Prospective study on acute toxicities of external beam radiotherapy in the management of pelvic malignancies in Lagos University Teaching Hospital

Bolanle Comfort Adegboyega; Habeebu Y Muhammad; Adedayo O Joseph; Babatunde M Alabi; Francis A Durosinmi-Etti

doi:10.4103/jcls.jcls_85_19

ORIGINAL RESEARCH REPORT

Year : 2020 | Volume : 17 | Issue : 3 | Page : 80-85

Prospective study on acute toxicities of external beam radiotherapy in the management of pelvic malignancies in Lagos University Teaching Hospital

Bolanle Comfort Adegboyega, Habeebu Y Muhammad, Adedayo O Joseph, Babatunde M Alabi, Francis A Durosinmi-Etti
Department of Radiotherapy, Lagos University Teaching Hospital, Lagos, Nigeria

Date of Submission	31-Dec-2019
Date of Acceptance	28-May-2020
Date of Web Publication	04-Jul-2020

Correspondence Address:
Dr. Bolanle Comfort Adegboyega
Department of Radiotherapy, Lagos University Teaching Hospital, Lagos
Nigeria

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcls.jcls_85_19

Abstract

Introduction: Radiation therapy is key to the management of pelvic malignancies. It not only induces cellular death in target organs but also results in adverse effects on the surrounding structures. These side effects are classified as acute or late toxicities based on the timing of its occurrence from the treatment time. The aim of this study was to describe the pattern and management of radiation side effects in pelvic cancer patients treated with external beam radiotherapy (EBR) at Lagos University Teaching Hospital. Methodology: This study was carried out on pelvic cancers patients treated with curative intent over 6 months. The weekly review of treatment related toxicities were graded using the National Cancer Institute Common Toxicity Criteria and analyzed. Results: A total of 106 patients aged between 32 and 83 years were studied. Mean age was 59.2 years and M: F of 3:7. The most common pelvic malignancy seen was cervical cancer in 50.9% of cases; prostate cancer in 17.0%, and endometrial cancer in 15.1%. The most common acute adverse event was perineal skin desquamation in 73.5% patients, genitourinary toxicities in 66% of patients, hematological derangements in 41.5% patients, and gastrointestinal toxicities in 37.7%. Grades 1 and 2 toxicities were the usual complaints in 62.1% patients and severe toxicities (G3 and 4) in 37.9%. Conclusion: Mild-to-moderate acute radiation induced toxicities is a common occurrence following EBR of pelvic cancer. Conservative management of these toxicities makes EBR tolerable and prevents treatment interruption.

Keywords: Acute toxicities of radiotherapy, external beam radiotherapy, pelvic malignancies

How to cite this article:
Adegboyega BC, Muhammad HY, Joseph AO, Alabi BM, Durosinmi-Etti FA. Prospective study on acute toxicities of external beam radiotherapy in the management of pelvic malignancies in Lagos University Teaching Hospital. J Clin Sci 2020;17:80-5

How to cite this URL:
Adegboyega BC, Muhammad HY, Joseph AO, Alabi BM, Durosinmi-Etti FA. Prospective study on acute toxicities of external beam radiotherapy in the management of pelvic malignancies in Lagos University Teaching Hospital. J Clin Sci [serial online] 2020 [cited 2023 Jun 2];17:80-5. Available from: https://www.jcsjournal.org/text.asp?2020/17/3/80/288909

Introduction

Pelvic malignancies including gynecological cancers such as uterine, ovarian, cervical, vulva, and vagina. Prostate, rectal, urinary bladder, testicular, and anal cancers accounts for 435,640 (23%) of the estimated number of new cancer cases in the United States in 2013 and >200,000 new cases are diagnosed each year.^[1] The incidence in the Western world is on a decline owing to improved screening modalities but still high in developing countries with associated late presentation which further contributes to increased morbidity and mortality in these regions. The etiologic and epidemiologic differences among these cancers vary and may impact their management as well.

Radiation therapy is an important modality of treatment of many pelvic cancers. Other modalities of treatments include surgery, chemotherapy, hormonal therapies, and targeted therapies and approximately 50% of these patients will require radiation therapy.^[2] Radiation therapy like other modalities of treatments can be associated with some complications which can occur at any time during the treatment to many years posttreatments. These toxicities are broadly classified into two groups, namely, acute and late toxicities based on the timing of its occurrence. Acute toxicities are those occurring during treatment to 90 days' post treatment, while late toxicities are those developed after 90 days of completing the treatment to several years later.^[2] In general, early effects are more common and less severe than late effects which sometimes can be life-threatening, irreversible or worsening with time.^[2]

The occurrence and severity of toxicities following radiotherapy depend on several factors such as; the site being treated, volume of tissue exposed, total dose, dose per fraction, type of radiation used, prior surgery, prior or concomitant use of chemotherapy, and host susceptibilities. Hence usually acute toxicity following abdomino-pelvic radiation is commonly in the gastrointestinal tract, genitourinary system, and the skin.

Conformal radiotherapy techniques using intensity- modulated radiation therapy (IMRT) when compared to the conventional treatment increases dose to the target volume and decreasing the dose received by surrounding normal tissues thus sparing some critical organs and this increases expectations that the incidence of late complications will be lessened. Unfortunately, this technique is still far from the reach of most African nations which leads to more anticipated severe toxicities.

Adverse events are graded to four groups based on the severity, Grade 1 is mild adverse event, Grade 2 is moderate adverse events, Grade 3 is severe adverse event, and Grade 4 being life threatening events. While some patients appear to recover from the adverse effects without interventions, some require minimal-to-moderate intervention but a few actually suspend treatment temporarily due to the severity. Acute toxicities are reversible and most resolve within 2–3 weeks after completing the treatment but must be managed appropriately to ensure patient compliance and prompt completion of treatment.

Methodology

The prospective study was conducted in Lagos University Teaching Hospital (LUTH) which is a referral centres of the South Western and Eastern regions of Nigeria, occasionally from the other parts of the country and some neighboring countries and some in Eko hospital.

The study population included patients with pelvic malignancies for radical radiotherapy who were counseled on the possible side effects of radiotherapy to expect. There was weekly monitoring during the period of treatment, with laboratory investigations and physical examinations watching out for these acute side effects and appropriate managements were instituted if need be. This also continued at regular intervals during follow-up visits till 3 months from the commencement of treatment. The study, however, enrolled 108 patients within the study period but 106 completed the study due to renal failure in 1 patients and death of 1 patient.

This study obtained ethical approval from the Health Research and Ethics committee of the LUTH and informed consent from all patients before their enrolment into the study.

Inclusion criteria

Inclusion criteria included all patients who had confirmed histologic diagnosis and radiotherapy for pelvic cancers up to a minimum of 45 Gy. These are patients who completed their treatments; they were compliant with the reaction clinics and follow up clinics for up to 3 months from the commencement of treatment.

Exclusion criteria

Patients were excluded if:

They had emergency treatments only
They had prior pelvic radiotherapy
They had incomplete treatment.

Patient's bio-data, history, and investigation findings were collected from the case file. Informed consent was obtained from the patients to participate in the study. While on radiotherapy, the patients were observed weekly and at regular intervals on follow-up visits. They were analyzed for general health status, laboratory test results, and radiation reactions from the skin, intestines, urinary, and hematologic system. Acute toxicity scores were recorded weekly during treatment and at regular intervals till 3 months post commencement of radiotherapy using the Common Terminology Criteria for Adverse Events, version 3.0.

The patients were treated with Megavoltage machines using photon beam Linear Accelerator machine (LINAC) photon energy 6 or 15MV for those in LUTH and Cobalt-60 machine energy 1.25MV for those treated in Eko hospital. Radiation doses given varied based on factors such as prior surgery, age, and performance status score. Some started with hemostatic Radiotherapy doses then continue to the prescribed radical dose following the Biologic Effective Dose calculation.

Collected data were analyzed using the Statistical Package for the Social Sciences (SPSS) version 22 Analyzed data are presented in frequency tables, charts, and cross tabulations.

Results

A total of 106 patients completed the study and were analysed. The ages of the patients ranged between 32 and 85 years, with the mean being 59.2 years [Figure 1]. Seventy-eight (73.6%) patients were female and 28 (26.4%) were male.

Figure 1: Age distribution of patients with pelvic cancers (n = 106)

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Cervical cancer was the most common (50.9%) pelvic cancer treated, followed by prostate cancer (17.0%), endometrial cancer (15.1%), rectal cancer (7.5%), and bladder cancer (5.7%). Others were vaginal cancer and vulvar cancer (1.9%) each. The most common stage at presentation was stage III recorded in 48 (45.3%) patients, stage IV disease in 34 (32.0%) patients, while the early stages I and II were found in 4 (3.8%) and 20 (18.9%), respectively.

Patients' past medical history revealed that 50.9% had comorbidities; 10 (9.4%) had both diabetes mellitus and hypertension; 40 (37.7%) had only hypertension; 2 (2%) had human immunodeficiency virus, and 2 (2%) patients were obese.

Some of the studied patients 63 (59.4%) had previous treatments either as monotherapy (surgery, chemotherapy, or hormonal therapy) or combination therapy, while 43 (40.6%) had no prior treatment. Radiation doses received varied between 45 Gy/20# and 60 Gy/30# with the mean dose being 52.5 Gy. 38 (35.8%) of these patients had 55 Gy in 25#, Eight of the 13 rectal cancer cases had 50 Gy in 25#, 12 (11.3%) of the endometrial cases had 45 Gy in 20#, while the rest 48 patients had 60 Gy/30# [Table 1].

Table 1: Radiation dose/fractionation received by 106 patients with pelvic malignancies

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Patients were assessed for adverse reactions such as gastrointestinal toxicities (GITs) such as vomiting (V), diarrhea (D), constipation (C), genitourinary symptoms (GUS) such as frequency (F), dysuria (D), incontinence, and nocturia (N). Others were skin toxicities and hematological (HEAM) toxicities such as anemia (A), leucopenia (L), and thrombocytopenia (T).

Skin reactions

a total of 78 (73.6%) patients had skin reactions with the commonest being grade 3(G3)/early moist desquamation in 40 (38%) patients, 20 (19%) had G4 (blister formation, skin peeling and ulceration), 15 (14.0%) had G2 (dry desquamation), and 3 (3.0%) had G1 (erythema/hyperpigmentation) [Table 2]. Furthermore, 40% of patients with DM have G4 skin toxicities, 30% have G3 and 30% had none, while 100% of the obese patients had G4 toxicities. Furthermore, maximum skin reaction was recorded from week 4 to week 6 and with the peak in week 5 and there was rapid resolution of symptoms following completion of treatment with only 4% left with side effects at week 12.

Table 2: Frequency distribution of the various grades of acute radiotherapy toxicities

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Hematological toxicities were recorded in 44 (41.5%) of the 106 patients studied. Grade 2 anemia (A2) was the most common variant recorded in 15 (14.2%) patients. There were no records of Grade 4 toxicities or thrombocytopenia in any of the patients. The peak incidence of hematological toxicities was in the 3^rd week with complete resolution by week 12.

Gastrointestinal system toxicities were recorded in 40 (37.7%) patients. G2 Diarrhea was the commonest presentation recorded in 14 (13.2%) patients and grade 3 diarrhea in 10 patients. Vomiting was mild-to-moderate and present in 4 patients while constipation was recorded in 6 (5.8%) patients. GIT toxicities peaked at week 3, but there was a sustained decline from then till the 12^th week when there was complete resolution [Table 2].

Reported cases of GUS toxicities were 70 (66%) with the most frequent being dysuria grade 2 (D2) and nocturia grade 2 (N2) seen in 18 (16.9%) patients and 14 (13.2%) patients, respectively. Other GUS toxicities recorded was frequency. The peak GUS toxicities was at the 4^th week and 28% persisted until the 12^th week [Figure 2].

Figure 2: Trends of symptoms of acute toxicity (peak and resolution) in patients with pelvic malignancies following radiation therapy

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Management of toxicities

The toxicities were managed based on their grade of presentation, though most were self-limiting. Diarrhea was treated by rehydration for Grade 3 and above, and anti-diarrheal agents given in some instances, those with vomiting also had anti emetic agents. Skin reactions had moisturizing cream and silver nitrate-containing creams. GUS were relieved by increased fluid intake, occasional analgesics, and antibiotics in some instances.

Discussion

This prospective study described the pattern of acute radiation toxicities and its management in 106 pelvic cancer patients managed both in the Department of Radiotherapy, LUTH from June-December 2016 and Eko Hospital from January to March 2018.

The analysis revealed that pelvic cancers commonly affect middle-aged and elderly individuals in both sexes with the mean age of 59 ± 13.5 years. This is similar to the findings by Savita et al.^[3] who reported a mean age of 52 years in 70 endometrial cancer patients and Roszak et al.^[4] who reported mean age of 54.0 ± 8.7 years for 120 cervical patients studied. The most common pelvic malignancy treated in our center was cervical cancer which accounts for 50.9% of cases seen, followed by prostate cancer seen in 17.0% of the cases. This finding is in accordance with the previous works on cancer incidence in South West Nigeria which put Cervical Cancer as the second most common cancer in Nigeria after breast cancer with prostate cancer as the third.^[5]

Majority of the patients presented with late stage diseases, 48 (45.3%) presenting in stage III, 34 (32.0%) patients in stage IV. Thus, 77.3% presented in stages 3 and 4. Only 22.7% of studied patient in stages I and II and this is the pattern in most developing countries. This late presentation according to Durosinmi-Etti^[6] and Ajekigbe^[7] has been attributed to poverty, ignorance and denial on the part of the patient, lack of adequate treatment facilities, incompetence of some primary physicians in making the right diagnosis and instituting early referrals. Rabiu et al.^[8] added visits to spiritual houses and alternative medicine before presenting at the hospitals.

Past medical histories of the studied population revealed existence of comorbidities like; hypertension and/or diabetes in 50 (47.1%) patients. This could be attributed to the predisposition of this age group to developing these essential diseases. However, the study showed that these comorbidities do not influence the compliance with treatment as reported by Fiorentino et al.^[9] in a previous study that showed that elderly patients with good performance score and low comorbidity profile have good tolerance for external beam radiation therapy plus brachytherapy. Although diabetes mellitus and obesity contributed to the development of severe skin toxicities, this should be well controlled in patients for radiotherapy so as to prevent and control the severity of the reaction.

Radiation doses varied according to the goal of radiotherapy either as adjuvant or sole treatment. Other variations in total dose or fractionation were based on the age, comorbidities, and prior hemostatic doses. None of the patients had brachytherapy as there was none functional as at then. This study revealed that 70 (66%) of patients had 55 Gy or more comprising majority of cervical cancer patients and all prostate cancer cases essentially because most of this subset had no neo-adjuvant surgery. Perez et al.^[10] noted the lower dose received by patients who had prior surgery as opposed to those without. He also pointed out relationship between high dose and the risk of radiation toxicities during radiotherapy, which has led to the use of IMRT in most centers in advanced countries with their attendant reduced rate of toxicity.^[11] Lanciano et al.^[12] in another study also reported high radiation dose >75 Gy, high radiation fraction size with daily fraction size >200 cGy and prior surgery among factors associated with an increase in complication rate following pelvic cancer radiotherapy.

In all 85 (84.0%) of patients in this study experienced various grades of acute radiation toxicities. This is higher than reported in a similar study by Savita et al.^[3] which showed that 75% of patients had any grade of radiation toxicities and Weiss et al.^[13] in another study reported acute toxicities in 65.4% of studied population. These lower rates in other studies could be attributed to the improved technologies employed in developed centers which allows for multiple treatment fields with smaller field size and higher radiation dose which however is not available in our centers.

Skin toxicities were the most common reported side effects found in 73.6% of patients and it accounts for most of the severe complication recorded in this study as 57% of the cases are grades 3 and 4 which includes 70% of DM patients. Severe skin toxicity is also the most distressing of all the toxicities but with no resultant treatment break or suspension recorded. These results are higher than as reported in an earlier study by Keys et al.^[14] who reported 1%–5% of severe toxicities in pelvic cancers and 85%–100% of grades 1and 2 skin toxicities in vulva cancer.^[13],[15] This disparity could be attributed to the advancements in technology and the use of multiple fields of treatment in developed countries as against our setting where all the studied patients had Anterior/Posterior (AP/PA) field radiotherapy planning technique.

This study also supported that diabetes mellitus is significantly associated with severe skin toxicity in accordance with the study by Savita et al.^[3] It is postulated that presence of excessive skin folds in obese patients and high susceptibility to fungal or bacterial infections in diabetic patients were known factors responsible for worsening radiation skin toxicities.^[3]

There was rapid resolution after treatment though 4% of cases persisted till the 12^th week and these were found in patients with comorbidities such as obesity and diabetes mellitus. Despite the severity of these adverse events, they responded to the conservative measures as recommended by literature such as use of prophylactic moisturizing creams, adequate counseling on clothing materials and exposure which either prevents development of skin toxicities or delay its onset or severity. The others were managed with topical steroids or silver containing creams which aid the rapid resolution of these symptoms.

Genitourinary toxicities were reported in 66.0% of studied patients. This is higher than an earlier study by Weiss et al.^[13] where GUS toxicity was 52.3% following pelvic irradiation and GOG-99 study conducted by Moore et al.^[15] of postoperative RT for Endometrial cancer recorded 43% GUS toxicity. Common presentations were frequency, dysuria, and nocturia. Grade 1 and 2 toxicities made up 97% of these toxicities. Grade 3 toxicities were seen in 10 patients, while grade 4 GUS toxicities occurred in 2 patients. Samples were sent for urinalysis and m/c/s to rule out infective process which necessitated use of antibiotics in those that had positive results based on the sensitivity patterns. Other modalities of treatment included non-steroidal anti-inflammatory drugs and liberal fluid intakes. There was significant resolution of symptoms following treatment though 24% persisted till the 12^th week.

The GITs recorded following pelvic irradiation in this study is 37.7%. This is lower than the study by Savita et al.^[3] where its seen in 51% of endometrial and 69.9% of cervical cancer patient on concurrent chemo-radiation. This is because concurrent chemo-radiation worsens the GIT symptoms as against those that had radiotherapy only.^[16] This may be related to the synergistic activities of both modalities of treatment, which though improve overall, and progression free survival, leads to the increased toxicity? Other factors responsible for the GIT toxicities could be large volume of intestine covered by high-dose irradiation, especially with the parallel opposed AP/PA fields used in all the patients in this study as against the 4-field box technique used in a study by Morris et al.^[17] However GIT toxicities recorded are mostly grade 1 and 2 toxicities while severe complication (grade 3) was only reported in 10 patients and no record of grade 4 GIT reactions in this study.

GIT toxicities are mostly self-limiting which subsided after completion of treatments. Those requiring management responded to supportive cares and conservative measures such as rehydration, anti-diarrheal, anti-emetics, and dietary modification but none necessitated treatment breaks.^[18]

Hematologic toxicities arise as a result of bone/bone marrow exposure to irradiation. This was experienced by 44 (41.6%) of the studied patients and this is comparable to the study by Tan et al.^[19] that reported 45.9% of HEAM toxicity. A study by Ikushima et al.^[20] also revealed that acute HEAM toxicity was significantly higher (86%) in patients that had chemo radiation than those with only radiotherapy. Hematologic toxicity predisposes patients to infection, hospitalization, and blood transfusions and growth factors replacement. It can also lead to treatment breaks^[21] this was experienced in this study when treatment break was recorded in 2% of patients and 2 mortalities were also recorded.

Study limitation

The proposed sample size could not be achieved owing to frequent equipment breakdowns
Financial constraints for some patients unable to carry out laboratory investigations as at when due
Differences in energy of machine used may cause differences in the degree of skin reactions in some patients, but this comparison was not done in this study.

Conclusion

Radiation treatment plays an important role in the management of pelvic malignancies. It is associated with some resultant treatment toxicities which can be acute or chronic.

Acute radiation toxicities reported in this study were mild-to-moderate grades mostly in the GIT and GUS, while the most severe toxicities were recorded in the skin which was worsened by Diabetes mellitus. The toxicities peaked between the 3^rd and 5^th weeks but regressed within 3 months of treatment. The toxicities recorded were managed satisfactorily with some residual symptoms after this study in the genitourinary system and the skin.

Acknowledgments

The authors acknowledge the contributions of Department and staff at Department of Radiotherapy and Oncology, LUTH, Idi-Araba, Lagos.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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