Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, it is the fourth most common malignant neoplasm in women, after carcinoma of the breast, colorectum, and endometrium. The incidence of invasive cervical cancer has declined steadily in the United States over the past few decades; however, it continues to rise in many developing countries. The change in the epidemiological trend in the United States has been attributed to mass screening with Papanicolaou tests (Pap smears).
History:
Because women are screened routinely, the most common finding is an abnormal Pap smear result.
Clinically, the first symptom is abnormal vaginal bleeding, usually postcoital.
Vaginal discomfort, malodorous discharge, and dysuria are not uncommon.
The tumor grows by extending upward to the endometrial cavity, downward to the vagina, and laterally to the pelvic wall. It can invade the bladder and rectum directly.
Symptoms that can evolve, such as constipation, hematuria, fistula, and ureteral obstruction with or without hydroureter or hydronephrosis, reflect local organ involvement.
The triad of leg edema, pain, and hydronephrosis suggests pelvic wall involvement.
The common sites for distant metastasis include extrapelvic lymph nodes, liver, lung, and bone.
Physical:
In patients with early-stage cervical cancer, physical examination findings can be relatively normal.
As the disease progresses, the cervix may become abnormal in appearance, with gross erosion, ulcer, or mass. These abnormalities can extend to the vagina.
Rectal examination may reveal an external mass or gross blood from tumor erosion.
Bimanual examination findings often reveal pelvic metastasis.
Leg edema suggests lymphatic/vascular obstruction from tumor.
If the disease involves the liver, some patients develop hepatomegaly.
Pulmonary metastasis usually is difficult to detect upon physical examination unless pleural effusion or bronchial obstruction becomes apparent.
Causes:
Early epidemiological data demonstrated a direct causal relationship between cervical cancer and sexual activity. Major risk factors observed include sex at a young age, multiple sexual partners, promiscuous male partners, and history of sexually transmitted diseases. However, the search for a potential sexually transmitted carcinogen had been unsuccessful until the last decade, when a breakthrough in molecular biology enabled scientists to detect viral genome in cervical cells.
Strong evidence now implicates human papillomaviruses (HPVs) as prime suspects. HPV viral DNA has been detected in more than 80% of squamous intraepithelial lesions (SILs) and invasive cervical cancers compared to a consistently lower percentage in controls. Both animal data and molecular biologic evidence confirm the malignant transformation potential of papilloma virus-induced lesions. SILs are found predominantly in younger women, while invasive cancers are detected more often in women aged 10-15 years older, suggesting slow progression of cancer.
HPV infection occurs in a high percentage of sexually active women. Most of these infections clear spontaneously within months to a few years, and only a small proportion progress to cancer. This means that other crucial factors must be involved in the process of carcinogenesis.
Three main factors have been postulated to influence the progression of low-grade SILs to high-grade SILs. These include the type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; host conditions that compromise immunity, such as multiparity or poor nutritional status; and environmental factors such as smoking, oral contraceptive use, or vitamin deficiencies. In addition, various gynecologic factors, including age of menarche, age of first intercourse, and number of sexual partners, significantly increase the risk for cervical cancer.
Medical Care:
The treatment of cervical cancer varies with the stage of the disease. For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom palliation. The treatment of choice for stage Ia disease is surgery.
Stage IB or IIA
For patients with stage IB or IIA disease, treatment options are either combined external beam radiation with brachytherapy or radical hysterectomy with bilateral pelvic lymphadenectomy.
Most retrospective studies have shown equivalent survival rates for both procedures, although such studies usually are flawed due to patient selection bias and other compounding factors. However, a recent randomized study showed identical overall and disease-free survival rates.
Quality-of-life data, particularly in the psychosexual area, is relatively scant.
Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with high-risk factors.
A recent randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and pelvic radiation.
Stage IIB-IVA
For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy traditionally has been the treatment of choice.
For treatment with radiation alone, 5-year survival rates reportedly are 65-75%, 35-50%, and 15-20% for stages IIB, III, and IVA, respectively.
Treatment begins with a course of external beam radiation to reduce tumor mass to enable subsequent intracavitary application. Brachytherapy is delivered using afterloading applicators that are placed in the uterine cavity and vagina.
Combined chemotherapy plus radiation therapy for cervical cancer
Recently, the report of 3 well-conducted studies of concurrent chemoradiation has changed the standard of care in this group of patients.
In the Radiation Therapy Oncology Group trial, 403 patients with bulky IB and IIB-IVA cancers were randomized to either radiotherapy to a pelvic and paraaortic field or pelvic radiation with concurrent cisplatin and fluorouracil. Rates of both disease-free survival and overall survival were significantly higher in the group that received combination treatment.
Rose and associates conducted a Gynecologic Oncology Group (GOG) trial for patients with stage IIB, III, or IVA cancer, comparing the combination of radiation with 3 different chemotherapy regimens (cisplatin alone, cisplatin/5-fluorouracil/hydroxyurea, and hydroxyurea alone). Overall survival rates were significantly higher in the 2 groups that received cisplatin-containing regimens.
In another GOG trial, patients with bulky stage IB disease were randomized to either radiation alone or a combination of weekly cisplatin and radiation. All patients had adjuvant hysterectomy. Both disease-free survival and overall survival rates were significantly higher in the combined-therapy group at 4 years of follow-up.
Based on the aforementioned study results, using cisplatin-based chemotherapy in combination with radiation for patients with locally advanced cervical cancer now is a reasonable option.
History:
Because women are screened routinely, the most common finding is an abnormal Pap smear result.
Clinically, the first symptom is abnormal vaginal bleeding, usually postcoital.
Vaginal discomfort, malodorous discharge, and dysuria are not uncommon.
The tumor grows by extending upward to the endometrial cavity, downward to the vagina, and laterally to the pelvic wall. It can invade the bladder and rectum directly.
Symptoms that can evolve, such as constipation, hematuria, fistula, and ureteral obstruction with or without hydroureter or hydronephrosis, reflect local organ involvement.
The triad of leg edema, pain, and hydronephrosis suggests pelvic wall involvement.
The common sites for distant metastasis include extrapelvic lymph nodes, liver, lung, and bone.
Physical:
In patients with early-stage cervical cancer, physical examination findings can be relatively normal.
As the disease progresses, the cervix may become abnormal in appearance, with gross erosion, ulcer, or mass. These abnormalities can extend to the vagina.
Rectal examination may reveal an external mass or gross blood from tumor erosion.
Bimanual examination findings often reveal pelvic metastasis.
Leg edema suggests lymphatic/vascular obstruction from tumor.
If the disease involves the liver, some patients develop hepatomegaly.
Pulmonary metastasis usually is difficult to detect upon physical examination unless pleural effusion or bronchial obstruction becomes apparent.
Causes:
Early epidemiological data demonstrated a direct causal relationship between cervical cancer and sexual activity. Major risk factors observed include sex at a young age, multiple sexual partners, promiscuous male partners, and history of sexually transmitted diseases. However, the search for a potential sexually transmitted carcinogen had been unsuccessful until the last decade, when a breakthrough in molecular biology enabled scientists to detect viral genome in cervical cells.
Strong evidence now implicates human papillomaviruses (HPVs) as prime suspects. HPV viral DNA has been detected in more than 80% of squamous intraepithelial lesions (SILs) and invasive cervical cancers compared to a consistently lower percentage in controls. Both animal data and molecular biologic evidence confirm the malignant transformation potential of papilloma virus-induced lesions. SILs are found predominantly in younger women, while invasive cancers are detected more often in women aged 10-15 years older, suggesting slow progression of cancer.
HPV infection occurs in a high percentage of sexually active women. Most of these infections clear spontaneously within months to a few years, and only a small proportion progress to cancer. This means that other crucial factors must be involved in the process of carcinogenesis.
Three main factors have been postulated to influence the progression of low-grade SILs to high-grade SILs. These include the type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; host conditions that compromise immunity, such as multiparity or poor nutritional status; and environmental factors such as smoking, oral contraceptive use, or vitamin deficiencies. In addition, various gynecologic factors, including age of menarche, age of first intercourse, and number of sexual partners, significantly increase the risk for cervical cancer.
Medical Care:
The treatment of cervical cancer varies with the stage of the disease. For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom palliation. The treatment of choice for stage Ia disease is surgery.
Stage IB or IIA
For patients with stage IB or IIA disease, treatment options are either combined external beam radiation with brachytherapy or radical hysterectomy with bilateral pelvic lymphadenectomy.
Most retrospective studies have shown equivalent survival rates for both procedures, although such studies usually are flawed due to patient selection bias and other compounding factors. However, a recent randomized study showed identical overall and disease-free survival rates.
Quality-of-life data, particularly in the psychosexual area, is relatively scant.
Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with high-risk factors.
A recent randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and pelvic radiation.
Stage IIB-IVA
For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy traditionally has been the treatment of choice.
For treatment with radiation alone, 5-year survival rates reportedly are 65-75%, 35-50%, and 15-20% for stages IIB, III, and IVA, respectively.
Treatment begins with a course of external beam radiation to reduce tumor mass to enable subsequent intracavitary application. Brachytherapy is delivered using afterloading applicators that are placed in the uterine cavity and vagina.
Combined chemotherapy plus radiation therapy for cervical cancer
Recently, the report of 3 well-conducted studies of concurrent chemoradiation has changed the standard of care in this group of patients.
In the Radiation Therapy Oncology Group trial, 403 patients with bulky IB and IIB-IVA cancers were randomized to either radiotherapy to a pelvic and paraaortic field or pelvic radiation with concurrent cisplatin and fluorouracil. Rates of both disease-free survival and overall survival were significantly higher in the group that received combination treatment.
Rose and associates conducted a Gynecologic Oncology Group (GOG) trial for patients with stage IIB, III, or IVA cancer, comparing the combination of radiation with 3 different chemotherapy regimens (cisplatin alone, cisplatin/5-fluorouracil/hydroxyurea, and hydroxyurea alone). Overall survival rates were significantly higher in the 2 groups that received cisplatin-containing regimens.
In another GOG trial, patients with bulky stage IB disease were randomized to either radiation alone or a combination of weekly cisplatin and radiation. All patients had adjuvant hysterectomy. Both disease-free survival and overall survival rates were significantly higher in the combined-therapy group at 4 years of follow-up.
Based on the aforementioned study results, using cisplatin-based chemotherapy in combination with radiation for patients with locally advanced cervical cancer now is a reasonable option.
