Assessment of late radiation toxicities and quality of life in patients with pelvic cancer – A cross-sectional study

INTRODUCTION

Radiotherapy is used in treating many pelvic cancers. In India, the distribution of incidence of pelvic cancers is cervical (9.4%), rectal (2.1%), endometrial (1.2%), prostate (2.6%), vaginal (0.42%), vulvar (0.26%), penile (0.8%), anal canal (0.41%), and bladder (1.6%). Pelvic malignancies collectively account for 16.46% of cancer-associated mortalities in India.^[1]

Pelvic radiation has been associated with a high level of grade 2 and above toxicity, with late toxicities manifesting in 10-15% of the patients.^[2,3] There is a lack of accessibility to conformal radiotherapy techniques for most of the Indian population, which is predominantly a low-middle-income economy.^[4] With increasing survival due to better screening and newer treatment modalities, we need to address long-term toxicities that impact survivorship.^[5,6]

This study assesses the rates of late radiation toxicities among all pelvic malignancies and analyses the underlying patient, disease, and treatment-related factors associated with the development of late radiation toxicities. It also assesses the patient-reported quality of life after the completion of pelvic radiation.

MATERIAL AND METHODS

The study is designed as an observational cross-sectional study, conducted at the Regional Cancer Centre, JIPMER, from June 2020 to June 2022. The patients who had completed therapeutic pelvic radiation at least 3 months before and within 5 years of recruitment were recruited. Clinical evaluation was done at the time of contact after completing radiation treatment. Development of late grade 2 and above toxicities of bladder, rectum, and skin was graded using CTCAEv5.0 and RTOG late toxicity scale. Patients who have received incomplete radiation treatment, brachytherapy as monotherapy, and pelvic reirradiation were excluded from the study.

Clinical examinations were carried out, which included general, local, and per-rectal examinations along with hemogram, electrolytes, renal function, and urine tests in symptomatic patients. In addition to the baseline tests, patients with skeletal symptoms were requested to get blood tests for serum calcium, serum alkaline phosphatase, and a regional X-Ray was done. The data was collected at the time of contact after completing radiation.

All patients were requested to follow up at the Radiation Oncology Follow-up clinic as per the department protocol. Quality of Life was assessed using a validated EORTC questionnaire – QLQ-C30 at the time of contact. All the baseline tests are part of routine follow-up as per department protocol. The treatment was done as per department protocol in patients for whom toxicity was identified.

Considering an expected proportion of patients developing late toxicities after therapeutic pelvic radiation as 40%, with an absolute precision of 5%, for a confidence interval of 95%, the sample size arrived at is 369. Accounting for attrition of 10% cases, which might be poor samples due to defective data, the final sample size arrived at was 406. Patients were recruited through consecutive sampling. Categorical variables are expressed as proportions with 95% confidence intervals. The normality of distribution was assessed by the Kolmogorov-Smirnov test. Categorical variables were evaluated using Chi-Square or Fisher's exact tests. All statistical analyses were carried out at 5% significance and a p-value <0.05 was considered significant. There is a possibility of selection bias due to loss to follow-up. All Statistical analyses were performed using IBM SPSS v19.0.^TM

The study was approved by the Institutional Ethics Committee for Observational studies at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, under the project number JIP/IEC/2020/052.

RESULTS

We recruited 502 patients with pelvic malignancies who had completed their radiation or chemoradiation treatment at least 3 months prior to recruitment. The median follow-up assessment period was 36 months. The median age of the study population was 53, with 91.6% of them being women and a predominant (98.8%) ECOG performance status score of 1-2 as observed in Table 1. About two-thirds of the patients had diabetes and hypertension. Among 7 patients with other comorbidities, 5 had bronchial asthma, and 2 had chronic renal disease. Only 14.9% of the patients were addicted to any substance, including smoking, alcoholism, and betel chewing.

93.6% belonged to socioeconomic strata 2 and 3 according to the Modified B.G. Prasad scale of socioeconomic classification. Most patients belonged to the normal category (37.1%) and the obese category (32.3%) under the Asia Pacific-modified WHO BMI scale. 78% belonged to the middle-aged group, while the remaining 22% comprised the AYA (Adolescents and Young Adults) and the elderly. Most patients had albumin levels less than 4 g/dL and a haemoglobin level of <10 g/dL. Most patients were seronegative for HIV, HBV, and HCV. 86.7% of patients in the study population had gynaecological malignancies. Cervical and rectal cancers were the most common primary tumour sites. Squamous and adenocarcinoma histopathology were the most common subtypes.

92.2% of patients belonged to the T2-T3 stage (AJCC 8^th edition). 21.5% had nodal disease prior to starting radiotherapy. 3 patients had metastatic disease at baseline and were treated with salvage intent. 24% of patients with gynaecological cancers had disease in the lower third of the vagina.

Bulky tumours comprised more than half of the study population, defined as >4cm in gynaecological malignancies and threatened circumferential margin in rectal tumours. Bleeding from the primary site was the most common presenting complaint among the patients, with 61.6% presenting with the same. The next most common symptom was white discharge per vaginum in 60.6% of patients. The majority underwent radical pelvic irradiation, with 82.1% receiving 2-dimensional conventional radiotherapy, and most received cisplatin or capecitabine-based chemotherapy.

In patients eligible for brachytherapy, 7 Gy x 4 fractions were the most common schedule, followed in 42.6% of the patients. 12.9% did not receive brachytherapy. 62.1% of patients completed their entire course of pelvic irradiation treatment in under 60 days. All patients, barring prostate malignancies, received 45-50.4 Gy as part of their external beam radiotherapy. Pelvic nodal boost was given as indicated. Patients received an EQD2 of 60-62 Gy. Sequential boosts and simultaneous integrated boosts were given to indicated patients, depending on logistics and slot availability, and according to radiobiologic rationale. Patients with prostate cancer received 74-76 Gy as part of EBRT.

As observed in Table 2 radiation proctitis and radiation-induced subcutaneous fibrosis formed the bulk of the late toxicities, with a proportion of 18-20%, followed by radiation-induced vaginal stenosis and pelvic insufficiency fractures. 1 patient developed sensorineural hearing loss attributed to the prescription of concurrent chemotherapy with cisplatin. Among the patients who presented with pelvic insufficiency fractures (n = 52), 30 developed fractures at the sacrum bone and the sacroiliac joint, while 22 developed insufficiency fractures on bilateral pubic bones. Of the study population, 237 patients had at least one late pelvic toxicity, accounting for 47.2% (95%CI, 42.8%-51.7%).

Most of the radiation cystitis, subcutaneous fibrosis, and vaginal stenosis were of Grade 2, while a majority of the radiation proctitis patients were of Grade 3 and presented with bleeding, requiring admission for management.

8 patients developed fistulae, of which 1 patient developed a vesicovaginal fistula, and 7 developed rectovaginal fistula and required diversion procedures for symptomatic management. The median time to onset of rectal fistulae was 911.5 days (range: 462-1888) from the completion of treatment. One patient developed a vesicovaginal fistula at 447 days from completion of treatment. Table 3 shows that 79.7% of the grade 2 and above late visceral toxicities occurred within the first three years of completion of pelvic irradiation. Only 3.5% of the late visceral toxicities occurred after year 5 of treatment completion. 427 patients remained disease-free at the time of follow-up, while 75 patients developed locoregional or distant relapse. 92.8% of the patients who relapsed within the first 3 years from completion of pelvic radiotherapy.

QoL analysis was carried out with EORTC QLQ-c30(v3.0) - global health status-QoL, functional scales, and symptom scales were assessed. Patients with grade 2 and above toxicities had a worse score in all functional scales except the emotional scale. They had a worse score on the symptom scales of nausea, vomiting, dyspnea, insomnia, appetite loss, and bowel complaints. Patients with treatment failure experienced worse scores in all parameters except financial difficulties, where the scores were similar to those who were disease-free at the time of recruitment.

DISCUSSION

Data regarding malignancies and associated late radiation toxicities in the Indian population are scarce. With patient-tailored treatment and prevention of undesirable adverse effects becoming standard, it becomes more necessary to identify patient-specific factors affecting toxicities. The study was performed during the COVID pandemic, and the defaults in follow-up due to logistics might impact the data and results.

The majority belonged to the age group of 40-60 years, which is in concurrence with the Indian epidemiological audits.^[7,8] A predominant proportion of pelvic malignancies in India comprises cervical cancer. Representatively, the study population is skewed towards a female majority. The distribution of patients with comorbidities also followed the Indian trend, ranging around 30% prevalence. India is categorised as a low-middle income country, and the study population reflects the same. The distribution of overweight and obese individuals also seems to be within the population norms of around 30-40%.^[1,4,9] All the patients included in our study had anaemia at baseline (Hb<11 g/dL). 59.4% of patients included in the study had a baseline level of low albumin, which is a poor prognostic marker of nutrition, cancer outcomes, and tumour response rates. In a nutritionally deficient population like India, literature reports a 37.5% prevalence of hypoalbuminemia, which could adversely affect outcomes and toxicities. The prevalence is expected to be higher in a lower-middle-income population with rural predominance. Bleeding and abdominal pain were the most common non-disease-specific presenting complaints observed, in addition to fatigue and weight loss.^[10-12]

Details regarding ADT usage were not collected as part of the study. Some patients deemed unfit to receive chemotherapy due to factors like elderly age group, comorbidities, and performance status received radical radiation alone as their standard treatment.^[13,14]

27.9% of patients could not complete treatment within the standard time duration. Treatment interruption causes included, but were not limited to, COVID infection, development of grade 3 and 4 acute toxicities requiring intensive care, financial and social causes, and personal reasons for defaulting treatment. Patients who underwent chemoradiation had more toxicities than patients undergoing radiation alone. The association of various clinical parameters with the onset and proportion of radiation related late toxicities have been demonstrated in Supplementary Table S1. A higher proportion of late toxicities was observed in patients who underwent abdominal surgery and received adjuvant radiation. Our study showed no difference between the chemotherapy and non-chemotherapy subsets. In most patients who did not receive chemotherapy, their performance status, age group, and comorbidities might have caused them to develop late toxicities in the same proportion as those of the patients who received chemotherapy.^[2,15]

Subcutaneous fibrosis and vaginal stenosis were present in a higher proportion of females, in accordance with the study population having more gynaecological malignancies. Increased instances of toxicities were observed in patients with addictions like alcohol, smoking, tobacco, and betel consumption, which are attributed to the development of fibrosis in oral squamous carcinomas due to higher systemic inflammation and TGF-β levels, causing angiogenesis as well. Increased BMI, obesity, and comorbidities caused more cutaneous toxicity, likely due to higher skin radiation dose due to anteroposterior separation. Lack of concern about sexual function, lack of awareness, and lesser education and social taboo in using vaginal dilators also contribute to the increased prevalence of vaginal stenosis in our population.^[16-18]

Pelvic insufficiency fractures were present in a higher proportion in the age group 40-64 and were associated with pre-existing diabetes mellitus. Patients with better performance status have a higher chance of insufficiency fractures, which can be attributed to ambulation and weight-bearing on irradiated bones, and also the higher proportion of patients with performance status 0 and 1. The study population has added risk factors of pelvic radiation, concurrent systemic anticancer agents, corticosteroid use as an antiemetic, and conventional radiation techniques.^[19]

Lower BMI is associated with an increased possibility of gastrointestinal and genitourinary complaints, which is reflected in the results of our study, where a significantly higher proportion of underweight patients had chronic toxicities compared to other age groups. Bulky tumours and lower vaginal involvement in gynaecological cancers, which require larger treatment fields for irradiation, are associated with a significantly higher proportion of all toxicities and insufficiency fractures.^[18]

The prevalence rate (20%) and median time to development of grade 2 and above late proctitis (8-12 months) were similar to the literature. However, slightly lower rates than those reported in this study were reported in trials of conformal radiotherapy.^[20]

In our study, 8.2% of patients developed grade 2 and above cystitis and urinary strictures. The median time to development of grade 2 and above late cystitis is around 36 months, and our study reports that 79.7% of the chronic visceral toxicities occur within the first 3 years after completion of radiotherapy.^[20-23]

In our study, 93% of patients with treatment failure relapsed within the first 3 years. The rate of distant relapse was 57%, while locoregional relapse accounted for 39% of the total treatment failures (nodal). In a retrospective audit of cervical cancers by Bandyopadhyay et al.,^[24] 34.7% of the study population had a treatment failure within the follow-up period. In comparison, our study had a relapse rate of 16.5% within the follow-up period.^[24-26]

Fewer instances of toxicities or relapses after the 4^th and 5^th year may be attributed to the default in follow-up after the initial period, due to a lack of active surveillance and follow-up, lack of motivation, or social support on the side of patients. It highlights the need for a robust follow-up policy.

In the quality-of life scores, patients with grade 2 and above toxicities and patients with treatment failures after completion of pelvic radiotherapy performed consistently worse than their counterparts. In patients with gynaecological cancers, Chan et al.^[27] observed that the global scores were high, and the symptom scores were worse following completion of treatment in the initial 6 months, lasting up to 24 months. This could be attributed to lesser pain tolerance in an undernourished and predominantly female study population. Hence, the reported pain, appetite, and insomnia scores are higher than in other similar trials.^[27,28] While other studies report a notably higher score in emotional and social functioning, our patients performed better in these domains. The treatment-induced remission and the disease-free life likely affected the social and emotional well-being of the patients.

Table 4 compares the proportion of various muco-cutaneous, genitourinary, and gastrointestinal toxicities across other important studies in the same time period with the proportion observed in our study.^[29-34]

Table 5 compares the mean quality-of-life scores (using the QLQ-C30 questionnaire) of our study population with those of other large, reported studies.^[28,35]

TAKE HOME MESSAGE

47.2% of patients reported grade 2 and above late pelvic organ toxicities following pelvic radiotherapy. Chronic proctitis, cystitis, subcutaneous fibrosis, vaginal stenosis, and pelvic insufficiency fractures were common. Chronic visceral toxicities manifested within the first 3 years of completion of radiation. Risk factors associated with chronic visceral toxicities included hypertension, obesity, bulky tumour presentation, and disease extension into the lower vagina. Gender (p = 0.047), addictions (p = 0.01), BMI category (p <0.001), bulky disease (p = 0.004), and lower vaginal involvement were found to be associated with higher mucocutaneous toxicities. Pelvic bone insufficiency fractures were numerically more common in the elderly, diabetics, people with poor performance status, lower vaginal involvement, and the conventional EBRT technique. The global health status of the quality-of-life score for all patients was found to be lower. In patients with Gr2 and above toxicities, we observed better scores on emotional and social scales but poorer scores on functional and symptoms scales than reported in the literature.