incidence of involvement of the lymph nodes.^65–67 In the absence of disease at the cone biopsy margins, a recurrence rate of 0% would be expected after simple hysterectomy. Conization itself represents adequate therapy in these cases, as long as the margins are definitely clear. A lesion cannot be classified as stage IA disease unless all margins of the cone biopsy are free of disease, because the entirety of the lesion may not have been identified. Alternative approaches such as laser vaporization and cryotherapy have success rates in excess of 95%, although obliteration of the margins may make it difficult to identify those patients with residual disease.^65,68

Patients with stage IA2 disease with maximum depth of invasion of 3 mm or less and no evidence of lymphatic vascular space invasion (LVSI) also have a risk of lymph node involvement that is less than 1%. A simple hysterectomy with no lymph node dissection and optional oophorectomy is standard therapy, although more conservative therapy such as conization or trachelectomy may be considered in the patient who is interested in further child-bearing.

The presence of LVSI or invasion to a depth greater than 3 mm is associated with a slight increase in the risk of spread to pelvic nodes or recurrence after hysterectomy. Up to 13% of patients with these findings may have lymphatic spread at time of hysterectomy (range 2%-13%),^66,67 arguing for more aggressive local therapy tailored to the histologic findings. Patients with LVSI but invasion to less than 3 mm and clear margins after cone-down application might be suitable for a simple hysterectomy and pelvic node dissection to reduce morbidity. If, however, the depth of invasion is from 3.1 to 5 mm and LVSI is present, an extended or radical hysterectomy should be performed. Under these conditions, if the patient strongly desires to maintain her ability to bear children, a therapeutic conization may be considered, but close follow-up is essential as invasive recurrences are reported in up to 5% of cases.^66,67

Surgical approaches are preferred for such minimal disease. In cases of medical inoperability, definitive radiation is an acceptable alternative with outstanding results.^67,69 Multiple intracavitary insertions are employed to deliver a dose of 60 to 70 Gy to the cervix. External-beam radiation is not routinely employed for stage IA disease, unless the risk of pelvic nodal spread is considered to be substantial, such as in a case with greater than 3-mm invasion, LVSI, and poorly differentiated histologic findings.

Surgery alone for stage IA disease has resulted in local recurrence rates of 2% to 5%, with the majority of recurrences being noninvasive and amenable to effective salvage. Kolstad, reporting on 496 cases of microinvasive disease treated with surgery in Norway, had recurrences in only 15 patients, all of whom were cured with further surgery.⁶⁷ In a review by Sevin and coworkers of six major series in the literature, 0.2% of 513 cases with disease invasion less than 3 mm recurred, versus 5.4% of 166 cases with invasion of 3.1 to 5.0 mm.⁶⁶

The results with radiation alone are comparable to those found with surgery. In Kolstad’s series, an additional 136 patients were treated with brachytherapy alone, and none had recurrences. Of 32 patients with IA disease treated at Mallinkrodt with radiation alone (either with brachytherapy alone or in combination with external-beam therapy), there was only one failure reported at 15 years.⁶⁹

Stage IA2/IB1/IIA (≤4 cm) (Surgical Candidates)

Stage IB cases include a wide variety of tumors, ranging from the smallest visible tumors with no pathologically involved lymph nodes to bulky endophytic endocervical tumors greater than 6 cm in diameter with positive pelvic and periaortic nodes. It is obvious that no one approach is suitable for all patients with stage IB disease. The treatment must be tailored to the physical characteristics of the lesion and the overall medical condition of the patient.

Stage IB1/IIA lesions that measure 4 cm or less can be managed with either definitive surgery or radiation. The decision usually hinges on the side effects and complications associated with each procedure and the medical condition of the patient. The standard surgical approach is the radical hysterectomy with pelvic and para-aortic lymph node dissection. Five-year disease-free survival rates of 80% to 92%^70,71 are reported after radical hysterectomy, whereas for radiation, the actuarial 5-year survival rates vary from 78% to 90%.^72–74

Caution must be used when comparing results with surgery and radiation in the treatment of early stage disease. Younger patients who are in better medical condition and with smaller burden of disease tend to be referred for surgery, whereas older or medically challenged patients and those with larger central burden of disease are referred for radiation. In addition, in a significant proportion of patients who have worrisome findings at exploratory laparotomy, such as positive pelvic lymph nodes, parametrial extension or surgical complications, the hysterectomy is not completed, and the patients are referred for definitive radiation. Because the clinical stage of these patients is unchanged by the surgical findings, they are lumped together in most reports of patients with early stage disease treated with radiation.

With that prelude, the retrospective reports reveal a notable similarity in results for radiation and surgery. Reporting on 978 consecutive patients with early stage disease who underwent radical hysterectomy between 1965 and 1990 at the University of Miami, Averette and colleagues⁷⁵ had a 90.1% 5-year actuarial survival overall, 90.5% for stage IB, and 65.7% for stage IIA. Breaking them down by histologic characteristics, SCC had a 90.7% 5-year survival, adenocarcinoma 80.5%, and adenosquamous carcinoma 63.5%. Of the 17.7% of patients who had positive pelvic lymph nodes, the 5-year survival was 63.5%, and 40.8% for those with positive para-aortic lymph nodes.⁷⁵ Overall complications in this series were as follows: 0.8% urinary fistulae, 8.5% wound-related problems, 20.5% bladder dysfunction, 6% ileus, and 2.6% chronic lymphedema.

Radiation results in reports on 5-year survival rates of patients with clinical stage IB range from 80% to 85% range for most modern series.^37,73,74,76 Stage IIA results range from 70% to 76%.^37,73,74 Considering the previous statements about treatment selection bias, these results compare quite favorably with those seen with surgery. Central disease control rates of 92% to 94% are reported for patients with stage IB cervical cancers treated with radiation alone.^37,76

The only prospective randomized trial between surgery and radiotherapy was reported by Landoni et al. in 1997.⁷⁷ During a period of 5 years, 343 patients with stage IB and IIA cervical carcinoma were randomized between surgery and radiotherapy. Adjuvant radiotherapy was given for patients found to have pathologic T_2b or greater lesions with margins smaller than 3 mm, cut-through, or positive lymph nodes. The result were analyzed based on intention to treat. With a median follow-up of 87 months, the 5-year overall and disease-free survival were identical between the two groups. Of the surgery group, 28% had severe morbidity compared with 12% of patients in the radiotherapy group (P = 0.0004). Patients who received combined surgery and radiotherapy had the worst morbidity. The result of this study suggests only patients with limited disease that can be completely excised may be offered the option of surgery.

Stage IB/IIA(>4 cm), Bulky Lesions (Not Surgical Candidates)

The addition of chemotherapy, either with a neoadjuvant or concomitant chemoradiation approach, has been a controversial issue. However, in 1999 a series of positive prospective randomized trials documented the advantage of concurrent cisplatin with radiotherapy. Concurrent chemoradiotherapy has become the standard treatment of locally advanced cervical cancer.

Based on prior small randomized studies of patients with stages IIB-IIIB cervical carcinoma treated at Roswell Park looking at the addition of hydroxyurea, the GOG initiated a group-wide phase III study of patients with stage IIIB-IVA disease (surgically staged and negative para-aortic nodes), randomly assigning patients to receive radiation therapy alone or radiation plus hydroxyurea.⁷⁸ Results of this study (the analysis pertained to only 97 of the original 190 patients entered; approximately half of the patients were considered inevaluable) showed a marginal improvement in complete clinical response and superiority in disease-free survival and overall survival rates in those receiving hydroxyurea. Significant toxicity was seen in the hydroxyurea arm (47%).

The Radiation Therapy Oncology Group (RTOG) randomly assigned patients with stage IIIB-IVA disease to receive radiation therapy with or without misonidazole, a radiation sensitizer, and found that misonidazole may have had a deleterious effect on overall survival compared with radiation therapy alone.⁷⁹ The median survival in the control arm was 1.9 years, compared with 1.6 years for the misonidazole arm, and the study was terminated early. A GOG study randomly assigned patients with stage IIB-IVA disease to receive radiation therapy plus hydroxyurea or misonidazole from 1981 to 1985.⁵² No difference was observed between the two arms in terms of progression-free survival or overall survival rates, although there was a trend favoring the hydroxyurea arm. Their conclusion was that “misonidazole was not superior to hydroxyurea as an adjunct to radiation.” The failure of hydroxyurea to show a clear superiority over misonidazole calls into question the inherent benefit of hydroxyurea, although this arm became the control arm for other GOG studies.

A series of landmark randomized trials were published in 1999. The RTOG protocol 90-01 randomized 403 patients with advanced cervical cancer stage to radiotherapy to pelvis and para-aortic lymph nodes or pelvis radiotherapy with two cycles of fluorouracil (FU) and cisplatin. Patients randomized included stages IIB-IVA, and stage IB-IA with tumor diameter at least 5 cm or involvement of pelvic lymph nodes. With a median follow-up of 43 months, there were statistically significant improvements in survival and disease-free survival at 5 years favoring the chemoradiotherapy group. The local-regional recurrences and distant metastases were significantly less in the chemoradiotherapy group.⁸⁰ The GOG protocol randomized patients with locally advanced cervical cancer to radiotherapy and one of three chemotherapy regimens. Patients who received two of the three regimens that contained cisplatin had higher rates of overall survival and progression-free survival.⁸¹ Another GOG protocol evaluated the role of adjuvant chemotherapy in patients with bulky stage IB cervical cancers (tumor diameter greater than or equal to 4 cm). All patients were treated with radiotherapy following adjuvant hysterectomy. Patients were randomized to weekly cisplatin versus radiotherapy alone. The 4-year overall survival and progression-free survival were significantly better in the group that received chemotherapy.⁸² Concurrent chemotherapy with extended-field radiation therapy has also been shown to be feasible for patients with metastatic disease to para-aortic lymph nodes. Results of these trials established the role of concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer; the role of neoadjuvant and adjuvant chemotherapy remains to be defined.

Bulky lesions, those exceeding 4 cm in maximum dimension, and endophytic lesions with significant extension into the lower uterine segment can be approached in a variety of ways. It is imperative, however, to first fully establish the shape and direction of growth of disease at the onset, especially in adenocarcinomas. External-beam therapy is necessary at the outset to allow tumor shrinkage for proper placement of tandem and colpostats. It is advisable to proceed with brachytherapy when the tumor has shrunk to less than 4 cm in diameter unless the tumor is eccentrically located to one side. A balance is necessary between tumor shrinkage and the inevitable restriction of the vaginal fornices that occurs with increasing external-beam dose. Doses as high as 45 Gy may be required to allow enough reduction in tumor size to proceed with an insertion, but doses in excess of 45 Gy before placement of a midline bar should be avoided because the risk of damage to bladder and rectum is directly related to the external dose to these organs.^51,73 For larger lesions confined to the cervix, doses to the tumor or point A in the 85 Gy region are recommended if no adjuvant surgery is planned. In cases in which an extrafascial hysterectomy is deemed necessary, the total dose to point A should be confined to 70 to 75 Gy, and the pelvic nodal dose should be held at 45 Gy.

Adjuvant Hysterectomy

A routine adjuvant hysterectomy in all cases of bulky disease is not recommended. Citing an increased risk of central failure after radiation therapy alone, Rutledge and colleagues in 1976 published recommendations for adjuvant extrafascial hysterectomy after radiation therapy for patients with bulky cervical cancers measuring 6 cm or greater in diameter with lower uterine segment involvement, presenting the results of 212 patients so treated at M.D. Anderson Hospital from 1954 to 1967.⁸³ A vesicovaginal fistula rate of 4.1% was reported after the combined procedures in a later report (four times the rate seen with radiation therapy alone). A prospective randomized trial, initiated by the GOG and RTOG in 1984 and closed in 1991, randomly assigned patients with lesions 4 cm or greater in maximum diameter to receive radiation alone (80 Gy to point A, 55 Gy to point B) or reduced radiation (75 Gy to point A), followed in 6 weeks by an extrafascial hysterectomy. There was no statistical differences in survival, between the two arms.⁸⁴

Distant dissemination of disease remains a problem in larger tumors. Perez reported that IB/IIA patients with 3 to 5 cm lesions had pelvic failure rates of 15% to 28% and distant metastatic rates of 27% to 30%.⁸⁵ These numbers rose to 20% to 30% and 37% to 57% for patients with tumors 5 cm or greater in size. Eifel found that disease-free survival dropped to 71% for patients with tumors 5 cm or greater in diameter, although pelvic tumor control rates remained at 85%.⁸⁶

Stage IIB-IVA

Disease extension into the parametria is a contraindication to radical hysterectomy, because the chance of cutting through tumor is high. These patients are ideally managed by definitive chemoradiotherapy. As in cases of large IB tumors, external-beam therapy is first administered to allow tumor shrinkage. Generally, 45 Gy is administered via whole-pelvis fields, followed by two insertions to bring the paracervical dose to 85 Gy total, with parametrial boosts to the involved sides of 50 to 60 Gy. This final parametrial dose should take into account the dose administered externally as well as the dose from the brachytherapy. In patients whose disease is massive, treatment with an interstitial template may be more appropriate. Central control rates of 78% and pelvic control rates of 69% to 83% have been reported. Overall survival rates of radiation alone are 60% to 68%.^37,74,87

Patients with stage III disease have a 17% to 67% chance of pelvic failure when treated with radiation alone.^88,89 These results differ according to the bulk of disease, the presence of unilateral versus bilateral pelvic sidewall involvement, the presence or absence of lower vaginal involvement, and the type of brachytherapy used. Involvement of the lower portion of the vagina represents one of the most challenging situations encountered by the radiation oncologist; fortunately, it is a rare condition, composing only 1% to 3% of all cases of stage III disease.^88,89 The approach depends on the extent and location of vaginal involvement, as well as the initial response to external-beam radiotherapy. Extension into the middle or lower third of the vagina is not adequately encompassed by tandem and colpostats. After initial external-beam therapy, response is assessed and the residual disease clearly defined in terms of its thickness and location. Brachytherapy plays an essential role in managing this portion of the disease, but care must be taken to respect the normal tissue tolerances of surrounding structures. Minimum tumor doses, in addition to the doses to the vaginal surface and normal tissues, must be followed closely. The goal is to deliver 85 Gy to the tumor volume while keeping the dose to the lower third of the vagina and vulva at 60 to 70 Gy. A tandem and cylinder with additional surface catheters and interstitial catheters is used to maximize the number of source positions in the region to optimize the dose distribution. Special attention should be given to dose at the skin-catheter interface. This is best achieved using 3-D planning technique and skin marker or molding. Pelvic control rates of 71% to 72% were reported for two small series of patients with IIIA disease from M.D. Anderson Hospital and Yale, in which most patients received a combination of external-beam and intracavitary or interstitial brachytherapy. Actuarial survival rates at 5 years range from 37% to 58%.^88,90

Disease with extension to the side walls (stage IIIB) has a 45% to 50% chance of locoregional failure when treated with standard tandem and colpostats in addition to external-beam therapy.^36,89 An additional interstitial catheter can be added to complement the intracavitary system. To improve the placement accuracy of these interstitial catheters, a transrectal ultrasound (TRUS)–guided technique combined with a template has been described.⁹¹ At the University of California–San Francisco (UCSF) we have been using a TRUS-guided free-hand technique to combine our interstitial catheters with the existing intracavitary systems. A more detailed description is provided later in this chapter. In patients not amenable to implant or insertion, external-beam therapy to a dose of 65 Gy, coming off all small bowel after 50 Gy, may have to suffice. Pelvic control rates for all stage III disease presentations are in the range of 50% to 60%, with overall survival rates of 30% to 55%.^{36,37,74,87,89}

For patients with bladder invasion but minimal or no parametrial invasion (stage IVA), an aggressive approach, including an anterior exenteration, is warranted. Likewise, those with extension into the rectum are candidates for posterior exenteration. Alternatively, definitive irradiation has been successful. Reports from Yale and M.D. Anderson Hospital revealed a low but significant cure rate of 18% to 46% depending on the aggressiveness of the treatment and the lateral extent of tumor.^92,93 The dose to the bladder is higher than is acceptable in cases without bladder involvement, because the risk of fistula formation is weighed against the prospects of an anterior exenteration. If more extensive parametrial extension is noted, definitive irradiation is the preferred approach. The decision to proceed with palliative or curative radiation must be based on an awareness of the full extent of disease (nodal spread, distant metastases), local aggressiveness (existence of fistulae or ureteral obstruction), the patient’s overall medical status, and the patient’s desires.

The management of patients with locally far-advanced cervical cancer (“frozen pelvis,” massive stage IIIB or IVA disease) or those with metastatic disease at presentation must be tempered by an understanding of the likelihood of local control, the effect of local progression on quality of life, and the morbidity of aggressive intervention. Although it may be reasonable not to place ureteral stents in the patient with bilateral ureteral obstruction and hydronephrosis who also has distant disease and consequently no meaningful hope for long-term survival, it may be quite justifiable to intervene in a similarly obstructed patient who has no distant disease. In the former case, the chance of cure is negligible and a death resulting from renal failure may be preferred by the patient to one resulting from continued spread of the disease both locally and distantly. In the latter case, however, locally aggressive management may result in an extended period of life with disease control. The issues of quality of that life and morbidity of treatment must be addressed with the patient.

Palliative radiotherapy in the setting of advanced carcinoma of the cervix should be tailored to the patient’s overall condition. The rapid fractionation approach tested by the RTOG in protocol 85-02 involved the delivery of 3.7 Gy twice daily for 2 days for a total dose of 14.8 Gy.⁹⁴ This is repeated after a 2- to 4-week break. After a final 2- to 4-week break, the field is reduced to exclude all small bowel and a third session of four treatments is administered for a total dose of 44.4 Gy. A tumor response rate of 42% was seen after completion of all three courses with response rates (complete and partial) of 75% for pain, 98% for bleeding, and 83% for tenesmus. The treatment course was well tolerated with a severe complication rate of only 5 of 132 patients (4%).

Disease in a patient with a frozen pelvis but no signs of spread elsewhere may be approached more aggressively, because the patient may live long enough to develop local progression after the rapid course just described. The effect of locally uncontrolled disease on quality of life is tremendous. Fistula formation, severe pain, and bleeding severely compromise a patient’s dignity and ability to interact with family and friends during her final months. It is not unusual to have a patient linger for many months with local progression before death occurs from systemic involvement, uremia, sepsis, or bleeding. Therefore, consideration should be given to aggressive radiotherapeutic palliation in patients who are likely to survive for longer than 6 months. External-beam therapy alone to doses of 60 to 65 Gy may be considered, as long as the small bowel is removed from the field after 50 Gy is administered. Alternatively, the judicious use of interstitial implantation may play a role in selected cases. Entry into protocols evaluating combined modality therapy or radiation with hyperthermia may also be warranted. In any such circumstance, however, the patient must be allowed to make the decision for herself after she has received sufficient information regarding her long-term prognosis, the possibilities for quality of life, and the expected morbidity of any proposed intervention.

Hyperthermia

The role of combined hyperthermia with radiotherapy has not been clearly established. The earlier prospective trial did not show any benefit of adding hyperthermia with radiotherapy.⁹⁵ Failure to demonstrate the benefit of hyperthermia was proposed to be the result of inadequate delivery of hyperthermia to deep-seated tumor. More recently using modern hyperthermia delivery system, the Dutch Deep Hyperthermia Group conducted a prospective randomized trial that reestablished the role of hyperthermia for cerrical cancer. One hundred and fourteen patients with stages IIB-IV locally advanced cervical cancer were randomized to radiotherapy alone or radiotherapy with hyperthermia. There was significant difference in 3-year overall survival and local control favoring the hyperthermia group.^96–99 The study is of particular interest because the benefit was seen in locally advanced disease and the toxicity associated with hyperthermia was minimal. The result of this trial has revived interest in hyperthermia with radiotherapy for treatment of cervical cancer.

Adjuvant Radiation After Hysterectomy

Patients who have undergone radical hysterectomy for early stage disease are at variable risk for recurrent disease, depending on factors that include tumor size, nodal status, parametrial extension, adequacy of margins, histologic findings, lymphatic space invasion, and depth of penetration of the cervical stroma. A rational approach depends on the definition of those subgroups who are at greatest risk for recurrence and therefore most likely to show a regional control benefit and potentially a survival benefit.

Patients at low risk for pelvic recurrence after radical hysterectomy who would not be expected to show any benefit from postoperative radiotherapy are those whose pelvic lymph nodes are negative and those with tumors less than 4 cm in maximum dimension, no evidence of lymphatic vascular invasion, and less than one-third of the thickness of the surgical stroma involved. The risk of microscopically involved nodes in these patients is less than 15%.^{70,71,100,101} The group of patients who might be expected to have improved local control are those found to have involved pelvic lymph nodes or positive parametrial or vaginal margins. For these patients who were found to have high-risk features, postoperative chemoradiotherapy has been shown to improve survival. In the Southwest Oncology Group trial the high-risk features were defined as positive pelvic lymph nodes, positive margins, and microscopic involvement of the parametrium. A group of 268 patients were randomized to concurrent chemoradiotherapy with cisplatin and 5-FU or radiotherapy alone. The chemoradiotherapy arm had a significantly improved overall survival and progression-free survival.¹⁰²

The intermediate risk group includes those who do not fall into either of the previous categories. This group may be more likely to show a benefit from adjuvant radiation because their disease is in an earlier stage than those with positive nodal spread.³² Patients in this group include those who have positive lymphatic vascular space involvement and at least one of the following characteristics: deep-third penetration of the cervix, middle-third penetration with a tumor 2 cm or greater in diameter, or superficial-third penetration with clinical tumor size 5 cm or greater. Alternatively, those with no LVSI with tumors 4 cm or greater in size with deep- or middle-third invasion of the cervix are considered intermediate risk. GOG performed a randomized study address the role of postoperative radiotherapy in cervical cancer. A group of 277 patients were randomized to postoperative radiotherapy or no further treatment; all patients had at least two of the following risk factors: greater than one-third stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Adjuvant pelvic radiotherapy significantly reduced the risk of recurrence in patients.¹⁰³

Patients found to have positive para-aortic nodes at the time of sampling have a poor prognosis, with survival rates as low as 9% to 29% at 3 years.^29,40 In a review of 98 patients in GOG surgical studies who were found to have clinically undetectable para-aortic node metastases, median survival was 15.2 months with a 3-year actuarial survival rate of only 25%.¹⁰⁴ A majority of these patients were treated with postoperative para-aortic radiation to doses of 40 to 60 Gy.

Elective Radiation of Para-Aortic Lymph Nodes

Two major prospective randomized studies have been carried out to determine the efficacy of treating the para-aortic nodes prophylactically in patients with cervical cancer. The European Organization for Research and Treatment of Cancer randomly assigned 441 patients with stage IB through IVA disease, with no clinical or radiographic evidence of para-aortic spread, to receive pelvic radiation either alone or in conjunction with 45 Gy para-aortic radiation.¹⁰⁷ No improvement was seen in local control or survival with the addition of para-aortic radiation, although there was a decrease in para-aortic and distant recurrence rates seen in the extended field group. Small bowel injury occurred in 0.9% of patients in the pelvic-only group versus 2.3% in the extended-field group. The severe complication rate in the para-aortic radiation arm was approximately twice that of the pelvis-only arm.

The RTOG study was limited to patients with bulky stage IB/IIA disease and those with any stage IIB disease, eliminating those patients with low-volume disease who might not be expected to show a benefit of the prophylactic extension of the field, as well as those with more advanced stage III disease in whom both local control and distant dissemination might mask any potential benefit of para-aortic radiation.¹⁰⁸ The 5-year survival rate was significantly better in those patients who received prophylactic para-aortic radiation, 66% versus 55% (P = 0.043). The incidence of severe and life-threatening complications was similar for both groups. The extended-field arm became the control arm in the next RTOG trial (RTOG 9001) comparing extended-field radiation to pelvic radiation plus concomitant chemotherapy with 5-FU and cisplatin. The result of this trial showed the benefit of chemotherapy, and elective radiation of the para-aortic lymph node is now less commonly used.

In RTOG protocol 9210 patients with positive para-aortic lymph nodes were treated with concomitant 5-FU and cisplatin with twice-daily fractionation of 1.2 Gy delivered to the pelvis (60 Gy) and para-aortic (48 Gy) regions, followed by brachytherapy. Unfortunately, this combination resulted in an unacceptable high rate of grade 4 late toxicity, and did not an show improved results.^105,106 However, there still may be a role for treatment of the para-aortic lymph node in combination with chemotherapy for patients with a known positive para-arotic node or high risk for involvement of the nodes.^109,110 Multiple phase II studies have demonstrated the safety of this approach.^110a,b A multivariate analysis suggests patients with a high squamous cell carcinoma antigen level, pelvic lymphadenopathy, or advanced parametrial involvement are predisposed to para-aortic node recurrence after definitive radiotherapy.^110c At UCSF, patients with known pelvic nodal involvement and patient with pelvic side wall extension are recommend to have elective treatment of para-aortic nodal radiation because of high risk of recurrence.

Radiotherapy After Simple Hysterectomy

A simple hysterectomy is inadequate treatment for cervical cancer that invades deeper than 5 mm (stage IA2) or that invades deeper than 3 mm in the presence of LVSI. Unfortunately, some patients who undergo simple hysterectomies for benign conditions may be found to have invasive cancer at the time of pathologic examination.¹¹¹ Two treatment options are available: immediate reoperation with radical parametrectomy and pelvic lymph node dissection or postoperative radiation.¹¹² Surgery results in a 5-year disease-free survival rate of 82% to 96% in patients with no gross residual disease.^111,113 The radiation approach depends on the volume and location of residual disease. Patients with no disease or microscopic disease only at the margins are approached with whole-pelvis radiation to a total dose of 45 to 50 Gy. An additional boost to the upper-third of the vaginal cuff to 60 Gy may be added using brachytherapy. Disease-free survival rates at 5 years of 71% to 90% are reported using this approach.¹¹³ For patients with gross residual disease, exenteration has produced approximately a 39% disease control,¹¹⁴ versus 23% to 43% for aggressive radiation intervention.¹¹³ Gross residual disease, which responds well to external-beam radiation therapy, may be treated with intracavitary brachytherapy, whereas greater residual volumes of disease should be considered for perineal interstitial templates to boost the residual disease sites to 65 to 70 Gy minimum tumor dose.

Cervical Cancer in the Setting of Human Immunodeficiency Virus

As with all other malignancies in the setting of HIV, treatment plans should take into account the patient’s overall immune status. With detailed assessment of the patient’s past history of opportunistic diseases, current levels and trends of viral burden and CD4 counts, and performance status, patients fall into three categories. At one extreme are those with relatively intact immune systems (CD4 > 200 cells/ml, no prior opportunistic diseases, and a low viral level) who have a long life expectancy with proper medical management of their HIV. At the other extreme are those with significant impairment of the immune system (CD4 < 50 despite aggressive antiretroviral therapy, one or more major opportunistic diseases such as progressive multifocal leukoencephalopathy or central nervous system toxoplasmosis, and a very poor performance status), whose life expectancy is measured in months. In between lies the group for whom overly aggressive management holds the greatest risk: those with CD4 counts in the 50 to 200 range but possibly falling, in reasonably good condition, but whose viral burdens are rising despite antiretroviral therapy.

The healthiest group should generally be managed for their cervical cancer as they would be in the absence of HIV, with some caveats. The use of prophylactic para-aortic radiation or overly aggressive chemotherapy regimens should be used sparingly to avoid further marrow suppression or bowel injury. The maintenance of highly active antiretroviral therapy (HAART) is important throughout this process. In the patient with early stage disease (non-bulky stage I/IIA) amenable to radical hysterectomy, surgery is preferable over radiation to avoid marrow suppression. In those with stage IB/IIA bulky, IIB, or III/IVA disease, combined radiotherapy and cisplatinum-based chemotherapy are appropriate, but with attention paid to maintenance of the HAART program and use of prophylaxis for opportunistic infections.

In the intermediate group, those with an immune status in decline, aggressive therapy is still warranted, but it must be tempered by an awareness of the risks of increased intolerance to radiation as well as the profound risk of development of concomitant opportunistic infections. Reports of intolerance (gastrointestinal [GI], skin, and hematologic) to aggressive treatment in HIV-positive patients with locally advanced cervical disease in developing nations bring up the difficult question of how best to manage such patients in settings where medical resources are limited or stretched.^118–121 An attempt to answer this question of tolerance was mounted by the GOG, but a decline in the incidence of invasive cervical cancer among HIV-positive women in the United States because of intensive cervical screening in this population resulted in a failure to accrue adequate numbers.¹²² The maximal management of this cohort, therefore, varies tremendously worldwide, depending on available resources. HAART should be maintained, and radiation fields should be kept as tight as possible to reduce irritation to bowels that may already be plagued by offenders such as cryptosporidiosis, mycobacterium avium intracellulare, or cytomegalovirus. Brachytherapy alone might be preferred for patients with early stage I disease, balancing the need to control clinically uninvolved nodes that might be microscopically positive against the potential for increased marrow suppression. The use of chemotherapy concurrent with radiation should be used judiciously in patients with more advanced disease, with the use of colony-stimulating factors to reduce the degree of iatrogenic immunosuppression.

The group with a devastated immune system and a brief life expectancy should be treated with the goal of palliation of symptoms. Reduction of pain and cessation of bleeding for the last remaining months are important in allowing patients to be managed at home with some degree of dignity and quality of life. Great care must be taken to minimize the exposure of diseased bowel to radiation.

Cervical Cancer and Pregnancy

The incidence of cervical cancer during pregnancy varies from 1.6 to 10.6 cases per 10,000 pregnancies.^123–126 The treatment approach differs depending on the gestational age of the fetus and the stage of disease at diagnosis as well as the informed consent of the patient. In the first two trimesters, the standard of recommendation is termination of the pregnancy and immediate hysterectomy or radiation for all but the most limited cases of invasive disease (microinvasive), which has been approached with cautious conization, rigorous follow-up, and hysterectomy after a full-course delivery in isolated cases. There is a case report of neoadjuvant chemotherapy followed by elective cesarean delivery and radical hysterectomy performed at 32 weeks gestation.¹²⁷ For patients in the late third trimester, early delivery via cesarean section at the time of fetal maturity may cause only minimal delay in dealing with the cancer. The difficulty arises in patients in the early part of the third trimester who are desirous of maintaining the fetus, but in whom a delay in intervention may decrease the expected survival rate. The survival for stage I patients using immediate intervention is excellent.¹²⁶ In a small series of patients with early stage disease who elected to continue their pregnancies, delaying their therapeutic intervention, delay did not have a negative affect. In a series of eight patients with stage IA/B disease who had delays from 53 to 212 days, no progression of disease was documented. In a historical review of 51 patients in the literature who delayed therapy, 77% of stage IA cases had attained no-evidence-of-disease (NED) status and 80% of stage IB cases were NED, although the follow-up was short in some cases.¹²⁶ In patients whose pregnancies are in early stages and who desire intervention to terminate the pregnancy, surgery or radiation may be selected based on the stage of disease, with cure rates similar to those expected in the non-pregnant patient.

Patient Follow-Up and Management of Complications

Rectal irritation caused by radiation may range from episodic diarrhea, rectal spasm, and occasional bleeding to localized ulceration and partial stenosis, recurrent and abundant hemorrhage with necrosis and obstruction, and finally rectovaginal fistula formation. Similarly, bladder irritation varies from mild dysuria with infrequent hematuria to protracted bladder spasm with continuous hematuria to necrosis and eventual vesicovaginal or urethrovaginal fistula formation. Diarrhea and pelvic cramping secondary to small bowel irritation may progress to intermittent small bowel obstruction and eventual complete obstruction or fistula formation with peritonitis.

Reports of incidence of severe complications requiring medical intervention, hospitalization, or surgical intervention or resulting in death provide conflicting evidence as to what factors are the most important in predicting adverse sequelae.^128–130 Most commonly discussed are brachytherapy doses; doses to various rectal, bladder, and paracervical points; and history of prior procedures or illness. The comparison of brachytherapy doses between separate institutions is made difficult by the various manners in which the normal tissue dose points are defined. Using the reference points defined in the International Commission on Radiation Units and Measurements (ICRU) 38 report, Perez et al. described the incidence of major sequelae in 1211 patients treated at Mallinkrodt between 1959 and 1986.¹³¹ Those patients who received a dose of less than or equal to 80 Gy to the rectal point had a 2% to 3% incidence of major rectal complications, compared with a rate of 6% to 13% at doses greater than 80 Gy. Urinary sequelae did not correlate well with dose to the bladder point, with a range of 2% to 6% at all doses analyzed. Small bowel injury increased as total dose to the lateral pelvic wall rose above 60 Gy (3.6%). In an earlier report, Perez had pointed out that age, prior surgery, history of pelvic inflammatory disease, external-beam dose, and type of midline block used all failed to correlate with major sequelae rate.¹²⁹

Lanciano and colleagues in the Patterns of Care Study reported a crude complication rate of 9.8% with 3- and 5-year actuarial rates of 10% and 14%, respectively, in 1558 patients treated only with radiation for all stages of disease at a large number of institutions in the United States.⁵¹ Of all complications, 61% occurred in the large and small bowel, 21% in the bladder, and 10% in the vagina. Of these complications, 64% required surgical correction, and 9% were fatal (total of 0.8% fatal complication rate). The median time to development of complications in the bowel was 13.5 months, bladder 23.2 months, and vagina 17.4 months. In this multivariate analysis, five factors were associated with an increased risk of major complications: the use of external-beam therapy, dose per fraction in excess of 2 Gy, the use of radium rather than cesium, paracentral dose, and dose to the lateral parametrium.

Target organ threshold doses are not by themselves reliable predictors of the risk of serious radiation sequelae, because they fail to take into account the volume of the organ incorporated in the high-dose region. This volume will vary significantly based on the total external-beam contribution to the organ and on the manipulation of source locations and dwell times possible with currently remote afterloading optimization systems. Crook and colleagues have recommended the use of a mean rectal dose (the average of the doses received at four different rectal points along the axis of the anterior rectal wall, in addition to the maximum rectal dose) to identify groups at low, intermediate, and high risk for major rectal sequelae.¹³² The critical dose is not a simple value at a point; rather, it is an estimate of the volume of tissue exposed to a high radiation dose from both the external and intracavitary components of treatment. Ideally, CT-based 3-D dosimetry with dose-volume histograms for tumor and normal tissues will allow more accurate prediction of and avoidance of major complications.

The risk of damage to the small bowel is related to the total dose delivered to the pelvis, the fraction size per dose, and the presence of physical factors such as multiple abdominal surgical procedures or pelvic inflammatory disease.^{51,129,130,133,134} Technical factors such as the treatment of one field per day, lower energy machines, or extended field coverage of the para-aortic nodes have also been implicated.^130,135 Doses of more than 45 Gy to the entire pelvis are associated with a rising incidence of the development of intermittent or surgical small bowel obstruction.¹³⁰ Methods proposed for the reduction in risk of small bowel morbidity include the treatment of all fields each day, the use of megavoltage equipment, treatment with the bladder full, and the placement of an omental or mesh sling to remove bowel from the field of radiation at the time of preradiation surgical exploration or lymphadenectomy.^130,136 The use of an extraperitoneal, rather than a transperitoneal approach for para-aortic lymph node sampling is associated with a reduction in radiation risk to small bowel and is the recommended approach in patients entered into GOG studies requiring para-aortic lymph node sampling.^108,137 Overall, for patients treated with radiation for carcinoma of the uterine cervix, the crude incidence of small bowel obstruction was 2% to 3% in the Perez report,¹³¹ 4% in the Patterns of Care Study,⁵¹ and 4% in the pelvic radiation therapy–alone arm of the RTOG para-aortic study.¹³⁵ This incidence increases to 9%, however, with extended-field radiation to cover the para-aortics, and to 17% in patients so treated who had a prior history of abdominal surgery.¹³⁵ Studies that have pushed the dose to 60 Gy have resulted in severe GI complication rates of as high as 57%.¹⁰⁴

Other risks associated with the treatment of cervical cancer include the development of thromboembolic phenomena or major cardiac complications during or immediately after brachytherapy procedures for surgical carcinoma, although the reported incidence is quite low at 0% to 4%.^138,139 One particularly bothersome side effect of radiation for cervical cancer is the development of vaginal adhesions, vaginal shortening, and, potentially, total agglutination of the vagina. Small adhesions form quickly in the irradiated patient, which can make sexual intercourse and future pelvic examinations quite painful. Therefore, at the completion of therapy, the patient is instructed in the use of a vaginal dilator, to be used on a daily or every-other-day basis for 5 to 10 minutes. The patient is started with a small dilator, instructed in its use with lubricating jelly, and encouraged to begin using it on a very regular basis. Dryness of the irradiated vagina is a common side effect, because of a combination of direct radiation effect and the onset of menopause. Vaginal lubricants and topical estrogen creams are beneficial in partially relieving these symptoms.

The risk of second malignancies rises over time after radiation for carcinoma of the cervix, although the exact increase over the rate expected in the general population is difficult to assess. Several reports suggest that the increase is not significant overall,¹⁴⁰ although some specific subtypes of cancer are seen with an increased rate over expected incidence rates.¹⁴¹ Analyzing data from a combination of the Connecticut Tumor Registry and SEER databases, Rabkin and colleagues reported on close to 25,000 women treated for cervical carcinoma with either surgery or radiation who were long-term survivors.¹⁴¹ The RR of developing a second tumor after radiation was greater than 2.5 for the development of anal carcinoma (4.6), larynx (3.3), lung (3.0), vulva or vagina carcinoma (5.6), bladder (2.7), and bone (2.7). However, the presence of shared causal factors, such as HPV in anal, vulvar, and cervical malignancies, or excess smoking in the population of cervix and lung cancer patients, makes it unclear that the treatment contributed to this excess risk.¹⁴⁰ Information from the Danish Cancer Registry in approximately 45,000 patients treated between 1943 and 1982 revealed an excess of only 64 cases per 10,000 women per year of tumors in the pelvises of irradiated patients, reaching a maximum at 30 years, indicating the need for prolonged follow-up in assessing the true increased incidence of second malignancies.¹⁴²