Removal of the uterus is the most common treatment. But limited surgery, which removes only the tumor and part of the cervix cures just as many patents. The Texas Cancer Center encourages limited surgery, as practiced by Dr. Daniel Dargent in Lyons, France. Additional medical research supporting our recommendations can be found in our "Medical Research" section. Most of this research is directly linked to the National Library of Medicine. There are no medical studies which refute this conservative treatment strategy.
INTRODUCTION
Cervical cancer is the fourth most common malignancy among women in the United States, accounting for about 2.5 per cent of all cancers afflicting women in the United States. About 13,500 women are diagnosed with cervical cancer and 4,400 die of this disease each year. Since 1940 cancer of the cervix has gone from being a common female malignancy to being among the least common. This success is largely due to the wide spread use of the Papanicolaou (Pap) smear, which successfully detects
patients with abnormal cells before they become malignant. Most cases of cervical cancer seem to be associated with the human papillomavirus (HPV).
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STAGES OF DISEASE
If cervical cancer is allowed to grow untreated it will progress through five clinical stages, stages 0 to IV. This staging system has been approved by International Federation of Gynecology and Obstetrics (FIGO) and is summarized in Table I. The staging system is primarily a clinical staging system, since it relies upon the findings of the gynecologist on physical examination. Since the lymph nodes cannot usually be felt on physical examination their status is not considered in this staging system. They must be removed and examined by a pathologist. Patients with positive lymph nodes have a worse prognosis than those with negative nodes. Both local recurrence and patient survival are determined primarily by the stage of disease, tumor volume, and the lymph node status.
Stage |
Clinical Findings |
0 |
Cancer in situ |
I |
Cancer is limited to the cervix. Fiveyear survival is 100%. |
|
Ia |
Cancer is diagnosed microscopically. |
|
|
Ia1 |
Cancer invades less than 1 mm. Fiveyear survival is 100%. |
|
|
Ia2 |
Cancer invades less than 5 mm over an area of less than 7 mm. Fiveyear survival is 90%. |
|
Ib |
Cancer is greater than Ia2, but still confined to the cervix. It is generally obvious to the naked eye. Fiveyear survival is 85%. |
II |
Cancer extends onto the upper 2/3 of the vagina or involves the parametrial tissue. |
|
IIa |
Does not involve the parametrial tissue. Fiveyear survival is 85%. |
|
IIb |
Involves the parametrial tissue. Fiveyear survival is 70%. |
III |
Locally advanced |
|
IIIa |
Involves the lower third of the vagina. Fiveyear survival is 45%. |
|
IIIb |
Involves the pelvic side wall or kidney obstruction. Fiveyear survival is 35%. |
IV |
Very advanced disease |
|
IVa |
Disease extends involves the inside lining of the bladder or rectum. Fiveyear survival is 25%. |
|
IVb |
Distant metastases or extends beyond the pelvis Fiveyear survival is 15%. |
Table I Stages of Disease
The American Society of Gynecologic Oncology (SGO) has a narrower definition for stage Ia. Any lesion which invades more than 3 mm or has lymphatic involvement is classified Stage Ib. This distinction is important, because in patients with stage Ia disease the cervix alone is usually treated. Patients with stage Ib disease are often treated with radical surgery. Because of the difference between the FIGO and the SGO staging systems, women in Europe are more likely to be treated conservatively, i.e., in a manner which preserves fertility. Some European gynecologists have argued that stage Ia should be expanded even farther, increasing the number of patients who are suitable for conservative treatment.
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TYPES OF TREATMENT
Almost all patients with early cervical cancer are treated by some form of surgery. Surgical therapy ranges from removal of a portion of the cervix (conization) to radical pelvic exenteration for recurrent disease. Few studies have attempted to compare the efficacy of hysterectomy versus conservative surgery (conization). Radiation therapy is generally used for more advanced disease, stages II IV. Chemotherapy is of little help. Neoadjuvant (preoperative) chemotherapy is being tried in several centers to shrink large tumors. Some tumors which respond to treatment may be surgically removed.
Surgery
The treatment of cervical cancer has remained stable in the United States. The use of conservative surgery to treat patients with superficial cancer (less than 3 mm of invasion) is the primary advance. Most other investigational therapy is conducted in Europe.
Radical hysterectomy - The operation removes the entire uterus including the cervix, and the upper third of the vagina. It also removes all the supporting ligaments and the parametrial tissues all the way to the pelvic side wall. The surrounding lymph nodes are also removed. Surgery is usually necessary to properly stage the disease, i.e., to learn the extent of lymph node involvement. Bladder dysfunction is the most common complication. It is persistent in about 3% of patients. Injury to the vagina and urinary tract can lead to communication between the ureter or bladder and the vagina. This abnormal channel is called a fistula. They occur in about 2% of cases.
Modified radical hysterectomy - This procedure spares portions of the supporting ligaments, which also contain nerves necessary for proper bladder function. The lymph nodes may also be removed.
Radical pelvic exenteration - This operation removes most of the important structures in the pelvis including the uterus, cervix, vagina, bladder and rectum. This requires reconstruction of the vagina. Urine and intestinal contents may be permanently diverted through separate openings in the abdominal wall urinary conduit and colostomy. This operation often results in complications. About 5% of patients do not survive the operation. It is performed on patients who develop recurrence after other forms treatment.
Total hysterectomy - This operation removes only the uterus and cervix either through the abdomen or the vagina.
Trachelectomy - The excision of the entire cervix.
Loop electrosurgical excision procedure (LEEP) or large loop excision - An electric current removes tissue from the transition zone in the endocervical canal. The depth of excision is about 1 cm.
Conization - The excision of a cone shaped area of tissue from the cervix. This is used to both diagnose and to treat early cancer. When the margins are negative for tumor cells following careful pathological examination, only about 1% of patients should developed local recurrence.
Punch biopsy - The removal of a small core of tissue about the diameter of a pencil lead.
Staging operations - It is impossible to learn if lymph nodes are involved with cancer without removing them and examining them under a microscope. Sometimes these nodes are removed to learn the extent of the disease. Patients with advanced disease may live longer if their lymph nodes are removed. Recently the laparoscopic technique has been used for sampling lymph nodes prior to radiation therapy. Laparoscopic lymphadenectomy is the least invasive method. It is a new procedure; however, and its risks and efficacy have not been determined. The risk of pelvic lymph node metastases increases with the volume of the cancer from 0% for tumors less than 0.5 cc to about 40% for tumors over 30 cc. tumor volume less than 0.5 cc 0%, tumor volume of 0.5 1.5 cc 12%, tumor volume of 1.5 3.5 cc 22%, tumor volume of 3.5 6.5 cc 27%, and tumor volume of 6.5 10 cc 40%. Conservative surgery of cervical cancer should include evaluation of the pelvic nodes.
In performing a hysterectomy the pelvic lymph nodes are usually examined first. If the cancer has spread to these nodes, many gynecologists will terminate the operation without removing the uterus. They believe that radiation therapy listed below, e.g., tandem and ovoids, can be delivered more effectively if the uterus is in place.
Radiation Therapy
Radiation therapy can be delivered with an external beam and with the insertion of radioactive material into the cervix. It is used primarily to treat more advanced disease, stage Ib and higher or in cancer, which may be difficult to remove surgically. Therapists usually administer 4000 5000 cGy over a 45 week period using an external beam. Most patients experience transient diarrhea, which may become chronic in some patients. Abdominal pain is another chronic side effect of external beam radiation. Drugs such as sucralfate and glutamine may protect the intestine from radiation injury.
Additional radiation can be administered with devices placed inside the patient, intracavitary radiation. Tandem and ovoids are usually placed under anesthesia in the upper vagina and inside the uterus, respectively. Later, a radioactive material, usually cesium, is placed into these devices after the patient has returned to her hospital room. The radioactive material remains in place for two to three days. Radioactive needles may be placed directly into the tumor itself. This is called interstitial radiation. Complications include inflammation of the bladder, intestines, and rectum. When radiation is administered as the principle or only therapy it can be curative. When radiation therapy is given following surgery, e.g., to kill microscopic disease in the lymph nodes, it is called adjuvant radiation therapy. In this case it can reduce local recurrence, but usually does not prolong overall survival.
Chemotherapy
Chemotherapy is largely investigational. Mitomycin, bleomycin, fluorouracil, and cisplatin can shrink tumors or relieve pain in some patients. These responses usually last for a few months. Rarely a remission will last several years. Some studies have suggested that preoperative chemotherapy may shrink large tumors. Hydroxyurea is a drug which is toxic to cancer cell in the S-phase, while they are synthesizing DNA. Cells in this phase are resistant to radiation therapy. Several studies have combined radiation therapy and hydroxyurea and achieved prolonged survival.
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TCC ANALYSIS
Many gynecologists are performing conization for stage Ia1 disease. Experience with conization for more invasive cervical cancer (stage Ia2) is limited. I have found no studies, which suggest that conization adversely affects the survival of patients with stage Ia disease.
I believe that some women of childbearing age may be safely treated with fertility-sparing procedures; the limits of this approach are determined by the extent of disease. The surgeon must be able to remove the tumor with a pathologically negative margin of several millimeters. Dr. Erich Burghardt has said,"A hysterectomy cannot achieve more than a conization with margins clear of disease." Nevertheless, patients with pathologically negative margins have been reported to have a 25% chance of having residual disease in the cervix. (The pathological examinations in these cases may have been incomplete.) But this should be reduced if the surgeon performs the wider excision of a deliberate cancer operation. Postoperative radiation therapy would sterilize many patients. This margin should be generous to avoid the need for postoperative radiation therapy. On the other hand, too great an excision may compromise the competence of the cervix during pregnancy.
The patient who desires fertility-sparing surgery and the physician recommending it should understand the added risks of this treatment: the risk of local recurrence and the risk of death that increases with the number of grave prognostic signs. The patient must understand that laparoscopic lymphadenectomy is a new procedure. She should understand that promptly treated local recurrence does not adversely affect the survival of patients with breast cancer. But, this conclusion is not proven for carcinoma of the cervix. I am not proposing this treatment for widespread use. But, it deserves to be tested in clinical trials. It should be offered to selected patients who have a strong desire to maintain their fertility. Problems with conservative treatment have been limited primarily to those patients whose recurrent disease was allowed to grow to a large size before being detected. As with breast cancer and other solid tumors, there is no evidence that promptly treated recurrent disease following conservative surgery adversely affects survival.
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TREATMENT OPTIONS
Stage 0 - Carcinoma in situ can be cured with a conization that has negative margins. Laser vaporization or excision is also successful for larger lesions. Other techniques are freezing the cervix (cryotherapy) and loop electrical excision, which can be performed in an doctor's office. It is usually preferable to totally excise the lesion in order to determine that all the disease has been removed and that no invasion has occurred.
Stage Ia1 - There is less than 1 mm of invasion. Traditional treatment is conization or total hysterectomy. The fiveyear survival rate is about 100%.
Stage Ia2 - There is less than 5 mm of invasion and less than 7 mm of the cervix is covered by the tumor. Abdominal hysterectomy is the standard treatment. Cervical conization is practiced for patients with less than 3 mm of invasion. Conization or wide excision of the cervix for deeper lesions should be considered. The fiveyear survival rate is over 90%.
Stage Ib - The tumor has greater tumor dimensions than Ia2, but is still confined to the cervix. Standard treatment is radical hysterectomy or radiation therapy. For patients whose tumor volume is less than 15 cc, consideration may be given to wide local excision of the cervix (trachelectomy) and intraabdominal lymphadenectomy. Most gynecologists would not support this form of treatment.
Stage IIa - The tumor extends onto the upper 2/3 of the vagina without involving the parametrium. Standard practice includes radical hysterectomy or radiation therapy. The latter usually the preferred treatment and includes both external beam and intracavitary treatment. In France, Dr. Dargent has treated at least two patients with an extended trachelectomy. I know of no gynecologists in the United States who would considered conservative surgery for this stage of disease.
Stage IIb - The tumor is greater than 3 cm in diameter. Standard practice in the United States is radiation therapy; however, gynecologists in Europe and Japan prefer a radical hysterectomy and abdominal lymphadenectomy.
Stages III and IV - The tumor is either locally advanced or it has metastasized. Radiation therapy is also the preferred therapy. Surgery is occasionally helpful to relieve symptoms. Chemotherapy is often added.
Cancer During Pregnancy
Carcinoma of the cervix is diagnosed in about 0.01% of pregnant patients. Some gynecologists believe that pregnancy makes the cancer worse, but reliable studies have challenged this theory. Gynecologists conventionally allow patients who are 24 weeks or more into gestation to wait until fetal viability. But, patients in the first and second trimester are usually encouraged to interrupt their pregnancy and begin conventional therapy. Exceptions have been made for patients with stage Ia disease, whose lesions have been completely removed.
I believe that conventional therapy is too cautious. Patients whose disease can be locally controlled can probably maintain their pregnancy. Some women may wish to accept some risk to bear children. Such women should understand the risks of conservative treatment and be prepared to accept responsibility for its outcome. They should not be denied the option of fertility-sparing surgery. Some gynecologists believe that Conization can be safely performed during the first 20 weeks of gestation. Others believe that conization during pregnancy has a 20% complication rate, including bleeding, abortion and premature delivery.
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MEDICAL RESEARCH
In the early 1800's cancer of the cervix was treated with amputation. By the 1890's Emil Ries of Chicago and John Clark of Baltimore had both described the radical hysterectomy including pelvic lymph node dissection. The procedure was popularized in Europe by Ernst Wertheim of Austria. By 1911 he had treated 500 patients and published a clear anatomical description of the way disease spread and his operative technique. This operation still bears his name.
Radiation therapy was also introduced to treat cervical cancer. Johns Hopkins Hospital was a leader in this field under Howard Kelly, the first professor of gynecology. In 1933, Joseph Meigs of the Massachusetts General Hospital began to use surgery to treat patients who failed radiation therapy. His extended radical hysterectomy which included pelvic lymph node dissection gained in popularity after World War II.
In 1948 Alexander Brunschwig of Memorial Hospital introduced pelvic exenteration for recurrent cervical cancer. All the pelvic organs were removed. This required a permanent colostomy, and diversion of the urinary tract. This operation is seldom used today. By the 1950's the limits of radical surgery had been reached. As with many other cancers, surgeons began to consider more conservative measures. For cancer of the cervix most of this work has been done in Europe.
From 1958 to 1988, Erich Burghardt and colleagues at the University of Graz in Austria performed conization on 26 patients with stage Ia2 cervical cancer.(1) Five-year results were available on 18 patients. Three developed local recurrence; all were treated with radical hysterectomy and/or radiation. One of these patients missed her follow-up appointment for three years and returned with stage IIb disease. She died three years following radical hysterectomy and radiation therapy. The other two patients were free of disease after treatment of the recurrence. One had radical hysterectomy; one had radiation therapy. Ninety-three patients with stage Ia1 disease were treated with conization. None developed local recurrence.
Dr. K. J. Lohe of the University of Munich in Germany and colleagues from the Universities of Erlangen, Freiburg, Heidelberg, and Cologne published their experience with 285 patients with stromal invasion (stage Ia1) and 134 patients with microcarcinoma (stage Ia2).(2) They treated most of the stage Ia2 patients (118) with hysterectomy -- about 20% also received radiation therapy. But, sixteen of these patients with stage Ia2 disease were treated with conization -- nine also had radiation therapy. After five years 94% were living, after ten years 85% were living. None of the patients treated with conization developed a recurrence or died of cervical cancer. The authors report an additional 28 patients reported in the literature who were treated by local excision. They conclude,"If proof is given that the microcarcinoma was totally removed with the conization, further operative measures, in general, may become unnecessary."
Holzer and colleagues from Austria treated 61 patients with conization alone (53 with stage Ia1 disease and eight with stage Ia2 disease). All patients whose tumor was completely excised were alive and well after three years. (Schink)
Dr. Per Kolstad of the Norwegian Radium Hospital in Oslo treated 48 patients with stage Ia disease with conization; fifteen were stage Ia2.(3) During the 3 to 17 year follow-up, four of the 48 developed local recurrence. All were treated with additional surgery or radiation therapy. None of these developed distant metastases.
Ebeling from the University of Berlin and colleagues from six other hospitals in the former East Germany reported on 530 patients treated for microinvasive carcinoma of the cervix; lesions up to 7 mm x 7 mm x 5 mm.(4) Three hundred seventy-one were treated with limited surgery, conization or hysterectomy. Twelve patients developed local recurrences. There was no significant difference in the case fatality rates between the limited surgery (1.1%) and radical surgery (2.8%). The authors noted that following limited surgery ". . . as a rule the recurrences can be easily treated with secondary treatment to avoid fatality."
Morris et al. from M. D. Anderson Hospital reported on 14 patients with microinvasive cancer (3 mm or less) treated with conization.(5) The mean depth of invasion was 1.6 mm and the median follow up was 26.5 months. No patient had developed a recurrent invasive or preinvasive lesion.
Since 1987, Dargent of the Hopital E. Harriot in Lyon, France, has treated nine patients with a wide excision of the cervix, trachelectomy.(6) These patients had stage Ia2 through stage IIa disease. On follow-up examination one patient was found to have a 2-cm endocervical adenocarcinoma. It was removed, but 18 months later the patient was found to have a large mass of undifferentiated cancer in the right iliac fossa. She died of cervical cancer. A second patient developed an HPV related cervical intraepithelial neoplasia (CIN), which was treated by laser therapy. One patient was treated for cervical stenosis; one was treated for amenorrhea. Eight of the nine women are alive and well; four have had children. The only patient who died of cervical cancer was found to have a massive adenocarcinoma, which was undetected on early follow-up examination.
Greer et al. from the University of Washington Medical Center in Seattle performed a conization biopsy on 50 patients with stage Ia2 squamous cell carcinoma of the cervix.(7) Thirty-three (66%) had positive margins, and 17 (33%) had negative margins. Following hysterectomy the uterus was examined. Four of the 17 patients (24%) with negative margins were found to have residual disease in the uterus. The conizations were performed at other institutions for biopsy only. Wider margins of excision and careful examination of the cone specimen should significantly reduce the number of patients with residual disease.
Rutledge and colleagues from the University of Western Ontario treated 47 patients who developed recurrence cervical cancer following radiation therapy.(8) Although radical exenteration has been commonly practiced for this condition, the authors concluded that conservative surgery -- radical hysterectomy -- could be prudently performed in selected patients.
Cancer during Pregnancy
Sivanesaratnam and associates from the University Hospital of Kuala Lumpur reported on 18 patients who developed cervical cancer during their pregnancy.(9) Four patients presented with advanced disease after delivery elsewhere; three of these died following hysterectomy. The remaining patients did as well as non-pregnant patients after conventional treatment. Monk and Montz from UCLA reported 13 patients treated between 1955 - 1991.(10) Following a cone biopsy, seven of these patients delayed their treatment until fetal maturation was documented -- one from the first trimester, and three each from the second and third trimesters. All patients eventually received conventional therapy. The only death occurred in a patient who had a large, deeply invasive lesion, diagnosed at 35 weeks. With an average follow-up of 20 months (range 2 - 228 months) all the remaining patients are alive and free of disease.
Duggan and associates from the University of Southern California delayed therapy in eight pregnant patients.(11) Four of them were less than twenty weeks pregnant. All eight patients had definitive therapy after delivery. They were all free of disease when last seen.
Patient survival is dependent upon the tumor burden. Patients in Kuala Lumpur died of untreated advanced disease. Patients at UCLA survived because all or most of their tumor was removed by the cone biopsy. This study would have been better had the investigators reported the extent of disease at time of delivery.
1. Burghardt E, Girardi F, Lahousen M, et al. Microinvasive carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics Stage IA. Cancer 1991; 67:1037-1045.
2. Lohe KJ, Burghardt E, Hillemanns HG, et al. Early squamous cell carcinoma of the uterine cervix II. Clinical results of a cooperative study in the management of 419 patients with early stromal invasion and microcarcinoma. Gyn Oncol 1978; 6:31-50.
3. Kolstad P. Follow-up study of 232 patients with stage Ia1 and 411 patients with stage Ia2 squamous cell carcinoma of the cervix (microinvasive carcinoma). Gynecol Oncol 1989; 33:265-272.
4. Ebeling K, Bilek, Johannsmeyer D, et al. Mikroinvasives karzinom der cervix uteri stadium Ia -- ergebnisse einer multizentrischen klinikbezogenen analyse. Geburtsh u Frauenheilk 1989; 49:776-781.
5. Morris M, Mitchell MF, Silva EG, Copeland LJ, Gershenson DM. Cervical conization as definitive therapy for early invasive squamous carcinoma of the cervix. Gynecol Oncol 1993; 51:193-6.
6. Dargent D. Traitement des cancers de l'exocol et du vagin par la chirurgie avec conservation de l'uterus et de ses annexes. Cah Oncol 1992; 1:21-25.
7. Greer BE, Figge DC, Tamimi KT, et al. Stage IA2 squamous carcinoma of the cervix: Difficult diagnosis and therapeutic dilemma. Am J Obstet Gynecol 1990; 162:1406-11
8. Rutledge S, Carey MS, Prichard H, Allen HH, Kocha W, Kirk ME. Conservative surgery for recurrent or persistent carcinoma of the cervix following irradiation: Is exenteration always necessary? Gyn Oncol 1994;52:353-9.
9. Sivanesaratnam V, Jayalakshmi P, Loo C. Surgical management of early invasive cancer of the cervix associated with pregnancy. Gynecologic Oncology 1993; 48:68-75.
10. Monk BJ, Montz FJ. Invasive cervical cancer complicating intrauterine pregnancy: treatment with radical hysterectomy. Obstet Gynecol 1992; 80: 199-203.
11. Duggan B, Muderspach LI, Roman LD, et al. Cervical cancer in pregnancy: reporting on planned delay in therapy. Obstet Gynecol 1993; 82:598-602.
Medical Research since 1995
The leader in fertility-sparing surgery is Daniel Dargent of Hopital Edouard Herriot in Lyon, France.(1) Between 1987 and 1995 he treated 47 women with radical trachelectomy and laparoscopic pelvic lymph node dissection. Twenty-nine patients were stage Ib or higher and seven patients had tumors which were 2 cm in diameter or larger. After a mean follow up of 52 months, 1 patient developed a local recurrence, 1 developed a distant metastasis, and a third died of progressive disease. Of the 16 patients who tried to become pregnant, 10 delivered a normal child.
M. Roy and M. Plante of Quebec City, Canada treated 30 patients with radical trachelectomy and laparoscopic pelvic lymph node dissection between 1991 and 1998.(2) A median of 25 months after surgery, 29 patients were alive and free of cancer. One patient developed an intraabdominal recurrence and died of advanced disease. Of the 6 patients who tried to become pregnant, 4 delivered healthy babies by caesarian section and 2 were pregnant when the paper was written. The authors updated their experience in May, 2000.(3)
A. Covens and associates of Toronto, Ontario, Canada, treated 32 patients with radical trachelectomy and laparoscopic pelvic lymph node dissection between 1994 and 1998.(4) One patient developed an intraabdominal recurrence and died of advanced disease. Of the 13 patients who tried to become pregnant, 4 became pregnant, 3 delivered healthy children by caesarian section. Surgeons in England, Germany and Italy are also beginning to use this fertility-sparing approach to cervical cancer. A group of surgeons at Tohoku University in Japan have begun to use conization for selected patients with 3 to 5 mm of invasion.(5)
The Texas Cancer Center believes that all available medical evidence continues to support the increased use of trachelectomy for selected patients with invasive cancer of the cervix. Recommendations to the contrary are based almost exclusively on outmoded ideas and practices.
1. Dargent D, Martin X, Sacchetoni A, Mathevet P. Laparoscopic vaginal radical trachelectomy: A treatment to preserve the fertility of cervical carcinoma patients. Cancer 88:1877-1882, 2000.
2. Roy M, Plante M. Pregnancies after radical vaginal trachelectomy for early-stage cervical cancer. Am J Obstet Gynecol 179:1491-1496, 1998.
3. Roy M, Plante M. Radical vaginal trachelectomy for invasive cervical cancer. [French] J Gynecol Obstet Biol Reprod (Paris) 29:279-281, 2000.
4. Covens A, Shaw P, Murphy J, DePetrillo D, Lickrish G, Laframboise S, Rosen B. Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix? Cancer 86:2272-2279, 1999.
5. Yaegashi N, Sato S, InoueY, Noda K, Yajima A. Conservative surgical treatment in cervical cancer with 3 to 5 mm stromal invasion in the absence of confluent invasion and lymph-vascular space involvement. Gynecol Oncol 54:333-337, 1994.
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The Texas Cancer Center gratefully welcomes contributions from all those 
