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Oncology treatment outcome in human immunodeficiency virus-positive cancer cervix patients: Where we are and what we achieved?


1 Department of Radiation Oncology, RMC & PRH, PMTPIMS, Loni, India
2 Department of Medical Statistics, PRH, PMTPIMS, Loni, India

Date of Submission26-Feb-2020
Date of Decision07-May-2020
Date of Acceptance12-Aug-2020
Date of Web Publication20-Aug-2021

Correspondence Address:
Chaitali Manohar Waghmare,
Department of radiation oncology, PRH & RMC, PMTPIMS-DU, Loni, Taluka-Rahata, Dist-Ahmadnagar, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_230_20

 > Abstract 


Objective: To find out the epidemiological factors and oncology treatment outcome in human immunodeficiency virus-positive cancer cervix patients (HPCCP).
Materials and Methods: After institutional ethics committee approval, hospital case records of HPCCP registered at the radiation oncology department from January 2011 to December 2018 were retrospectively studied.
Results: The case records of 22 eligible HPCCP were studied. Median age at presentation was 42.5 years. 90.90% of the patients were below 55 years of age. The duration of symptom was <3 months in 63.64% of patients. 68.18% of the patients were FIGO Stage III. Only 11 patients completed the planned treatment. Total target equivalent dose of 2 Gy per fraction delivered was 66 Gy. Seven patients had complete response. Four patients had local recurrence. Median disease-free and overall survival was 27 (14–38) and 18 months (2–48), respectively.
Conclusion: HPCCP present at relatively early age and advanced stage despite short symptom duration. Poor patient compliance and treatment alteration have led to suboptimal outcome.

Keywords: Cancer cervix, human immunodeficiency virus, radiation therapy



How to cite this URL:
Waghmare CM, Bhanu A, Dwivedi S, Pawar HJ, Ravichandran M, Jain VS. Oncology treatment outcome in human immunodeficiency virus-positive cancer cervix patients: Where we are and what we achieved?. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=324163




 > Introduction Top


India has the third highest number of human immunodeficiency virus (HIV)-infected people after South Africa and Nigeria.[1] Because of successful implementation of national acquired immunodeficiency syndrome (AIDS) Control Program Phase IV (2012–2017), the rate of new HIV infection has decreased. Simultaneously, due to rapid expansion of access and improvements in antiretroviral therapy (ART), AIDS-related deaths have decreased. Even though the incidence of HIV infection in India is less, due to large population, the estimated population living with HIV/AIDS is more. It was 2.1 million in 2017.[2]

In 1993, cancer cervix was declared as an AIDS defining malignancy.[3] Cervix is the second most common site of cancer in Indian females.[4] Both cancer cervix and HIV infection increase the morbidity.[5] Majority of the HIV-positive cancer cervix patients (HPCCP) present at locally advanced stage.[6] Radiation therapy (RT) is the mainstay of treatment in locally advanced cancer cervix. Radical RT with equivalent dose of 2 Gy per fraction (EQD2) of 80 Gy to point A[7] and concurrent chemotherapy (CT) using cisplatin is standard of care in locally advanced nonmetastatic cancer cervix.[8] Delivering this standard treatment in HPCCP is a challenge. Majority of the literature on treatment outcome in HPCCP is from the African continent.[9],[10] Large multicenter prospective treatment trials are lacking in HPCCP.

Considering the high burden of HIV infection and cancer cervix in Indian females, there is need to formulate specific treatment guidelines to treat HPCCP. This study was undertaken to find out different epidemiological factors, present pattern of oncology care, and oncology treatment outcome in HPCCP at length. This will be of help as a future guide for an alternation in pattern of care, if any, while treating HPCCP and will add on to the existing knowledge of cancer care in HPCCP.


 > Materials And Methods Top


After receiving an approval from the institutional ethics committee, hospital case records of HPCCP registered at the radiation oncology department from January 2011 to December 2018 were retrospectively studied. Demographic profile, disease details, and treatment record were filled in the patient record form. An updated 2018 FIGO staging was used[11] to stage the patients from clinical and radiological data available in the case record files. The toxicity grading was done according to the Common Terminology Criteria for Adverse Events (CTCAE-v 5,)[12] and response evaluation was done according to the Response Evaluation Criteria for Solid Tumors-v1.1.[13] The clinical, laboratory, and radiological details available in the case record were used for the same. Statistical analysis was done using Graph-Pad, Instat-3 software (California Inc).


 > Results Top


Out of 1661 cancer cervix patients registered in the radiation oncology department from January 2011 to December 2018, 22 (1.32%) patients were HIV positive. The case records of these 22 eligible patients were studied. The median age at presentation was 42.5 years, and 90.90% of patients were below the age of 55 years. Seven patients were newly diagnosed as HIV positive during the routine evaluation for cancer cervix and were started on ART before starting cancer therapy, while 15 patients were already on ART at the time of diagnosis of cancer cervix. Duration of symptoms suggestive of cancer cervix was <3 months in 63.64% of the patients. The characteristics of the study group are described in [Table 1].
Table 1: Characteristics of study group (n=22)

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Two patients reported to our institute after hysterectomy with preoperative clinical details suggestive of FIGO Stage IB2 disease, and histopathology report suggested intermediate-risk group. One patient had liver metastasis at presentation. The disease was of locally advanced stage in 86.36% of the patients. The disease parameters are described in [Table 2]. The correlation between duration of symptoms and the stage was assessed using Chi-square test (χ2), which showed no statistically significant correlation (χ2 = 1.591, P = 0.8102) [Table 3].
Table 2: Disease characteristics (n=22)

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Table 3: Relation between duration of symptoms and stage of disease

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Out of 22 registered HPCCP, seven patients did not take any treatment. Two patients who reported after surgery were planned for adjuvant chemoradiotherapy (CTRT). One patient received neoadjuvant CT followed by CTRT. One patient was treated with radical RT alone. Ten patients were treated with radical CTRT. One patient with Stage IVB was planned for palliative RT followed by palliative CT. Of 14 patients who were planned for radical treatment, 11 patients completed the planned treatment. As per the departmental protocol for HPCCP, RT was delivered to whole pelvis with external-beam RT (EBRT) to a dose of 50 Gy in 25 fractions (five fractions a week) followed by EBRT boost to primary disease to a dose of 16 Gy in eight fractions (five fractions a week) using three-dimensional conformal radiotherapy (3-DCRT) technique. None of the patients received brachytherapy boost. The concurrent CT used was injection cisplatin 40 mg/m2 in seven patients and 30 mg/m2 in three patients. Only five patients completed the five cycles of planned concurrent CT. Three patients could not complete the treatment because of Grade III–IV hemoglobin (Hb) and Grade II–III white blood cell (WBC) count toxicities according to the CTCAE v 5.0. Among these three patients who could not complete radical treatment, two patients were newly diagnosed with HIV infection and were started on ART. Eleven patients completed the radical treatment with a RT gap of 8–20 days in five patients. Grade II–III hematological (Hb and WBC), skin, and mucosal toxicities were 54.54%, 63.64%, and 72.73%, respectively, in 11 patients who completed radical or adjuvant CTRT/RT alone.

Response to treatment in radically treated patients is described in [Table 4]. Two patients who had progressive disease and one patient who had partial response were planned for further palliative CT but two of them defaulted for further treatment. One patient with partial response was treated with three cycles of palliative CT but because of grade III Hb and WBC toxicities, she was advised best supportive care. Out of seven patients who had complete response (CR), four patients had local recurrence at median disease-free survival of 27 months (minimum 14–maximum 38 months), two patients were alive without disease, and one patient died because of pneumocystis carinii pneumonia. The median overall survival was 18 months (minimum 2–maximum 48 months) for all patients who completed planned radical treatment. The status at the time of last hospital/follow up visit for all 22 patients is described in [Table 5].
Table 4: Treatment response according to the Response Evaluation Criteria for Solid Tumors 1.1 (n=11)

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Table 5: Status at last follow-up (n=22)

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 > Discussion Top


Improvements in ART have led to the improved survival of HIV-positive patients. Hence, there is need to improve survival and cancer cure in HIV-positive cancer patients. The first report of association of cancer cervix and HIV infection dates back to 1983.[14] Since then, there have been many advances in ART and cancer cervix treatment. Despite this, the recently reported 5-year survival in HPCCP is poor as compared to HIV-negative cancer cervix patients,[9] objecting to the standard of cancer care provided to HPCCP.

HPCCP present at an early age and advanced stage of disease.[9],[10],[15],[16] Majority of our patients (90.90%) were below the age of 55 years and 86.36% patients were of the locally advanced stage. We found no significant association between duration of symptoms and stage of disease although majority of patients (63.64%) presented with short duration of cancer related symptoms. This could be because of a small sample size.

The CTRT is the standard of care in locally advanced carcinoma cervix.[8] According to the Indian Council for Medical Research guidelines for cancer cervix, the cervical cancer in HIV-positive patients should be treated same as in HIV-negative patients, except for the CT which is to be tailored as per the performance and immune status of the patient.[17] The only Indian study published in the literature on treatment outcome in HPCCP states that concurrent CT with RT should be avoided if CD4 counts are below 200.[16] Our group of patients received concurrent cisplatin to a dose of 30–40 mg/m2. However, only 50% of the patients had tolerated and completed all planned five cycles of CT. The recommended radical RT dose is 80 Gy EQD2 to point A.[7] All our patients received the RT dose of 66 Gy EQD2 to point A. All patients received 3-DCRT boost to primary disease. The Grade II–III hematological toxicities were 54.54% in our study. Simonds et al. had shown significant difference in hematological toxicities in HPCCP versus HIV-negative cancer cervix patients treated with CTRT,[10] while other authors have shown no difference[18],[19] in hematological toxicities.

Only 50% of our patients completed the planned treatment and 63.63% achieved CR. Shrivastava et al. had reported a 50% treatment compliance rate with 50% CR.[16] The documented response to oncology treatment is poor in HPCCP as compared to HIV-negative patients.[18],[20],[21] The poor treatment outcome in HPCCP can be because of inadequate treatment due to factors associated with patient's HIV management or physician bias.[22] Simonds et al. had found significant difference in the brachytherapy dose, CT cycles, and the number of blood transfusions received in HIV-positive versus HIV-negative patients.[9] The treatment response was correlated with pre-treatment CD-4 count in anal cancers.[23] However, there are no such studies in HPCCP.

The major limitation of this study is that it was a retrospective study. The record of CD4 count was not available for most of the patients. The total EQD2 delivered was less than the standard recommended dose. The brachytherapy was not given due to institutional constraints. All patients received EBRT boost to primary disease.


 > Conclusion Top


HPCCP present at relatively early age and advanced stage despite a short symptom duration. Poor patient compliance has led to a suboptimal outcome. Treatment alterations based on the patient's HIV status add on to the morbidity. Future multicenter studies are needed to formulate the guidelines to treat HPCCP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
HIV AIDS in India. Available from: https://www.avert.org. [Last accessed on 2019 Oct24].  Back to cited text no. 1
    
2.
National AIDS Control Organization. Annual Report 2016-2017. Ch. 24. p. 339. Available from: https://www.naco.gov.in/sites/default/files/Naco%20ANNUAL%20REPORT%202016-17.pdf. [Last accessed on 2019 Oct 24].  Back to cited text no. 2
    
3.
Castro KG, Ward JW, Slutsker L, Buehler JW, Jaffe HW, Berkelman RL. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992:41:1-19.  Back to cited text no. 3
    
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Globocan 2018: India factsheet. India against cancer. Available from: http://cancerindia.org.in/globocan-2018-factsheet. [Last accessed on 2020 Jan 13].  Back to cited text no. 4
    
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Sahasrabuddhe V, Makhija S. Double jeopardy: HIV and cervical cancer in Indian women. Int J Gynecol Cancer 2005;15:1-3.  Back to cited text no. 5
    
6.
Miaman M, Pruchter RG, Serur E, Remy JC, Feuer G, Boyee J. Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol 1990;3893:377-82.  Back to cited text no. 6
    
7.
Viswanathan AN, Beriwal S, De Los Santos JF, Demanes DJ, Gaffney D, Hansen J, et al. American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: High-dose-rate brachytherapy. Brachytherapy 2012;11:47-52.  Back to cited text no. 7
    
8.
Green J, Kirwan J, Tierney J, Vale C, Symonnds P, Fresco L, et al. Concomitant chemotherapy and radiation therapy for cancer of uterine cervix. Cochrane Database Syst Rev 2005;20:CD002225.  Back to cited text no. 8
    
9.
Simonds HM, Botha MH, Neugut AI, Van Der Merwe FH, Jacobson JS. Five-year overall survival following chemoradiation among HIV-positive and HIV-negative patients with locally advanced cervical carcinoma in a South African cohort. Gynecol Oncol 2018;151:215-20.  Back to cited text no. 9
    
10.
Simonds HM, Neugut AI, Jacobson JS. HIV status and acute haematological toxicity among patients with cervix cancer undergoing radical chemoradiation. Int J Gynecol Cancer 2015;25:884-90.  Back to cited text no. 10
    
11.
Bhatla N, Aoki D, Sharma DN, Sankarnarayanan R. FIGO Cancer Report-Cancer of cervix uteri. Int J Gynecol Obstet 2018;143 Suppl 2:22-36.  Back to cited text no. 11
    
12.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guidelines (version 1.1). Europ J Cancer 2009;45:228-47.  Back to cited text no. 12
    
13.
Common Terminology Criteria for Adverse Events (CTCAE version 5.0). Available from: http://evs.nci.gov>ftp1>CTCAE. [Last accessed on 2019 Sep 29].  Back to cited text no. 13
    
14.
Centers for Disease Control (CDC). Immunodeficiency among female sexual partners of males with acquired immune deficiency syndrome (AIDS)-New York. MMWR Mob Mortal Wkly Rep 1983;31:697-8.  Back to cited text no. 14
    
15.
Maiman M, Fruchter RG, Serur E, Remy JC, Feuer G, Boyce J. Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol 1990;38:377-82.  Back to cited text no. 15
    
16.
Srivastava SK, Engineer R, Rajadhyaksha S, Dinshaw KA. HIV infection and invasive cervical cancer, treatment with radiation therapy: Toxicity and outcome. Radiother Oncol 2005;74:31-5.  Back to cited text no. 16
    
17.
Special situation. Chapter 6. In – Consensus Document for Management of cancer cervix. Prepared as outcome of ICMR subcommittee on cancer cervix. In: Kaur T, Shrivastava SK, editors. Division of publication and information on behalf of Secretory DHR & DG, ICR, New Delhi. ICMR; 2016. p. 27. Available from: https://www.icmr.nic.in/sites/default/files/reports/cervix%20Cancer.pdf. [Last accessed on 2019 Nov 25].  Back to cited text no. 17
    
18.
Dryden-Peterson S, Bvochora-Nsingo M, Suneja G, Efstathiou JA, Grover S, Chiyapo S, et al. HIV Infection and survival among women with cervical cancer. J Clin Oncol 2016;34:3749-57.  Back to cited text no. 18
    
19.
Grove S, Bvochora-Nsingo M, Yeager A, Chiyapo S, Bhatia R, MacDuffie E, et al. Impact of human immunodeficienct virus infection on survival and acute toxicities from chemoradiation therapy for cervical cancer patients in a limited resource setting. Int J Radiat Oncol Biol Phys 2018;101:201.  Back to cited text no. 19
    
20.
Simonds HM, Wright JD, du Toit N, Neugut AJ, Jaconsn JS. Completion and earl response to chemoradiation among human immunodeficiency virus infection (HIV) positive and HIV negative patients with locally advanced cervical carcinoma in South Africa. Cancer 2012;118:2971-9.  Back to cited text no. 20
    
21.
Ferreria MP, Conghill AE, Chaver CB, Bergmann A, Thuler LC, Soares EA, et al. Outcome of cervical cancer among HIV infected and HIV uninfected women treated at the Brazilian National Institute of Cancer. AIDS 2017;20:1645-54.  Back to cited text no. 21
    
22.
Ghebre RG, Grover S, Xu MJ, Chuang LT, Simonds H. Cervical cancer control in HIV-infected women: Past, present and future. Gynecol Oncol Rep 2017;21:101-8.  Back to cited text no. 22
    
23.
Welton L, Klencke B, Weinberg V, Krieg R. The significance of pre treatment CD4 count on the outcome and treatment tolerance of HIV positive patients with anal cancer. Int J Radiat Oncol Biol Phys 1999;44:127-31.  Back to cited text no. 23
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

 
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