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 Table of Contents  
ORIGINAL ARTICLES
Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 141-148

Treatment outcomes of concurrent weekly cisplatin with intracavitary brachytherapy in patients with cervical carcinoma, pre-treated with concurrent chemo-radiotherapy


Department of Radiotherapy, Malda Medical College and Hospital, Malda, West Bengal 732101, India

Date of Submission02-Feb-2022
Date of Acceptance01-Apr-2022
Date of Web Publication17-Jun-2022

Correspondence Address:
Dr. Swapan K Mallick
Department of Radiotherapy, Malda Medical College and Hospital, Malda, West Bengal 732101
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_9_22

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  Abstract 

Objective: Cervical carcinoma is one of the leading causes of cancer-related deaths. This study evaluates improvement of quality of life, response to treatment, and compliance of concurrent weekly cisplatin with intracavitary brachytherapy (ICRT) in patients with cervical carcinoma, pre-treated with concurrent chemo-radiotherapy. Materials and Methods: This study was conducted in the Department of Radiotherapy, Government Medical College, from October 2018 to March 2020, meeting specified inclusion and exclusion criteria; patients willing to participate in the study were included. Results: On analyzing the pattern of response, 91.0% of patients have a complete response. The incidence of nausea and vomiting was observed at grade 1 or 2 in 80.0% of patients, grade 3 in 17.0% of patients, and more than grade 3 in 3.0% of patients. Neutropenia is occurred at less than grade 3 in 30.0% of patients and grade 3 or more in 3.3% of patients. Vaginal mucositis was also observed in 85.0% of the patients in less than grade 3 and 11.6% in grade 3 or more. The incidence of renal dysfunction less than grade 3 was seen in 35.0% of the patients and grade 3 or more in 5.0% of the patients. After 6months, there was cystitis found in less than grade 3 in 10.0% of the patients and more than grade 3 in 3.3% of the patients. Conclusion: In locally advanced squamous cell carcinoma of the uterine cervix, the addition of concurrent injection of cisplatin to ICRT significantly improves locoregional response but increases the incidence of hematological and mucosal toxicity, which is manageable.

Keywords: Cervical cancer, chemoradiation, cisplatin, external beam radiotherapy, intracavitary brachytherapy


How to cite this article:
Mallick SK, Deb AR, Nahid GK. Treatment outcomes of concurrent weekly cisplatin with intracavitary brachytherapy in patients with cervical carcinoma, pre-treated with concurrent chemo-radiotherapy. MGM J Med Sci 2022;9:141-8

How to cite this URL:
Mallick SK, Deb AR, Nahid GK. Treatment outcomes of concurrent weekly cisplatin with intracavitary brachytherapy in patients with cervical carcinoma, pre-treated with concurrent chemo-radiotherapy. MGM J Med Sci [serial online] 2022 [cited 2022 Dec 6];9:141-8. Available from: http://www.mgmjms.com/text.asp?2022/9/2/141/347694




  Introduction Top


Cervical cancer is the third most common cancers in India for both sexes. According to Globocan 2020, the number of new cases of cervical cancer in India is 123,907 (9.4%) among all ages and sexes [Figure 1]. It is also the second most common cause of death from cancer in India.[1] Patients usually present to us with stages IIB, III, and IV as per the International Federation of Gynaecology and Obstetrics (FIGO), in which concurrent chemo-radiotherapy (CCRT) plays a major role in the management.[2],[3]
Figure 1: Incidence of new cases of cervical carcinoma in India

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Factors that were mostly associated with an increased risk of cervical cancer are the early age of first intercourse, multiple sexual partners, a male partner with a history of multiple sexual partners, early age of first childbirth, a large number of pregnancies, etc. Infections causing cervical cancer such as the history of sexually transmitted diseases (STDs), including gonorrhea, chlamydia, herpes simplex virus II, human immunodeficiency virus (HIV), and/or human papilloma virus (HPV) transmission,[4],[5] are also at risk factors. In developing countries like India, most cases are locally advanced stages,[6] which are being identified. The earliest symptoms of advanced invasive cervical carcinoma are usually abnormal vaginal bleeding, following coitus, and this may be associated with clear or foul-smelling vaginal discharge. Completely asymptomatic infections are found mostly in the early stages of cervical cancer.[7],[8] Low back pain may be due to locoregionally invasive disease. Other symptoms are loss of appetite, anemia, weight loss, fatigue, leg edema, leaking of urine from the vagina when there was a vasicovaginal fistula.[9]

In the early stages, cervical carcinoma is quite radiosensitive. Radiosensitizers, such as Inj. Cisplatin, with concurrent chemoradiation are given every week, followed by intracavitary brachytherapy (ICRT), which is the standard treatment in locally advanced cervical carcinoma. The long-term outcome in locally advanced stages has constantly remained bleak due to central or peripheral failures. In an attempt to treat pelvic area,[10],[11] almost half of the locally advanced disease fails according to recently published literature. Standard treatment is external beam radiation with concurrent cisplatin chemotherapy. It is followed by brachytherapy wherever possible, which remains ideal for such cases.[12]


  Materials and methods Top


This study is a single institutional, prospective, longitudinal, randomized study. Patients attending the Radiotherapy OPD (Outpatient Department) with locally advanced cervical cancer are being considered. These patients are included in our study for the period from October 2018 to March 2020.



Sample size

60.

Method of data collection

Pre-treatment data will be collected in a case-record form with history, physical examination, detailed clinical examination including gynecological examination, radiological assessment, and laboratory investigations. Hematological and renal function parameters will be assessed weekly during the study, keeping all investigation reports and treatment records.

Definition of population

Patients suffer from histologically proven squamous cell carcinoma of the cervix in the locally advanced stage (stages IIB to IVA), attending the Outpatient Department, Department of Radiotherapy, Government Medical College and Hospital.

Inclusion criteria

  • 1. Age: 40–60 years.


  • 2. Histology: Histologically confirmed squamous cell carcinoma of the cervix.


  • 3. FIGO stages IIB to IVA.


  • 4. Performance status: ECOG 0 to 2.


  • 5. Newly diagnosed.


  • 6. Normal hematological function:
    • a. Hemoglobin >9 g/dL (patients could be transfused before treatment to achieve this level).


    • b. Total leucocyte count >4000/mm3 or ANC (absolute neutrophil count) >1500.


    • c. Platelet count >100,000/mm3.


  • 7. Patients with no systemic co-morbidities that alter treatment outcome.

  • 8. Patients who have given written informed consent are only included in our study.



Exclusion criteria

  1. Age: Below 40 years and above 60 years.


  2. Histology: Cervical cancer other than squamous cell type.


  3. Stage: Early-stage disease (stages I and IIA) and metastatic disease.


  4. Performance status: Poorer than ECOG (Eastern Cooperative Oncology Group) 2.


  5. Previously diagnosed with cervical cancer or any other pelvic cancers.


  6. Previously treated with radiation therapy or chemotherapy for this or any other cancers.


  7. Patients with systemic co-morbidities or severe uncontrolled infection may alter treatment outcomes.


  8. Pregnant or nursing women.


  9. Patients with a narrow vagina or poor pelvic geometry that precludes satisfactory intracavitary applicator placement.


Sample design

Patients will be randomized and outcomes will be prepared on an MS EXCEL Sheet.

Laboratory investigations

  • 1. Hematological:
    • a. Routine: Hemoglobin, total leucocyte count, platelet.


    • b. Renal function tests, i.e., blood urea, serum creatinine.


    • c. Liver function tests, i.e., bilirubin, alanine transaminase, aspartate transaminase (SGOT, SGPT)


    • d. Others: Fasting blood sugar, postprandial blood sugar, etc.


  • 2. Radiological:

    • a. CT (computer tomography) scan of the whole abdomen and pelvis (plain and contrast-enhanced).


    • b. Chest X-ray.


    • c. Ultrasound of the whole abdomen.


    • d. Bone scan (if necessary).


    • e. Others.


  • 3. Histopathology.



Study tools

  • 1. EBRT (external beam radiotherapy) machine “Bhabatron II” with Co60 source.


  • 2. “Nucletron” Microselectron HDR Brachytherapy unit with Ir192 source.


  • 3. Philips CT simulator system for treatment simulation.


  • 4. Planning Treatment System, i.e., Oncentra Treatment (version 4.5) for EBRT planning.


  • 5. Planning Treatment System, i.e., Oncentra Treatment (version 4.5) for brachytherapy planning.


  • 6. Injection of Cisplatin as a chemotherapeutic agent.


  • 7. Investigations:
    • a. Complete blood count and biochemistry (hemoglobin, total leucocytic count, differential count, platelet count, fasting blood sugar, serum bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatize, total protein, albumin, globulin, and serum urea and creatinine).


    • b. FIGO staging workup (pelvic examination under anesthesia, colposcopy, punch biopsy, endocervical curettage, hysteroscopy, chest X-ray, skeletal X-ray, intravenous pyelogram, barium enema, cystoscopy, rectosigmoidoscopy).


    • c. USG (ultrasonography) whole abdomen.


    • d. CT scan of whole abdomen and pelvis.


    • e. Routine and microscopic examination of urine in selected cases.


  • 8. Response evaluation criteria in solid tumor (RECIST)) criteria version 1.1 for the assessment of locoregional (LR) control.

  • 9. Toxicity assessment tools, i.e., Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  • 10. According to the National Comprehensive Cancer Network (NCCN) guidelines, patients are to be followed up: cervical and vaginal cytology—PAP (Papanicolaou Test) smear, chest X-ray, blood counts and biochemistry, USG/CT scan whole abdomen, and MRI pelvis.

  • 11. Statistical analysis using IBM SPSS Statistics version 23.0.



Study technique

Pre-treatment assessment consisted of a gynecological examination and a panel of laboratory and radiological tests. These tests include a routine blood test, chest X-ray PA view, CT scan whole abdomen/MRI (magnetic resonance imaging) scan of the abdomen and pelvis, and urography. All patients will receive treatment with concurrent chemo-radiotherapy followed by ICRT with concurrent weekly cisplatin. Weekly injection cisplatin (40 mg/m2) is administered 1 day before ICRT following which they will undergo intracavitary HDR brachytherapy with 7 Gy in three fractions.

Schedule of data collection

Initial data will be collected before treatment. The remaining data will be collected during the treatment procedure.

Statistical analysis plan

Data will be analyzed with an appropriate statistical test as applicable.

Parameters

Outcomes will be studied clinically, using laboratory tests, and radiologically and comparison will be done in the following parameters:

  • 1. Assessment of toxicities;


  • 2. Assessment of local response to treatment.


In RECIST version 1.1, responses were assessed using RECIST criteria. Acute and late toxicities were assessed using CTCAE version 4.0. Prognostic outcomes of each patient were assessed on the following parameters: (1) acute and late side effects (grading by RTOG criteria); (2) disease-free (DF) survival for a minimum of 7 months; (3) LR control for complete response (CR) or partial response (PR); and (4) recurrence.

Patients were reviewed weekly during the treatment. After treatment completion, patients will be reviewed every month for 7 months. These patients were reviewed every 3 months for 10 months.


  Results Top


This study was conducted in a government hospital from October 2018 to March 2020. A total of 60 patients were included in the study. Toxicities like nausea, vomiting, neutropenia, thrombocytopenia, anemia, vaginal mucositis, cystitis, renal dysfunction take place during the ICRT, but the patient tolerated the treatment well. The outcome of our study is in the form of CR, PR, stable disease, and progressive disease.

Distribution of age of patients

Out of 60 patients, 38.0% pf the patients are of 45–50 years. The maximum number comes from lower socioeconomic status: incidence of neutropenia [Figure 2], thrombocytopenia [Figure 3], nausea and vomiting [Figure 4], vaginal mucositis [Figure 5], and cystitis [Figure 6]. The patients had grade 3 or more toxicity due to cisplatin-induced renal dysfunction [Figure 7], and the maximum number of patients had a CR of 91.0% [Figure 8].
Figure 2: Incidence of neutropenia

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Figure 3: Incidence of thrombocytopenia

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Figure 4: Incidence of vaginal mucositis

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Figure 5: Incidence of nausea and vomiting

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Figure 6: Incidence of cystitis

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Figure 7: Incidence of renal dysfunction

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Figure 8: Response to treatment

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  Discussion Top


This study is aiming to find out the acute toxicities and local control of locally advanced cervical carcinoma patients after concurrent cisplatin chemotherapy with brachytherapy. It further aims to quantify objectively to improve the LR control. DF control can be achieved by radiation alone. This is viewed by several authors.[3],[13],[14],[15],[16] The study of weekly cisplatin 40 mg/m2 with concurrent chemo-radiotherapy in locally advanced cervical cancer gives good outcomes, which was found by Punushapai et al.[16] In a meta-analysis of 19 randomized prospective trials, 4580 patients with CCRT were found to be superior to RT alone. Green et al.[17] show that CCRT is the better option for controlling both local failure and distant relapse. Another meta-analysis also reported that CCRT is the better option as per the NCI (National Cancer Institute) statement.[18] In Germany, Strauss et al.[19] treated 27 patients with FIGO stage IIB-IIIB cervical cancers and with brachytherapy and concurrent cisplatin. In our study, the CR rate was 91.0% (n = 55), the PR rate was 5.0% (n = 3), the stable response rate was 2.0% (n = 1), and disease progression was seen in 2.0% (n = 1) of the patients. During follow-up, 80.0% of the patients were DF in 19 months. Hematological toxicity in the form of acute effects less than grade 3 was seen in 30.0% of the patients and thrombocytopenia was seen in 5.0%, respectively.

After a thorough examination, the clinical appearance of the primary tumor at the initiation of treatment was noted. During the treatment, all patients were clinically examined weekly for any complaints. Before starting chemotherapy, complete hemogram and biochemical investigations were performed and noted. The regression of primary tumor during the treatment was assessed and noted biweekly. Treatment interruption was also noted, and necessary gap correction for radiotherapy was done due to delay in treatment. Chemotherapy was withheld in our study during radiotherapy interruptions. While radiotherapy was continued, chemotherapy was being discontinued due to hematological toxicities. The disease response was assessed after treatment and subsequent follow-up. The response was assessed as per the World Health Organization criteria, and the results of the study group were analyzed in terms of compliance, toxicities, and tumor response. Acute toxicities were assessed as per RTOG (Radiation Therapy Oncology Group) acute radiation morbidity scoring criteria. As per the Common Terminology Criteria for Adverse Events (v4.03), National Cancer Institute (USA), chemotherapy-induced toxicities such as nausea, vomiting, and renal and hematological toxicities were assessed. Patients were evaluated every month on follow-up with detailed clinical examination to assess local disease response and to note any bladder/bowel symptoms. Wherever indicated, hematological tests, biochemical tests, and imaging studies were suggested.

In our present study, concurrent EBRT followed by concurrent ICRT with an injection of cisplatin, toxicity, and LR control were assessed. Inj. cisplatin at a dose of 40 mg/m2 weekly is used globally as a standard regimen, as a sensitizing agent for concurrent chemo-radiotherapy.[3],[12],[13],[14],[15]

Incidence of grade 3 or more neutropenia (3.3%) exists similarly; anemia, thrombocytopenia, and vaginal mucositis also occur. There was renal dysfunction due to cisplatin during treatment, which was temporary and subsided during follow-up. The incidence of renal dysfunction less than grade 3 was seen in 35.0% (n = 21) of the patients. There were only two patients found with more than grade 3 incidences of nausea and vomiting, although the incidence of nausea and vomiting in grade 1 or 2 is more (80.0%). During follow-up for 6 months, cystitis more than grade 3 was found in 3.3% (n = 2) of the patients.

Less than grade 3 neutropenia is seen in 30.0% (n = 18) of the patients, whereas only two patients had grade 3 neutropenia. In our study, vaginal mucositis had more incidence than expected. Interruption of treatment occurred in seven patients, who were found to have grade 3 vaginal mucositis. It was noted that out of all patients (n = 60), 91.0% of the (n = 55) patients have CR, 5.0% (n = 3) of the patients have PR, 2.0% (n = 1) of the patients have stable disease, and disease was progressed in 2.0% (n = 1) of the patients. After CT scan, residual necrotic mass was seen in three patients, which was histologically proven to be non-malignant during follow-up.


  Conclusion Top


An overall survival gain in our study was accomplished with concomitant chemo-radiotherapy followed by concomitant ICBT. Unfortunately, a significant proportion of patients, 30.0–35.0%, are still dying from locally advanced cervical carcinoma. It was observed that in locally advanced squamous cell carcinoma of the cervix, the addition of concurrent injection of cisplatin to ICRT significantly improved LR response. It was associated with an increased incidence of biochemical, hematological, and vaginal mucosal toxicity, without an increase in mortality.

Limitations

The limitations of the study were as follows:

  1. The OPD attendance was hindered by the Covid-19 pandemic and related complete lockdown during this period.


  2. Lack of an adequate number of patients and long-term follow-up obscured patient outcomes being a single institutional study; results derived cannot be extrapolated to the entire study. Therefore, more clinical studies with more clinical parameters and sample sizes are suggested.


  3. Detailed stage analysis was required for identifying risk factors in individual cancers.


Ethical consideration

The ethical approval has been provided by the Institutional Ethics Committee Letter No. P/MLD-MC/IEC 22/05 dated February 15, 2022 for performing the present research work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
International Agency for Research on Cancer. GLOBOCAN 2020: The Global Cancer Observatory: India: Number of New Cases in 2020, Both Sexes, All Ages. Lyon, France: WHO-IARC; 2021.  Back to cited text no. 1
    
2.
Viswanathan AN Uterine cervix. In: Halperin EC, Wazer DE, Perez CA, Brady LW, editors. Principles and Practice of Radiation Oncology. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2013. p. 1355-9.  Back to cited text no. 2
    
3.
Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin‑based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144‑53.  Back to cited text no. 3
    
4.
DeVita VT, Lawrence TS, Rosenberg SA DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2011. p. 1315.  Back to cited text no. 4
    
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Bruni L, Barrionuevo-Rosas L, Albero G, Aldea M, Serrano B, Valencia S, et al. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in the World. Summary Report 04 August 2015. Available from: http://www.hpvcentre.net. [Last accessed on February 25, 2022].  Back to cited text no. 5
    
6.
Kumar V, Abbas AK, Fausto N, Mitchell RN Robbins Basic Pathology. 8th ed. Philadelphia: Saunders Elsevier; 2007. p. 718-21.  Back to cited text no. 6
    
7.
Canavan TP, Doshi NR Cervical cancer. Am Fam Phys 2000;61: 1369-76.  Back to cited text no. 7
    
8.
Nanda R “Cervical Cancer.” MedlinePlus Medical Encyclopedia. Bethesda, MD: National Institutes of Health; 2006.  Back to cited text no. 8
    
9.
Vasishta S, Varghese A, Ragheb A Patterns of failure in cervical carcinoma and outcome of salvage therapy: A retrospective study. Gulf J Oncol 2007;1:43-9.  Back to cited text no. 9
    
10.
Perez CA, Breaux S, Madoc-Jones H, Bedwinek JM, Camel HM, Purdy JA, et al. Radiation therapy alone in the treatment of carcinoma of uterine cervix. I. Analysis of tumor recurrence. Cancer 1983;51:1393-402.  Back to cited text no. 10
    
11.
Perez CA Uterine cervix. In: Perez CA, Brady LW, editors. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1998.  Back to cited text no. 11
    
12.
Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL III, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154-61.  Back to cited text no. 12
    
13.
Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: A Gynecologic Oncology Group and Southwest Oncology Group Study. J Clin Oncol 1999;17:1339-48.  Back to cited text no. 13
    
14.
Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137-43.  Back to cited text no. 14
    
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Peters WA III, Liu PY, Barrett RJ II, Stock RJ, Monk BJ, Berek JS, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18: 1606-13.  Back to cited text no. 15
    
16.
Punushapai U, Yuenyao P, Chumworathayi B, Luanratanakorn S, Udomthavornsuk B Weekly cisplatin 20 mg/m2 in patients with carcinoma of cervix receiving pelvic radiotherapy at Srinagarind hospital: A randomized controlled trial. Asian Pac J Cancer Prev 2010;11:201-7.  Back to cited text no. 16
    
17.
Green J, Kirwan J, Tierney J, Symonds P, Fresco L, Williams C, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev 2001;4: CD002225.  Back to cited text no. 17
    
18.
Lukka H, Hirte H, Fyles A, Thomas G, Elit L, Johnston M, et al; Cancer Care Ontario Practice Guidelines Initiative Gynecology Disease Site Group. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer—A meta-analysis. Clin Oncol (R Coll Radiol) 2002;14:203-12.  Back to cited text no. 18
    
19.
Strauss HG, Kuhnt T, Laban C, Puschmann D, Pigorsch S, Dunst J, et al. Chemoradiation in cervical cancer with cisplatin and high-dose rate brachytherapy combined with external beam radiotherapy. Results of a phase-II study. Strahlenther Onkol 2002;178:378-85.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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