*Professor, Dept of Radiotherapy, PG Institute of Medical Education and Research, Chandigarh

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1 Health Administrator Vol: XVII, Number 1: ,pg. CANCER CERVIX: TREATMENT AND ITS PROBLEMS Firuza D Patel* I. INCIDENCE Carcinoma cervix is a major public health problem, as we have about 100,000 cases of cervix cancer every year. 20% of all cervical cancers worldwide occur in India and 75% present in advanced stages. According to the latest ICMR report of the National Cancer Registry Programme 1, cancer of the cervix is the leading site among all females in the Bangalore, Barshi, Bhopal and Chennai population based registries. In Delhi and Mumbai it is second to cancer of the breast. Both these sites together account for over 40% of cancers in urban women and over 65% of cancers in the rural registry in Barshi, where more than 50% of cancers in females is cancer of the cervix. Thus carcinoma of the uterine cervix is the commonest malignancy to affect the female population in India. Unlike malignancies in other areas there are two very important advantages, which need to be taken into account for the management of this disease. The first advantage is that this disease has a natural history where the malignant epithelial transformation evolves over many years, and passes through distinct, easily clinically recognized stages of dysplasia, ca-insitu to frankly invasive lesions. Simple preventive action taken at the right time can avert the development of cancer. The second is that the anatomical accessibility of the cervix to physical examination should be exploited so that with effective screening and down staging the disease can be detected at an early stage, when definite cure is readily achieved by surgery or radiotherapy. The easy access to the cervix leads also to the skillful application of radiation techniques even for advanced stage disease which have resulted in some of the best overall cure rates for any malignancy found in human beings. II. SCREENING Screening by Papanicolau smear and if necessary colposcopy guided cervical biopsy have had the most dramatic impact on the rate of mortality in cancer cervix. This also forms a part of the 1984 National Cancer Control Programme in India. However, facilities for nationwide screening in such large numbers are not possible in our vast country due to paucity of trained manpower, infrastructure, quality assurance, frequency of screening and costs involved. Most screening in India is opportunistic screening and is not population based. Screening is more popular in the metropolitan areas and in women with good socioeconomic status who are usually a low risk population for developing cancer cervix. Therefore, alternative approaches have been evaluated that may be easier to implement in developing countries and can target the population at risk in the rural areas. 1. Unaided visual inspection: Naked eye visualization of the cervix without acetic acid application by health workers, widely known as down staging. An Indian study found that about 2/3 rd of women with early cancer were detected through this approach but the major drawback was that it primarily identifies cancer and not precancerous conditions. 2. Aided visual inspection: is better for inspecting dysplasia/ca-in-situ. - VIA -In this naked eye visual inspection of the cervix is done after application of 3-5% acetic acid. - VILI-Visual inspection is done after application of Lugol s iodine. - VIAM-This is visual inspection with acetic acid using a small light weight monocular telescope called a gynoscope which magnifies the lesion 2.5 times. Though there is a large body of data on the test accuracy of VIA, the efficacy and cost effectiveness of VIA based screening programme in reducing the cervical cancer incidence and mortality is not known and is being evaluated by 2 cluster-randomized controlled intervention trails in India and the results are expected to emerge around Along with effective organized screening primary prevention by education of women, husbands and school children via health workers, school teachers, group leaders and through the mass media like TV *Professor, Dept of Radiotherapy, PG Institute of Medical Education and Research, Chandigarh 162

2 and radio should also be undertaken. Raising age of marriage, improving literacy rates, postponement of child birth and education of genital hygiene as well as signs and symptoms of cervical cancer with improvement in obstetrical services would indirectly reduce the risk and be a step towards preventive oncology. Screening can only be effective if an abnormal test can be further investigated and offered appropriate treatment without any delay. Majority of these patients live in rural areas where no treatment facilities are available to them and they have to travel long distances to receive treatment. In a small review at our Institute we found that about 28% of our patients come from a distance less than 50KM away. Eight percent traveled km and 64% of the patients traveled more than 100Kms. to seek treatment. As these patients come from poor socio-economic strata of society they can only afford treatment in Government hospitals which are grossly overburdened and patients generally have to wait for weeks to a few months before their treatment can be started due to long waiting lists. Therefore, there is an urgent need for increasing the radiotherapy services away from the big cities into the smaller towns and rural areas. Along with a teletherapy unit brachytherapy facilities should also be started which can be a simple manual remote afterloading facility. III. STAGING Cancer of the cervix is the only gynaecological malignancy which uses a clinical staging system. Therefore, accurate staging is a must for further treatment planning. The International Federation of Gynecology & Obstetrics (FIGO) has defined the most widely accepted staging system for carcinoma of the cervix 2-3. The latest (1994) update of this system is summarized in Table-1. FIGO stage is based on careful clinical examination and the results of specific radiologic studies and procedures. These should be performed and the stage should be assigned before any definitive therapy is administered. The clinical stage should never be changed on the basis of subsequent findings. When it is doubtful to which stage a particular case should be allotted, the case should be assigned to the earlier stage. FIGO warns that, because it is impossible to tell from clinical examination whether a smooth and indurated parametrium is truly cancerous or only inflammatory, a case should be classified as stage III only if the parametrium is nodular out on the pelvic wall or if the growth itself extends out on the pelvic wall. In the rules for clinical staging, FIGO states that palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and radiologic examination of the lungs and skeleton may be used for clinical staging. Suspected bladder or rectal involvement should be confirmed by biopsy. Findings of bullous edema or malignant cell in cytologic washings from the urinary bladder are not sufficient to diagnose bladder involvement. FIGO clearly states that findings by examinations such as lymphangiography, arteriography, venography, and laparoscopy are of value for planning therapy but, because these are not yet generally available and the interpretation of results is variable, the findings of such studies should not be the basis for changing the clinical stage. Examination under anesthesia is desirable but not required. The rules and notes to the FIGO staging system are integral parts of the clinical staging system and should be strictly observed to minimize inconsistencies in staging between institutions. IV. PRIMARY THERAPY Patients with cervical cancer usually present with disease that is clinically confined to the pelvis, hence locoregional disease control is the primary challenge for physicians. Surgery is generally reserved for the early stage patients only, however, radiotherapy is used for all stages but needs to be carefully tailored to a particular patient and to the extent of the disease. Treatment must ideally have a combination of external - beam irradiation and brachytherapy. The role of chemotherapy as a radiosensitizer is currently the subject of various clinical studies. V. PREINVASIVE DISEASE STAGE OF DISEASE Preinvasive lesions are best treated by large loop excision of transformation zone. Other local ablative procedures include cryosurgery or laser ablation. However, ablative treatment is contraindicated if the entire transformation zone has not been well visualized or if colposcopy or pap smear suggests invasive disease. In these situations, conization should be performed to rule out invasion and to treat the preinvasive lesion. Total abdominal or vaginal hysterectomy is an accepted therapy for patients who have completed their family and is particularly indicated when the neoplastic process extends to the inner cone margin. 163

3 Table - 1 Stage Stage O Stage 1 StageIA Definition Carcinoma in situ, intraepithelial carcinoma; cases of Stage 0 should not be included in any therapeutic statistics for invasive carcinoma. The carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded) Invasive cancer identified only micro- scopically. All gross lesions, even with superficial invasion, are Stage-IB cancers. Invasion is limited to measured stromal invasion with a maximum depth of 5 m and no wider than 7mm. (The depth of invasion should not be more than 5mm taken from the base of the epithelium, either surface or glandular, from which is originates. Vascular space involvement, either venous or lymphatic, should not alter the staging) Stage IA1 Stage IA2 Stage IB Stage IB1 Stage IB2 Stage II Stage IIA Stage IIB Stage III Stage IIIA Stage IIIB Stage IV Stage IVA Stage IVB Measured invasion of stroma no greater than 3 mm in depth and no wider than 7mm Measured invasion of stroma greater than 3mm and no greater than 5 mm in depth and no wider than 7mm. Clinical lesions confined to the cervix or pre-clinical lesions greater than IA. Clinical lesions no greater than 4 cm. Clinical lesions greater than 4 cm. The carcinoma extends beyond the cervix, but has not extended onto the pelvic wall; the carcinoma involves the vagina, but not as far as the lower third. No obvious parametrical involvement Obvious parametrical involvement. The carcinoma has extend onto the pelvic wall; on rectal examination there is no cancer-free space between the tumor and the pelvic wall; the tumor involves the lower third of the vagina; all cases with a hydronephrosis or nonfunctioning kidney should be included, unless they are known to be due to other cause. No extension onto the pelvic wall, but involvement of the lower third of the vagina. Extension onto the pelvic wall or hydronephrosis or nonfunctioning kidney. The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder or rectum Spread of the growth to adjacent organs. Spread of distant organs. 164

4 VI. CARCINOMA CERVIX STAGE IA. (Clinically non-visible lesions) Patients must be subjected to a cone biopsy with endocervical curettage as the further management depends on depth of invasion and presence or absence of lympho-vascular space invasion. Stage IA 1 patients are conventionally treated with a simple (Type-I) abdominal or vaginal hysterectomy if there is no lympho-vascular invasion. Lymph node involvement is also very low in these patients and hence lymph not dissection is not required. For selected patients, who wish to maintain fertility and who agree to close follow up conization alone may be appropriate for these patients. Although Stage IA1 patients are usually treated with hysterectomy, patients with medical contra indications to surgery can be very effectively treated with radiotherapy. As the incidence of lymph node involvement is sufficiently low external beam therapy is not required and brachytherapy alone gives 10-year progression free survival rates of %. Treatment is usually given in two low dose rate insertions giving 65-75Gy to point A. For stage IA2 patients the incidence of regional lymph node involvement is reported to be 5-10%, surgical treatment therefore, includes a radical hysterectomy with pelvic lymph node dissection. If radiotherapy has to be delivered for these patients a combination of 40-45Gy of external beam radiation with intracavitary radiation must be used. Five year survival with either surgery or radiotherapy is > 95%. VII. CARCINOMA CERVIX STAGE IB AND IIA: Reported results of treatment with hysterectomy and those of radiation therapy for FIGO Stage IB cervical cancer are comparable with about 80% of patients surviving 5 years. The choice of treatment depends upon the age of the patient, desire to preserve ovarian function, co-morbid conditions, associated gynaecological conditions requiring surgery, facilities and expertise available. However, surgeons tend to select young patients with relatively small tumours and refer patients with large tumors or evidence of regional spread for irradiation. For patients with FIGO stages IB and II disease treatment results are strongly correlated with tumor size. In a report of the only randomized trial comparing radical surgery (with or without post operative radiation) with irradiation alone, Landoni and colleagues4 reported a 5 year acturial survival rate of 87% for Stage IB - IIA tumors < 4 cm. in diameter treated with surgery compared to 90% for those treated with radiotherapy. Similarly in the patients with bulky FIGO Stage IB2 and IIA tumors the 5 years survival was 70% for patients treated with surgery and 72% for patients treated with radiotherapy. However, it is worth noting that in the surgery group 62 of 114 women (54%) with cervical diameter of < 4cm. and 46 of 55 (84%) with diameters larger than 4 cm also received post-operative radiotherapy. Forty-eight (28%) surgery group patients had severe morbidity compared to 19(12%) in radiotherapy group patients. This increased morbidity is most likely due to the combination of surgery and radiotherapy which increases the complication rates mainly urological. A recent National Cancer Institute (NCI) consensus conference concluded that primary therapy should avoid the routine use of both radical surgery and radiation therapy5. If clinical evaluation reveals risk factors that would require pelvic irradiation after radical hysterectomy, radiotherapy should be considered the primary treatment of choice. Prognostic factors that identify patients at high risk for failure include, multiple or bulky positive pelvic nodes, large tumor size, deep stromal penetration, lympho-vascular space invasion and parametrial extension. VIII. CARCINOMA CERVIX STAGES IIB-IIIB These are patients with locally advanced disease and the treatment of choice for most patients is radiation therapy using a combination of external beam irradiation and brachytherapy. External beam radiation is used to treat the central disease and to sterilize known or suspected regional metastases. For patients with bulky central disease, a course of external beam radiation to the pelvis usually causes significant tumor regression, potentially improving the dose distribution of subsequent intracavitary radiation by shrinking the endocervical disease to bring it within the high dose range of inctracavitary therapy or by reducing exophytic tumor that would have caused undesirable caudal displacement of intracavitary vaginal applicators. The origin of cervical cancers at the mouth of a hollow, relatively radioresistant organ makes the disease ideal for intracavitary treatment. Carefully placed sources in the uterus and the vagina gives a flattened pear shaped distribution, which delivers a high dose to the cervix and paracervical tissues and a reduced dose to the critical normal tissues like bladder and rectum. The amount of dose given with external beam or intracavitary radiation must be balanced 165

5 carefully. Proportion of external radiation increases with increase in tumor bulk and stage, and except for small tumors external radiation generally preceeds intracavitary treamtent. For early stage patients and patients with small cervical disease two intracavitary sessions give better results than a single intracavitary application (73% vs 60%). Even for Stage-III patients the role of brachytherapy is indisputable. The MDACC report6 of 1007 patients of Stage-III disease has shown that disease specific survival rate was 43% for patients who had intracavitary irradiation versus 21% for those treated with external beam radiation alone. The combined dose from external radiation and brachytherapy should be 75-80Gy to the paracentral area and the pelvic side wall dose should be 44-50Gy for microscopic disease and at least 60Gy for clinically involved nodes. It is also very important to complete the entire treatment in the shortest time possible. Several studies have suggested that there may be as much as a 1% decrease in survival and local control for each extra day of treatment beyond a total treatment time of days 7,8. IX. CARCINOMA CERVIX STAGE-IV (Advanced Disease Palliation): Radiation therapy can play an important role in the palliation of patients with incurable advanced disease. Hypofractionated pelvic irradiation giving 2-3 fractions of 10Gy at 1-month interval can control bleeding and frequently provides prompt relief or pelvic pain. The RTOG report 9 and the MDACC experience10,11 have shown a symptomatic response rate of 57-75%. Other fractionation schemes of Gy in 10 fractions have also been used. X. CHEMORADIATION Concurrent Therapy The National Cancer Institute (NCI) 12 issued a clinical alert in February 1999 with regard to positive survival advantages found with cisplatin based concurrent chemoradiation in each of five randomized prospective Phase-III trials for cervix cancer Patient population included those with FIGO IB2-IVA in which primary radiotherapy was planned, or patients with poor prognosis StageI-IIA lesions following surgical resection. All the trials demonstrated significant survival benefit when compared with irradiation alone. The risk of death from cervical cancer was decreased by 30-50% with concurrent chemoradiation. Based on these results, the NCI clinical announcement suggested that strong consideration should be given to the incorporation of concurrent cisplatin based chemoradiation in women who require irradiation as a component of treatment for cervix cancer. A systematic review of all known randomized controlled trials done by Green 18 suggests chemoradiation improves overall survival and progression free survival, with absolute benefits of 12% and 16% respectively. There was some evidence that the effect was greater in trials including a high proportion of Stage-I & II patients. Chemoradiation also showed significant benefit for both local and distant recurrence. Grade 3-4 haematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group than the control group but data on long term side effects were sparse. Neo Adjuvant Therapy: Investigators have advocated neo-adjuvant chemotherapy on various theoretical advantages, however, nine randomized trials have compared treatment with neo-adjuvant chemotherapy followed by irradiation with irradiation alone in patients with locally advanced cervical cancer Only one study 22 showed some benefit for neoadjuvant therapy, the rest showed no benefit and one large trial by Tattersall and colleagues 25 actually showed poorer survival for the neoadjuvant arm. Thus neoadjuvant chemotherapy with the presently available agents has failed to show any benefit over radiotherapy alone. While accepting that chemoradiotherapy is perhaps the new standard of care according to the western literature we need to remember that these results were obtained in a trial setting, in women from affluent countries with good nutritional and performance status. The review also shows that the beneficial effect was more in early stage patients. Hence, before blindly accepting chemoradiation for all our patients we need to remember that our patients are from poor socio-economic status with poor nutritional and performance status and majority of the patients are of stage-iii and are likely to have compensated or poor renal functions. By combining chemotherapy and radiotherapy we should not compromise either the radical radiotherapy dose nor should the treatment time be increased because of poor tolerance due to side effects as both these factors will result in poorer results than standard radical radiation alone. XI. POSTOPERATIVE RADIATION FOR CARCINOMA CERVIX 10-12% of cancer cervix patients seen in a referral radiotherapy department are following 166

6 surgery. Radical surgery for early stage disease gives results comparable to radical radiotherapy. However, surgery done in advanced stage patients is never adequate and is inappropriate treatment as it compromises the patients radical radiation. In an unpublished study from at our institute we found that 9.6% of cancer cervix patients referred to us are following surgery. Out of 128 patients 25 patients had radical surgery performed, and 103 (80%) patients were referred after a simple hysterectomy. All patients with inadequate surgery were given post-operative radiation. In the group who had radical surgery 10/25 patients were given immediate post operative radiation for high risk factors of recurrence and all the patients had local control of disease. In the 15 patients who were kept on followup only after radical radiotherapy 8 patients had local failure. In the patients with incomplete surgery (64%) of patients were referred when they had local recurrence and inspite of post operative radiation local control could be achieved in only 12% of patients as against this patients who did not have macroscopic local disease at the time of post operative radiation had a local control rate of 73% which is similar to the 76% local control seen in patients treated by radical radiotherapy alone. However, in patients receiving both surgery and radiotherapy the rectal morbidity and subacute intestinal obstruction was significantly greater than in the radical radiotherapy group. The increased morbidity is due to the fact that adhesions may fix small bowel loops in the pelvis increasing the risk of complications and the extirpation of uterus causes the bladder and rectum to get higher doses with brachtherapy. XII. CONCLUSIONS Carcinoma cervix is the commonest malignancy in females in India and if detected early has a high cure rate. Unfortunately majority of the patients present with advanced stage disease. Educational and screening programmes so far have been grossly inadequate hence we need to educate the women and their families regarding the early symptoms and we need to take away their shyness regarding the symptoms and the fear of the disease and its treatment. Screening needs to be organized and targeted to the population at risk.. Further radiotherapy facilities need to be developed away from the big cities into smaller towns and rural areas so that it is easily accessible to the patients. We also need to ensure that once the disease is diagnosed there is no delay in starting the appropriate treatment. Physicians need to be educated about the results and morbidity following simple surgery for these patients as the number of patients referred after such surgery is increasing. There is no role for neo-adjuvant chemotherapy and it should not be used as a stop gap arrangement while patient is waiting to start radiotherapy. Each center needs to address its palliative treatment schedules either to a single fraction or the shortest treatment possible so that patients requiring curative radical treatment need not wait. White concurrent chemoradiation is accepted as the standard of care in the west we need to evaluate this in the Indian set up where the patient profile is quite different. Well designed multicentric clinical trials need to be developed to find the best treatment suited for our patients. REFERENCES 1. National Cancer Registry Programme. Consolidated report of the population based cancer registries (ICMR, New Delhi). 2. International Federation of Gynaecology & Obstetrics. Annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet (Suppl): 36-27, International Federation of Gynaecology & Obstetrics. Staging announcement: FIGO staging of gynecologic cancers: cervical and vulva. Int J Gynaecol Cancer 5:319, Landoni F, Maneo A, Colombo A, et al: Randomized study of radical surgery versus radiotherapy for stage lb-lia cervical cancer. Lancet 350: , National Institute of Health Consensus Development Conference Statement on Cervical Cancer. Gynecol Oncol 66: , Eifel PJ, Jogsdon MD: FIGO Stage IIIB squamous cell carcinoma of the uterine cervix: Natural history, treatment results, and prognostic factors. Int J Radiat Oncol Biol Phys 36 (Suppl): 217, Petereit DG, Sarkaria JN, Chappell R, et al: The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 25: , Fyles AW, Dembo AJ, Bush RS, et al: Analysis of complications in patients treated with abdomino-pelvic radiation therapy for ovarian carcinoma. Int J Radiat Oncol Biol Phys 22: , Spanos WJ, Wasserman T, Meoz R, et al: Palliation of advanced pelvic malignant disease with large fraction pelvic radiation and misonidazole: Final report of RTOG phase I/II 167

7 study. Int J Radiat Oncol Biol Phys 13: , Adelson MD, Wharton JT, Delclos L, et al: Palliative radiotherapy for ovarian cancer. Int J Radiat Oncol Biol Phys 13: 17-21, Boulware RJ, Caderao JB, Delclos L, et al: Whole pelvis megavoltage irradiation with single doses of 1000 rad to palliate advanced gynecologic cancers. Int J Radiat Oncol Biol Phys 5: , NCI Clinical Announcement: Concurrent Chemoirradiation for cervical cancer. February Whitney CW, Sause W, Bundy BN et al: Randomized comparison of flurouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative paraortic lymph nodes. A Gynecologic Oncology Group and Southwest Oncology Group Study. J Clin Oncol 17: , Morris M, Eifel PJ, Lu J, et al; Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for high risk cervical cancer. A randomized radiation therapy oncology group clinical trial. N Engl J Med 340: , Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based chemoradiation improves progression free and overall survival in advanced cervical cancer: Results of a randomized Gynecologic Oncology Group Study. N Engl J Med 340: , Keys HM, Bundy BN, Stehman FB, et al: A comparison of weekly cisplatin during radiation therapy versus irradiation alone, each followed by adjuvant hysterectomy in bulky stage IB cervical carcinoma: A randomized trial of the Gynecologic Oncology Group. N Engl J Med 340: , Peters WA III, Liu PY, Barrett RJ, et al: Cisplatin and 5-flurouracil plus radiation therapy are superior to radiation therapy as adjunctive in high-risk early-stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: Report of a phase III intergroup study. Soc Gynecol Oncol Abstracts, Green JA.: Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix; a systematic review and meta-analysis. Lancet: 358: 781-6, Cardenas J, Olguin A, Figueroa F, et al: Neoadjuvant chemotherapy (CT)2 +radiotherapy (RT) vs. RT in stage IIB, III carcinoma of the cervix: A cooperative study of the French Oncology Centers. Proc Am Soc Clin Oncol 11: A 743, Kumar L, Kaushal R, Nandy M, et al: Chemotherapy followed by radiotherapy versus radiotherapy alone in locally advanced cervical cancer: A randomized study. Gynecol Oncol 54: , Leborgne F, Leborgne JH, Doldan R, et al: Induction chemotherapy and radiotherapy of advanced cancer of the cervix: A pilot study and phase III randomized trial. Int J Radiat Oncol Biol Phys 37: , Sardi J, Sananes C, Giaroli A, et al: Results of a prospective randomized trial with neoadjuvant chemotherapy in Stage-IB, bulky squamous carcinoma of the cervix. Gynecol Oncol 49: , Souhmi L, Gil R, Allan S, et al: A randomized trial of chemotherapy followed by pelvic radiation therapy in Stage-IIIB carcinoma of the cervix. Int J Radiat Oncol Biol Phys 9: , Sundfor K, Trope CG, Hogberg T, et al: Radiotherapy and enoadjuvant chemotherapy for cervical carcinoma. Cancer 77: , Tattersall MHN, Larvidhaya V, Vootiprux V, et al: Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer, J Clin Oncol 113: , Tattersall MHN, Ramirez C, Coppleson M: A randomized trial comparing platinum based chemotherapy followed by radiotherapy vs. radiotherapy alone in patients with locally advanced cervical cancer. Int J Gynecol Cancer 2: ,