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Treatment

If cervical cancer prevention programs are to be truly effective and of public health value, testing should always be linked to appropriate treatment for any precancerous lesions detected.

What Lesions Need to be Treated? 

There is clear consensus that high-grade squamous intraepithelial lesions (HGSIL/CIN II–CIN III) must be treated because a majority of these lesions, in time, progress to cancer. For low-grade squamous intraepithelial lesions (LGSILs/CIN I), the experience in developed countries has been that the majority of lesions will regress spontaneously and thus do not require treatment. In situations where close followup is not possible, however, treatment of LGSIL may be advisable, particularly if the treatment is not highly invasive or associated with serious side effects, complications or long-term sequellae (see below, Managing Precancerous Disease for further discussion).

Factors Affecting Choice of Treatment 

Unlike cervical cancer which peaks in later years, precancerous lesions of the cervix occur most frequently in women who are still in their childbearing years—30s and 40s. This fact must be kept clearly in mind when treatment policy decisions are made. In choosing a method of treatment for younger women with cervical dysplasia, it is also important to recognize and consider its effect on fertility as well as its safety in pregnancy. Other factors that need to be considered are:

• Method effectiveness
• Safety and potential side effects
• Who is allowed to (or can legally) provide treatment and what training is required to qualify such persons
• The size, extent, severity and site of the lesion
• Acceptability of treatment offered to women
• Equipment and supplies
• Availability
• Cost/affordability

Inpatient versus Outpatient Treatment 

In developed countries, treatment of early cervical changes has shifted from use of surgery, such as cone biopsy and hysterectomy, to simpler, safer outpatient procedures. Although still used in limited circumstances, these inpatient surgical procedures are expensive and they require use of significant resources for anesthesia, equipment and hospitalization for recovery. They can be associated with serious complications, such as hemorrhage and infection. Frequently such inpatient procedures are used when less invasive (including operative) techniques would have sufficed.

In the USA, three outpatient procedures—cryotherapy, laser vaporization and loop electrosurgical excision procedure (LEEP) are used, and each has it supporters and critics. Additionally, in some countries, electrosurgery (cauterization) is still being used. Over the years, there has been much discussion about which of these methods is best in terms of safety, efficacy and costs. All are outpatient procedures that can be used either to destroy tissue (cyrotherapy, laser vaporization or electrosurgery) or remove it (LEEP). Proponents of cryotherapy have emphasized its reliability, ease of use, low complication rate and low cost. Concerns about cryotherapy, electrosurgery and laser vaporization are that they do not provide a tissue specimen that can be examined histologically. Also compared to laser therapy, cryotherapy and electrosurgery are not easily tailored to the size of the lesion. With LEEP, however, the entire squamocolumnar junction (SCJ) is removed and a surgical specimen is provided. This reduces the possibility of missing invasive cancer.

Of these outpatient procedures, cyrotherapy, using a liquid coolant (compressed carbon dioxide or nitrous oxide gas), and LEEP are most widely used (Table 4). Cryotherapy, which only freezes cells, may be the most practical for use in low-resource settings where there are few physicians because of its simplicity and minimal discomfort. LEEP, in addition to requiring more training and skill, is best suited to facilities where medical backup is available because of the small risk of postoperative bleeding. Electrosurgery, although very inexpensive and easy to use, is associated with several side effects (pain, usually requiring local anesthesia, and postoperative bleeding). Finally, laser vaporization is very costly and requires more training and skills than the other two procedures. In addition, it is associated with more safety issues (eye injuries and unintended burns). These factors make it unsuitable for large-scale use in low-resource settings.

Table 4. Outpatient Treatment Options 

Procedure	Outpatient	Anesthesia	Electrical Power	Non-physicians	Costa
Cryotherapy	Yes	No	No	Yes	Low
Electrocautery	Yes	Yes (local)	Yes	Yes	Low
Cold cautery (100°C)	Yes	Yes (local)	Yes	Yes	Low
LEEP	Yes	Yes (local)	Yes	No	High
Laser vaporization	Yes	Yes (local)	Yes	No	High
Cone biopsy	No	Yes (general or regional)	Yesb	No	High
Hysterectomy	No	Yes (general or regional)	Yesb	No	High

^a Low = <$500, Moderate = $500–1500, High = >$1500
^b Required for use of operating room lighting and equipment

Until recently, which of the treatment options is most effective has been disputed. Fortunately, a randomized clinical trial conducted by Mitchell and colleagues (1999) provides strong evidence that cyrotherapy, laser vaporization and LEEP are equally effective with high success rates (74–83%). In order to reduce bias in their study, all patients were stratified by the size (area) of the lesion and by type of lesion (histologic grade). In addition, they were followed up for a longer time than any previous study of this type to more accurately determine the recurrence rate. Of the 390 patients enrolled, the total surface area of the cervix affected was one-third or less in 75% and 123 had CIN I, 124 CIN II and 143 CIN III. As shown in Table 5, the rate of persistence plus recurrence was higher, but not statistically significantly so, with cryotherapy (26%) than with laser therapy (17%) or LEEP (17%) (p = 0.24). The major differences between these three treatment options was in recurrence rates, but these differences also were not statistically significant.

When lesion size, type of lesion and location were taken into account, only lesion size was statistically significantly associated with higher rates of persistence. Women with lesions covering more than two-thirds of the surface of the cervix were 19 times more likely to have persistent disease than those with smaller lesions, whatever procedure was used. Other factors that increased the risk of recurrence at least two-fold were:

• age over 30 years,
• positive HPV test (types 16 or 18), and
• previous treatment for CIN.

Although LEEP and laser therapy had higher rates of complications, 8% and 4% respectively than cryotherapy (2%), these differences were not statistically significant (Table 5). Furthermore, less than 1% of women developed cervical stenosis or pelvic infection regardless of the type of procedure used. The main difference in complications among the procedures was the higher risk of postoperative bleeding with LEEP (3%) versus either laser (1%) or cryotherapy (0%).

Table 5. Comparison of Treatment Options 

	Cryotherapy (n=139)	Laser Vaporization (n=121)	Leep (n=130)
Effectivenessa Persistenceb Recurrencec	76 7 19	83% 4% 13%	83% 4% 13%
Complications	2%	4%	8%
Bleeding (peri- and post-operative)	0%	1%	3%

^aAt 1 year
^bDisease detected within 6 months
^cDisease detected after 6 months

Source: Mitchell et al 1998.

In a separate study, Montz (1996) reviewed the potential effect of these same three procedures, plus electrocautery and surgical conization, on infertility (Table 6). Theoretically, these procedures could affect fertility in four ways—by cervical stenosis, decreased volume or quality of cervical mucus, cervical incompetence and tubal scarring or occlusion as a result of post-treatment pelvic infection. Only conization was found to have any negative affect on fertility resulting in an increased risk of second trimester abortion, preterm labor and low-birthweight infants. This increased risk was found to be related to the volume and length of endocervical tissue removed. Because the amount of tissue destroyed or removed by cryotherapy, laser or LEEP is small, not surprisingly these procedures had no adverse effects on fertility or pregnancy outcome.

Table 6. Risk of Long-Term Sequellae

Sequellae	Cryotherapy or LEEP	Cone Biopsy
Infertility Cervical stenosis Cervical incompetence Decreased cervical mucus Tubal scarring	No No No No	Yes Yes Yes Yes
Pregnancy outcome 2nd trimester abortion Preterm labor Low birthweight	No No No	Yes Yes Yes

Source: Montz 1996.

In summary, several procedures are available for outpatient, localized treatment of precancerous cervical lesions. Success rates are comparable but capital expenses, maintenance costs, the need for local anesthesia, side effects and complication rates vary considerably for each procedure. And, with the exception of cryotherapy, all require electrical power. Although cryotherapy has become less popular in the USA in recent years, this has more to do with: 1.) the attraction of physicians to high-tech equipment (laser vaporization and LEEP); 2.) the perception that laser/LEEP is significantly more effective than cryotherapy; and 3.) the perceived need for a tissue diagnosis (biopsy specimen); than with the failure rate of this simpler, low-tech, but less expensive procedure. For most countries with limited resources, some combination of cryotherapy and LEEP offer the most affordable solution to treating precancerous lesions on a large scale. At a minimum, LEEP could be made available in referral centers, where physicians and medical back up, local anesthesia (paracervical block) and electrical power exist. By contrast, cryotherapy could be made widely available in low-resource settings where only nurses or nurse-midwives are posted and electric power is often unreliable (Sivanesaratnam 1999). Table 7 summarizes the advantages and disadvantages of cryosurgery and LEEP.

Table 7. Advantages and Disadvantages of Cryotherapy and LEEP 

TREATMENT	ADVANTAGES	DISADVANTAGES
Cryotherapy	Effective with mild and moderate lesions (85–95% cure rate) Inexpensive Nonphysician can perform No local anesthesia required No electricity required Associated with few complications/side effects Can be performed during pregnancy	Variable success rate with large, severe lesions (70–90% cure rate) Destructive (leaves no tissue sample for confirmatory diagnosis) Difficult to determine exact amount of tissue destroyed Associated with profuse watery discharge for 4–6 weeks following treatment Requires access to and resupply of coolant (CO2 or N2O)
LEEP	Effective (90–96% cure rate for all lesions—more effective with severe lesions than cryotherapy) Enables tissue sampling for diagnosis  Associated with few complications/side effects	More expensive than cryotherapy ($4–6000) Primary side effect is perioperative bleeding (about 3–8%) Physician required to perform Requires local anesthesia Requires electricity (but could be battery powered) Requires resupply of loops Should not be performed during pregnancy

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