HIV AND CERVICAL CANCER

Introduction
Cervical cancer is the most common cancer among women in India and its incidence in India alone is estimated as 100,000 in 2001 AD. The incidence of HIV infection in India is increasing at an alarming rate. The relation between HIV infection and cervical neoplasia was recognized in the 1980s and, in 1993, the CDC criteria for defining AIDS were modified to include invasive squamous cancer of the cervix as an AIDS defining condition in an HIV positive woman.

Etiology and pathogenesis
The association between cervical cancer and human papillomavirus (HPV) is well known, but its association with human immunodeficiency virus (HIV) is controversial although co-infection with HPV and HIV is to be expected. Epidemiological data from Africa showed in 1993 that cervical cancer was a common AIDS defining neoplasm in women, although this view currently is not so strongly held. Unlike other AIDS defining neoplasms, the occurrence of cervical cancer is not strongly dependent on immune compromise. HIV alters the natural history of HPV infection, with decreased regression rates and more rapid progression to high grade and invasive lesions, which are refractory to treatment, requiring more stringent intervention and monitoring. The more aggressive behaviour is mirrored by a different molecular pathway. HIV-associated cervical cancers are considered to progress through the DNA microsatellite instability pathway, whereas HIV negative cancers progress through loss of heterozygosity. Interaction is probably via viral proteins, with HIV proteins enhancing effectiveness of HPV proteins, and perhaps contributing to cell cycle disruption. Dysregulation of the cellular and humoral arms of the local and systemic immune systems may accelerate disease progression. Furthermore, HPV infection may predispose to HIV infection and facilitate its progression. [1]

The impact of concurrent HIV on the rate of progression in CIN is uncertain. Anecdotal reports suggest that the rate of transformation may be increased in certain individuals, but there is little hard evidence to suggest that this invariably applies to all patients.

Epidemiology
The risk of squamous intra-epithelial lesions (SIL) in patients attending Sexually Transmitted Disease (STD) clinics and drug addiction clinics is further increased (x 2) by the acquisition of HIV infection [2, 3]. The prevalence of HIV infection in 2198 patients recruited from gynecology outpatient clinics in Cote d’Ivoire was 21.7% [4]. The same authors report that, of 94 women with SIL, 38 (40%) were HIV positive. These data are provocative but there are few hard data to support the contention that HIV infection causes invasive cancer of the cervix: the association may simply reflect the common epidemiological background for the two viral infections, HPV and HIV. Many patients may acquire their HIV infection after they develop their malignant cervical changes [5].

Clinical features
The cardinal symptom of invasive cervical cancer is post-coital bleeding. Intermenstrual bleeding, excessive menstrual bleeding or post-menopausal bleeding suggests moderately advanced disease. In the later stages of the disease, foul-smelling chronic discharge, anemia, lower abdominal pain and backache may occur. Hematuria and rectal bleeding indicate invasion of the bladder and rectum respectively.

Diagnosis
Asymptomatic cervical malignant change can often be diagnosed cytologically by cervical (pap) smear. Unfortunately, there is some evidence that the false negative rate may be higher in HIV positive, as opposed to HIV negative women. False negative rates of 15 to 20% are reported. This implies that it may be unwise to rely on a “normal” smear to exclude cervical malignancy in an HIV positive woman. Maiman et al. [6] in a study of 248 HIV infected women all of whom had cytology; colposcopy and biopsy concluded that 38% of all CIN in 13% of all the total patients would have been missed if colposcopy and biopsy had not been done. Baseline colposcopy in HIV infected patients is therefore essential.

Since the prevalence of disease is greater in HIV positive patients than in the general population optimal screening strategies should therefore take an important position. Screening high risk populations, although the intention is to detect early intra-epithelial lesions, may detect a significant number of lesions that have already progressed to invasive carcinoma. The definitive diagnosis of cervical neoplasia requires biopsy of the cervix.

The definitive diagnosis of cervical neoplasia requires biopsy of the cervix. In some of the preinvasive lesions diagnosis and therapy can be combined as a cone biopsy.

Staging (FIGO)

FIGO (International Federation of Gynaecologists and Obstetricians) is designed as a clinical staging system with the minimum of special investigations. Analysis of subgroups, for example barrel (>4 cm) cervix within Stage I, or the presence or absence of ureteric involvement within Stage III, may provide additional prognostic information but the basic classification system has nevertheless proved very valuable for clinical use.

The staging may be summarized as follows :

0 Carcinoma in situ
     I. Cervical carcinoma confined to the cervix. Pre-clinical invasive carcinoma diagnosed by microscopy only

lA.l.    Minimal microscopic stromal invasion <3 mm in depth; <7 mm in width

IA.2.  Tumor with invasive component 5 mm or less in depth taken from the base of the epithelium and 7mm or less in horizontal spread

I.B. Tumor larger than IA2. Confined to the cervix

II. Cervical carcinoma invades beyond uterus but not pelvic wall or the lower third of the Vagina.

II.A. Without parametrial invasion. [Up to upper 2/3 of the vagina]
II.B. With parametrial invasion

III. Cervical carcinoma extends to the pelvic wall or involves lower third of vagina or causes hydronephrosis or non functioning kidney.

III.A. Tumor involves lower third of the vagina with no extension to pelvic walls
III.B. Tumor extends to pelvic wall or causes hydronephrosis or non functioning kidney unless known to be due to other cause
IV.A. Tumor invades mucosa of bladder or rectum or extends beyond true pelvis
IV.B. Distant metastasis

Diagnosis and management of cervical intra-epithelial neoplasia (CIN)
Screening programs for cervical neoplasm are expected, given adequate facilities for treatment, to reduce both the incidence and mortality rates. It has been demonstrated that HIV positive women have an increased rate of abnormal cytology including inflammatory changes. Initial accurate diagnosis can therefore be difficult. Therapeutic results for CIN in HIV infected patients are less predictable than those in HIV negative women. Fruchter et al [7] compared a group of 127 HIV positive women who underwent standard treatment for CIN with a group of 193 HIV negative patients. Three years after treatment, 62% of the HIV positive women, but only 18% of the HIV negative women, had developed recurrent CIN. The degree of immunosuppression, assessed as decreased CD4 count, correlated with the development of recurrent disease.

The optimal screening strategy for HIV positive women in the developed world is, after two negative smears six months apart, to screen using annual smears. This is, however, an expensive strategy. The management of established CIN is surgical. The precise techniques will depend upon local expertise and resources. Complications, however, are significantly more frequent in HIV positive patients [8].

Diagnosis and management of invasive cervical cancer in HIV negative women
The standard approaches to the management of invasive cervical cancer in HIV negative women may be summarised as follows:

Stage IA
Local surgery is the preferred management. Limited procedures include: conisation; excision! destruction of whole transformation zone by diathermy loop or electrocautery; cryocautery; cold-coagulation; laser ablation. (prior colposcopy mandatory). Alternatively, simple hysterectomy or radiotherapy is as effective as surgery and, where surgical expertise is not available, is a satisfactory alternative. Brachytherapy alone to a dose of 60 Gy to point A in a single low dose rate application is sufficient to control the cancer.

Stages IB and IIA
The results of treatment with radical surgery (Wertheim’s hysterectomy) are comparable to those of radical radiotherapy (45-50 Gy / 22-25 Fraction / 5 weeks with external beam therapy and intracavitary treatment to the LDR equivalent of 25-30 Gy to point ‘A’) and the initial decision should be based on available local expertise.

Stages lIB, IlIA and IlIB
Although these patients have moderately advanced disease, they can still be controlled. The usual approach is to treat these patients solely with radiotherapy. However, after the NCI alert, combined approaches, integrating radiotherapy and concurrent chemotherapy have been considered as a standard treatment.

Radiotherapy
Radiotherapy : 45-50 Gy in 22-25 fractions over 5 weeks with external beam therapy and intracavitary treatment to the LDR equivalent of 25-30 Gy to point ‘A’ given before or after the end of external beam therapy.

Stage IV (Palliative radiotherapy)
Palliative treatment is all that can be offered and there is nothing to be gained from the use of protracted treatment schedules. Various palliative schedules have been recommended. Single fractions of 10 Gy four weekly will often relieve pain and bleeding and can be repeated to a total of three fractions (30 Gy in 3 fractions) [9]. Weekly fractions of. e.g. 3 Gy once per week for 4 fractions, then a 3-week gap, then 3 Gy once per week for 4 fractions (24 Gy in 8 fractions in 9 weeks) have been recommended in IAEA TECDOC 2001. Another schedule tested by the Radiation Therapy Oncology Group consisted of 3.7-Gy fractions given twice a day for 2 days (14.8 Gy) repeated after 2-4 weeks for a maximum of 44.4 Gy. The late toxicity was significantly lower (7%-actuarial), therefore for patients who may survive 6 months or longer, this second schedule is preferable.

Invasive cervical carcinoma in women with low CD4 counts, as opposed to simply HIV positive women, present with more advanced tumors [10]. There is no evidence that invasive cancer follows a more aggressive clinical course, recurrence rates are higher nor that survival is shorter. Treatment strategies for HIV positive women must take into account and be modified according to both the degree of immunodeficiency and the stage of the cancer.

Patient with intact immune system : CD4 >200
There is no evidence that customary management need be changed in patients with patients with essentially intact immune systems. The use of anti-retrovirals and prophylaxis against opportunistic infections should be continued during this period.

Patients with moderate immune impairment : CD4 count 50 to 200 A standard management approach is advocated but be the physician should be alert to early signs of intolerance to radiotherapy and the possibility of developing infection. Care should be exercised in minimizing the field sizes. The trimming of comers in the pelvic fields, even if not usually practiced, may be advantageous in these patients. The use of antiretroviral and prophylaxis against opportunistic infections should be continued during this period.

Patients with severe immune impairment : CD4 <50
These severely immune-compromised patients should receive palliative radiotherapy.

Outcome and prognosis
For patients with early stage disease and profound immunosuppression, the HIV infection, rather than the tumor will dictate prognosis. Conversely, for patients who present with advanced cervical cancer, but with normal CD4 counts, the outlook will be dominated by the progress of the tumor. Most patients will lie somewhere between these two extremes and it is, consequently, not possible to be dogmatic about outcome. An infinite number of permutations are possible. The essential rule is to make decisions based on the management of the patient as a whole, rather than simply looking at the tumor or at the HIV infection. The presence of a positive HIV test should not exclude a woman from having adequate management for her cervix cancer, nor should a diagnosis of cancer of the cervix necessarily compromise the management of a woman’s HIV infection. Survival rates for HIV positive women with cervical cancer have not been specifically reported. It is evident the survival with HIV negative carcinoma cervix is good and therefore all patients with HIV positive should not be treated with palliative intent.

Enhanced mucosal reactions in AIDS patients receiving radiotherapy in oropharyngeal cancer and Kaposi’s sarcoma have been reported. This increased radiosensitivity has been attributed to inherent cellular radiosensitivity and glutathione deficiency. A retrospective analysis of 42 patients of invasive cervical cancer treated with radiotherapy alone at Tata Memorial Hospital reported Grade III–IV acute gastrointestinal toxicity in 14% of the patients, and grade III acute skin toxicity in 27% of patients, leading to treatment delays and poor compliance to treatment [11]. Therefore attention should be given to improve compliance and reduce the normal tissue toxicity by planning radiation excluding as much as normal tissues and judicious use of radiation in these patients.

Future developments and studies
There is a need to establish the effect of radical radiotherapy on the immune system of an HIV infected patient with cervical carcinoma. This can be done by monitoring the levels of CD4 cell count before and after therapy and also on 3-month follow-up.
A multicenter study initiated by IAEA to develop more effective and less toxic radiation therapy for cancer of the Uterine Cervix in HIV/AIDS patients has been undergoing to answer tolerance of these patients to radiotherapy. The seropositive patients of invasive cervical cancers stage IB to IIIB are being randomized to either radiotherapy alone or radiotherapy combined with chemotherapy.

There is also a need to look into the use of retinoids and 5-Fluorouracil creams in HIV infected patients. These topical agents have been found to offer high cure rates in the treatment of CIN in HIV negative patients.

ABSTRACTS
1. Intra-epithelial and invasive cervical neoplasia during HIV infection. M. Boccalon, U. Tirelli, F. Sopracordevole and E. Vaccher. Eur. J. Cancer, 32A:2212-17 (1996).

Patients affected by human immunodeficiency virus (HIV) infection present an elevated risk of developing cancer. In the last 10 years, the relationship between human papilloma virus (HPV) infection and female cervical intra-epithelial neoplasia (CIN) has been established. Several studies have described an increased prevalence of both cervical HPV infection and CIN among HIV-positive women compared to HIV-negative ones. A high recurrence rate of CIN after standard treatment has been noted in HIV-infected women and the severity of these lesions seems to be inversely correlated to immune function. Taking into account these data, the Centers for Disease Control (CDC) since 1993 have included invasive cervical carcinoma among the AIDS-defining conditions. Once cervical cancer develops in HIV-positive women, the disease may be aggressive and less responsive to treatment. A primary means by which HIV infection may influence the pathogenesis of HPV-associated cervical pathology is by molecular interaction between HIV and HPV genes. Although these have not been well defined, an upregulation of HPV E6 and E7 genes expression by HIV proteins (such as tat) has been postulated by some authors. Cervical cytology appears to be adequate as a screening tool for the cervical intra-epithelial neoplasia in HIV-positive women, but the high recurrence rate and multifocality of this disease reinforces the need for careful evaluation and follow-up of the entire anogenital tract in these women. Probably in the next few years, cervical tumours will represent one of the most frequent complications of HIV infection, a part of progression through AIDS. This points to a need for greater interdisciplinary co-operation for a best disease definition and for the development of effective prevention measures.

2. Cervical intraepithelial changes & HIV infection in women attending sexually transmitted disease clinics in Pune. Joshi S, Chandorkar A, Krishnan G, Walimbe A, Gangakhedkar R, Risbud A, Jadhav V, Bollinger R, Mehendale S. National AIDS Research Institute (ICMR), Pune, India. Indian J Med Res. 2001 May;113:161-9

BACKGROUND & OBJECTIVES: Cervical cancer is the most important cause of malignancy associated deaths among women in India. Western studies have reported higher risk of abnormal Pap smears in HIV infected women. A large burden of HIV infection and increasing HIV epidemic in women. A large burden of HIV infection and increasing HIV epidemic in India threatens to exacerbate incidence of cervical cancer. The objective of this study was to assess the frequency of Pap smear abnormalities and its association with HIV infection in women attending sexually transmitted disease (STD) clinics and to identify associated risk factors. METHODS: Between June 1996 and September 1999, women attending two STD clinics in Pune were screened for HIV infection, offered STD laboratory diagnosis and treatment and their Pap smears were evaluated. RESULTS: Squamous cell abnormality was detected in 10 per cent of HIV sero negative women attending STD clinics. This proportion was nearly double (19.2%) (Odds ratio = 2.14, 95% C.I. 1.03-4.48, P = 0.04) in HIV seropositive women. Having more than one life time partners and presence of STDs were also significantly associated with Pap smear abnormality in univariate analysis. In multivariate analysis, women presenting with STD and HIV infection both, were 2.8 times more likely to have inflammatory Pap smear and 3.5 times more likely to have abnormal Pap smear compared to HIV seronegative women presenting without STDs.

INTERPRETATION & CONCLUSION: Pap smear abnormalities were common in women attending STD clinics in Pune. Presence of HIV infection further increased the risk two-folds. Therefore, women suffering from STDs should undergo periodic Pap smear screening for early detection of cervical abnormalities and should receive appropriate management to reduce morbidity and mortality.

3. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, Wright TC Jr. Division of HIV/AIDS Prevention, Surveillance, and Epidemiology, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA. JAMA. 2000 Feb 23;283(8):1031-7

CONTEXT: Women infected with human immunodeficiency virus (HIV) are at increased risk for cervical squamous intraepithelial lesions (SILs), the precursors to invasive cervical cancer. However, little is known about the causes of this association. OBJECTIVES: To compare the incidence of SILs in HIV-infected vs uninfected women and to determine the role of risk factors in the pathogenesis of such lesions. DESIGN: Prospective cohort study conducted from October 1,1991, to June 30, 1996. SETTING: Urban clinics for sexually transmitted diseases, HIV infection, and methadone maintenance. PARTICIPANTS: A total of 328 HIV-infected and 325 uninfected women with no evidence of SILs by Papanicolaou test or colposcopy at study entry. MAIN OUTCOME MEASURE: Incident SILs confirmed by biopsy, compared by HIV status and risk factors. RESULTS: During about 30 months of follow-up, 67 (20%) HIV-infected and 16 (5%) uninfected women developed a SIL (incidence of 8.3 and 1.8 cases per 100 person-years in sociodemographically similar infected and uninfected women, respectively [P<.001]). Of incident SILs, 91% were low grade in HIV-infected women vs 75% in uninfected women. No invasive cervical cancers were identified. By multivariate analysis, significant risk factors for incident SILs were HIV infection (relative risk [RR], 3.2; 95% confidence interval [CI], 1.7-6.1), transient human papillomavirus (HPV) DNA detection (RR, 5.5; 95% CI, 1.4-21.9), persistent HPV DNA types other than 16 or 18 (RR, 7.6; 95% CI, 1.9-30.3), persistent HPV DNA types 16 and 18 (RR, 11.6; 95% CI, 2.7-50.7), and younger age (<37.5 years; RR, 2.1; 95% CI, 1.3-3.4). CONCLUSIONS: In our study, 1 in 5 HIV-infected women with no evidence of cervical disease developed biopsy-confirmed SILs within 3 years, highlighting the importance of cervical cancer screening programs in this population.

4. Squamous intraepithelial lesions of the cervix, invasive cervical carcinoma, and immunosuppression induced by human immunodeficiency virus in Africa. La Ruche G, Ramon R, Mensah-Ado I, Bergeron C, Diomande M, Sylla-Koko F, Ehouman A, Toure-Coulibaly K, Welffens-Ekra C, Dabis F. Dyscer-CI Group. Cancer 82:2401-8(1998)

BACKGROUND: Squamous intraepithelial lesions (SILs) of the cervix are associated with human immunodeficiency virus (HIV) infection, but multiple risk factors must be considered in this context. The authors performed a cross-sectional study to assess the prevalence of and the factors associated with SILs and invasive cervical carcinoma (ICC). METHODS: In Abidjan, Cote d’Ivoire, women were recruited from three outpatient gynecology clinics and screened for both cervical disease and HIV infection. A CD4 cell count was performed for HIV-infected women. RESULTS: A total of 2198 women were included in the study. The prevalence of HIV infection was 21.7%. Of the 2170 women who underwent a cervical screening, 254 (11.7%) presented with a dysplasia or neoplasia: 7.6% had low grade SILs (LSILs), 3.3% had high grade SILs (HSILs), and 0.8% had ICCs. In multivariate analyses, factors associated with these lesions were as follows: for LSILs, HIV-1 seropositivity, age <24 years, parity >1, consultation for genital infection, and no use of oral contraception in the past; for HSILs, HIV-1 seropositivity, chewing tobacco use, low educational level, and parity >1; and for ICCs, age >33 years, parity >3, and illiteracy. In women infected with HIV-1, the prevalence of LSILs increased with a decrease in CD4 cell count, whereas this relation was not found among patients with HSILs. ICCs were linked to HIV-2 infection, but not to HIV-1 infection, in univariate analysis. CONCLUSIONS: In Africa, the prevalence of SILs is high. The factors associated with precancerous and cancerous lesions are different. Cancers in women infected with HIV-1 often may not reach the invasive stage. These findings could have implications for cervical screening programs in the future.

5. Is HIV infection a risk factor for advanced cervical cancer? Fruchter, R.G, Maiman, M., Arrastia, C.D., Matthews, R., Gates, E.J.; Holcomb. K. Department of Obstetrics and Gynecology, State University of New York–Health Science Center at Brooklyn, 11203, USA. J. Acquired Immune Deficiency Syndromes and Human Retrovirology. 18:3 (1988).

OBJECTIVES: To compare HIV-infected and HIV-negative women with invasive cervical cancer with respect to predictors of advanced disease. METHODS: A retrospective analysis of 28 HIV-positive and 132 HIV-negative women with invasive cervical carcinoma was conducted and the two groups were compared with regard to stage of disease, demographic and behavioral variables, and risk factors for advanced disease. RESULTS: Overall, HIV-infected women were more likely to have advanced disease, because 78% of HIV-positive women had Stage II to IV compared with 55% of HIV-negative women (odds ratio [OR] = 3.1; p = .03). Substance abuse was strongly associated with HIV infection, as were high-risk sexual variables. Although HIV infection was associated with a threefold increase in advance stage cervical cancer in a univariate analysis, only symptom duration and lack of a recent Papanicolaou smear were significant predictors of advanced disease in a multiple logistic regression analysis.

CONCLUSIONS: The major predictors of advanced cervical cancer are similar in HIV-positive and HIV-negative women, although the reasons for these predictors may be very different. It is likely that a large proportion of HIV-positive patients with cervical cancer acquire HIV infection after initiation of the neoplastic process.

6. Prevalence, risk factors, and accuracy of cytologic screening for cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Maiman M, Fruchter RG, Sedlis A, Feldman J, Chen P, Burk RD, Minkoff H. Department of Obstetrics and Gynecology, State University of New York-Health Science Center at Brooklyn 11203, USA. Gynecol Oncol. 1998 Mar;68(3):233-9.

OBJECTIVES: The objective was to evaluate the sensitivity and specificity of cervical cytology in women infected with the human immunodeficiency virus (HIV), risk factors for abnormal cytology in HIV-infected and uninfected women, and risk factors for histologic diagnosis of cervical intraepithelial neoplasia (CIN) in HIV-infected women. METHODS: Methods included a cross-sectional analysis of cervical cytology, colposcopic impression, and histology in 248 HIV-infected women and multivariate analyses of risk factors for abnormal cytology in 253 HIV-infected and 220 uninfected women and risk factors for CIN in 186 HIV-infected women. RESULTS: The sensitivity and specificity of cytology for all CIN grades were 0.60 and 0.80 and, for high-grade CIN, 0.83 and 0.74. The prevalence of abnormal cytology was 32.9% in HIV-infected and 7.6% in HIV-negative women. Independent risk factors for abnormal cytology were immunodeficiency [odds ratio (OR) 8-17, P < 0.001] and human papillomavirus (HPV) infection (OR = 5, P < 0.001). The prevalence of CIN on histology was 32% in HIV-infected women, and the only independent risk factor for CIN was oncogenic HPV type (OR = 5, P = 0.005). CONCLUSION: Given the high prevalence of abnormal cytology and CIN in HIV-infected women, cytologic screening has significant limitations. Both immunodeficiency and type of HPV infection are important risk factors.

7. Multiple recurrences of cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Fruchter RG, Maiman M, Sedlis A, Bartley L, Camilien L, Arrastia CD. Department of Obstetrics and Gynecology, State University of New York-Health Science Center at Brooklyn, Brooklyn, NY, USA. Obstet Gynecol. 1996 Mar;87 (3):338-44.

OBJECTIVE: To evaluate the long-term outcomes after treatment of cervical intraepithelial neoplasia (CIN) in women infected with the human immunodeficiency virus (HIV). METHODS: Human immunodeficiency virus-infected and HIV-negative women treated for CIN by ablation or excision were followed-up prospectively by cytology and colposcopy for periods of up to 73 months. RESULTS: Among 127 HIV-infected CIN patients, 62% developed recurrent CIN by 36 months after treatment, compared with 18% of the 193 HIV-negative CIN patients. Recurrence rates reached 87% in 41 HIV-infected women with CD4 counts less than 200 cells/mm3. Progression to higher-grade neoplasia, including one invasive cancer, occurred by 36 months in 25% of HIV-infected and 2% of HIV-negative women. After adjusting for age, CIN severity, and treatment type, predictors of recurrence included HIV infection (rate ratio 4.4), and, in HIV-positive women, low CD4 count (rate ratio 2.2). In patients treated by excision, predictors of recurrence included HIV infection (rate ratio 2.0) and residual CIN after treatment (rate ratio 2.7). After a second treatment,a second CIN recurrence developed in 14 of 33 HIV-infected and in one of 17 HIV-negative women. After a third treatment, three of six HIV-infected women developed a third recurrence. With long-term follow-up, 45% of treated HIV-infected CIN patients had chronic condylomatous changes in the cervix compared with 5% of HIV-negative women. CONCLUSION: In HIV-infected women, CIN may recur despite multiple treatments, and chronic condylomatous changes are common. Innovative therapies for controlling CIN in HIV-infected women are needed.

8. Complications after treatment of cervical intra epithelial neoplasia in women with the human immunodeficiency virus. Maiman M, Fruchter RG, Lopatinsky I, Cheng CC. Department of Obstetrics and Gynecology, State University of New York, Brooklyn, NY 11203, USA. J. Reprod. Med. 40: 823-828 (1995).

OBJECTIVE: To compare the frequency of complications after treatment of cervical intraepithelial neoplasia (CIN) in human immunodeficiency virus (HIV)-infected and -seronegative women in an ambulatory setting. STUDY DESIGN: A retrospective record review of 15 HIV-infected and 44 HIV-negative women treated by laser therapy or cone biopsy and retrospective interviews of 20 HIV-infected and 44 HIV-negative women treated by cryotherapy. RESULTS: Four of 35 (11%) HIV-infected women had excessive bleeding after laser/cone or cryotherapy as compared to one of 88 (1%) HIV-negative women (odds ratio 11.27, P = .02). After laser/cone therapy, significantly more HIV-infected women (53%) had cervicovaginal infections than did HIV-negative women (18%). A higher prevalence of infection was associated with more severe immunodeficiency. CONCLUSION: HIV-infected women are vulnerable to complications after treatment of CIN and should be monitored closely.

9. Radiation palliation of cervical cancer. Spanos WJ Jr, Pajak TJ, Emami B, Rubin P, Cooper JS, Russell AH, Cox JD. Department of Radiation Oncology, University of Louisville School of Medicine, KY 40202, USA. J Natl Cancer Inst Monogr. 1996;(21):127-30.

Radiation is a useful modality for palliation of local-regional disease in patients with cervical cancer who require palliation because of distant metastases, extensive local-regional disease, medical consideration, or patient concerns. Two radiation schedules have been reported on for the treatment of advanced pelvic disease including cervical cancer. The large single-dose schedule consisted of 10-Gy fractions repeated at monthly intervals to a maximum of 30 Gy. This schedule has produced good palliative results with symptomatic improvement in approximately 50% of patients and objective response in 35%-80%. However, severe late toxicity was shown to be as high as 42% (actuarial). The second schedule tested by the Radiation Therapy Oncology Group consisted of 3.7-Gy fractions given twice a day for 2 days (14.8 Gy) repeated after 2-4 weeks for a maximum of 44.4 Gy. There were 284 patients accrued, and the subgroup of 61 cervical cancer patients is analyzed in this article. The subjective response (50%-100% complete response) and objective response (53%) were similar to those observed with the large single-fraction schedule. The late toxicity was significantly lower (7%-actuarial). For patients who may survive 6 months or longer, this second schedule is preferable.
10. Human immunodeficiency virus infection and invasive cervical cancer in South Africa. Lomalisa P, Smith T, Guidozzi F. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Johannesburg Hospital and University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa. Gynecol Oncol. 2000 Jun;77(3):460-3.

PURPOSE: The goal of this study was to determine whether South African HIV-seropositive women with invasive cervical cancer present with disease that is more advanced than that of HIV-seronegative women and whether degree of immunosuppression affects the extent of disease at initial presentation. METHODS: This study is a retrospective review of 60 HIV-seropositive and 776 HIV-seronegative new cases of invasive cervical carcinoma seen at the combined gynecologic oncology unit of the University of the Witwatersrand, Johannesburg, South Africa. RESULTS: The HIV seroprevalence was 7.2%. Squamous cell carcinoma was the histologic subtype in more than 90% of both cohorts of patients. Although the HIV-positive patients presented with invasive cervical cancer almost 10 years earlier than the HIV-presented with invasive cervical cancer almost 10 years earlier than the HIV-negative patients, i.e., mean age 44 years +/- 9.8 versus 53 years +/- 12.7, respectively (P </= 0.001), there was no difference in the distribution of advanced lesions in the two groups, i.e., 65% in HIV-positive and 55.4% in HIV-negative patients (P = 0.177). At initial diagnosis 26 of the HIV-seropositive patients had a CD(4) cell count less than 200/mm(3), 20 (77%) of whom presented with stage III or IV cervical cancer; the remaining 34 had a CD(4) cell count above 200/mm(3), 19 (56%) of whom had advanced-stage disease. This was not significantly different (P = 0.109). However, HIV-seropositive patients with CD(4) cell counts less than 200/mm(3) had significantly more advanced-stage disease than HIV-seronegative patients, i.e., 77% versus 55.8% respectively (P = 0.041).

CONCLUSION: HIV-seropositive patients presented with invasive cervical cancer almost 10 years earlier than HIV-seronegative patients. Even though HIV seropositivity on its own did not appear to adversely affect extent of disease at presentation, patients with CD(4) cell counts below 200/mm(3) are significantly more likely to have advanced-stage disease at initial diagnosis than HIV-negative patients.

11. HIV infection and invasive cervical cancers, treatment with radiation therapy: toxicity and outcome. Shyam Kishore Shrivastava, Reena Engineer, Sunil Rajadhyaksha, Ketayun A. Dinshaw. Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai 400012, India. Radiotherapy and Oncology 74 (2005) 31–35

Background and purpose: To determine the effect of radiotherapy in HIV seropositive cervical cancer patients, tumour response and toxicity and compliance of patients to the treatment. Patients and methods: This study is a retrospective review of 42 HIV seropositive patients diagnosed with carcinoma cervix, between 1997 and 2003 at the Tata Memorial Hospital. The age and symptoms of presentation, clinical stage, response, compliance and tolerance to radiotherapy were studied. Results: Mean age at presentation was 41 years. All patients presented with the symptoms of cervical disease. Of these patients 31(74%) patients had ‘Karnofsky Performance Scale’ (KPS) more than 80%. Twenty-one (50%) of the patients were of Stage IIIb–IVa. Thirty-two (76%) were started on radiotherapy with radical intent. Compliance to radiotherapy was poor with 24% patients discontinuing after few fractions of radiotherapy. Seven (17%) patients were given palliative radiotherapy. Twenty-two patients completed prescribed radical radiotherapy and 50% of these achieved complete response. Grade III–IV acute gastrointestinal toxicity was seen in 14% of the patients, and grade III acute skin toxicity was seen in 27% of patients, leading to treatment delays. There was good relief of symptoms in patients treated with palliative intent. Conclusions: Radiotherapy is effective in this set of patients. Palliative fractionation schedules are effective for patients with poor performance status and locally advanced cancers in relieving the symptoms related to carcinoma cervix. An emphasis should be given to the increased acute mucosal and skin toxicity and to improving compliance and clinical outcome of these patients.