Quality of Life among Survivors of Locally Advanced Cervical Cancer Treated with Definitive Chemoradiotherapy in a Decade of Transition

Introduction

Cervical cancer is the fourth most common cancer in women.¹ In 2018, around 570,000 women were diagnosed to have cervical cancer, and almost half died of this disease.² Despite worldwide implementation of prevention and early detection strategies, like the Papanicolaou smear and Human Papillomavirus vaccination, cervical cancer remains to be prevalent and is associated with significant morbidity, especially among the low to middle income countries. It has a crude annual incidence rate of 13.6 per 100,000 women, with up to 30% of new cases being diagnosed at a locally advanced stage (IIA to IVA).³

The current standard treatment for locally advanced cervical cancer (LACC) is concurrent chemoradiation (CRT). As demonstrated by five landmark trials, the addition of cisplatin-based chemotherapy to external beam radiotherapy (EBRT) improved oncologic outcome for LACC.^4,5,6,7,8 A meta-analysis in 2008 of 18 randomized trials showed a 6% improvement in the 5-year survival with CRT compared with EBRT alone.⁹ In the past decade, advancements in EBRT and brachytherapy (BRT) led to improvement in locoregional control and toxicity. These include the use of three-dimensional conformal (3DCRT) and intensity-modulated radiotherapy (IMRT),¹⁰ nodal boost,^11,12 image-guided radiotherapy,¹³ image-guided brachytherapy (IGBT),¹⁴ and hybrid intracavitary-interstitial brachytherapy (ICISBT) techniques.¹⁵ These strategies are aimed to improve tumor coverage and increase tumor dose, while improving organ-sparing, thus improving local control and decreasing radiotherapy-related complications.

Cervical cancer will affect quality of life (QoL) from diagnosis, during treatment, and up to the survivorship phase. This can be positive or negative and will differ at different time points.¹⁶ As treatments improve survival, more emphasis should be given to QoL and survivorship. Since late toxicities could be persistent and their impact on QoL pervasive,^16,17 preventative, supportive, rehabilitative, and compensatory strategies need to be defined. While reasons for looking into these long-term QoL outcomes are compelling, most of the randomized controlled trials with radiotherapy have a limited follow-up period.¹⁸ There is a lack of data regarding long-term QoL and treatment-related side effects among LACC survivors.

This systematic review synthesized published data from 2010 to 2020 on long-term QoL and toxicity among LACC survivors treated with definitive CRT (CRT followed by BRT). Furthermore, the investigators sought to review clinical determinants of QoL.

Methodology

Results

Search Results

The search was conducted on October 15, 2020. Fig. 1 shows the flow diagram for selection of studies.

Close

Fig. 1 Flow diagram for selection of studies.

Export to PPT

A total of 2,025 articles were identified by searching the databases, of which 129 duplicates were removed. All remaining articles underwent title and abstract screening, and 1,841 articles were excluded after not meeting the initial inclusion criteria. From these, 55 articles remained, and subsequent full-text assessment yielded four eligible papers.

Manual search was performed after, wherein 1,215 studies were retrieved and screened. Of these, nine papers were retrieved for review. Four were excluded, as they were identified to be updated, outcome-specific analyses of an already included study. Five were retained, making a total of nine studies for inclusion in the final review and synthesis.

Discussion

Advancements in the management of LACC in the past decade have resulted in improved disease control and survival. This increased survival means that post-treatment morbidity and QoL have become more relevant. Indeed, QoL has emerged as an important clinical end point in trials.^22,34,35

The EORTC QLQ-C30 and QLQ-CX24 are well-validated³⁶ and have been widely used in clinical trials. Their availability in several languages allows use in different countries. As we begin to understand better long-term QoL among cervical cancer survivors, the EORTC has begun developing and validating QoL tools specific to cancer survivors. Currently, survivorship modules for breast, colorectal, and prostate cancer are under development.³⁷

In our review, the EORTC QLQ-C30 and CX24 were the most commonly used tools in evaluating health-related and disease-specific QoL.^{19,22,23,25,26,27} Two papers characterized the temporal evolution of health-related QoL among LACC survivors.^19,21 One reported improvement at 12, 24, and 36 months.¹⁹ In this cohort, 3DCRT or IMRT, and IGBT were used entirely, and hybrid ICISBT was an available modality. The other employed 2D BRT in the majority of its cohort and reported worsened QoL at 12 months.²² A cross-sectional study reports that, at 4 years, global health impairment among survivors remains prevalent.²⁷

Significant QoL impairment was documented in four domains: gastrointestinal, genitourinary, sexual, and psychosocial.

Gastrointestinal dysfunction is among the most prevalent and persistent.^19,25 While constipation tended to improve, diarrhea persisted beyond 24 months. Diarrhea, due to chronic radiation enteropathy,³⁸ needs to be differentiated from pseudodiarrhea, or increased stool frequency that could be due to chronic radiation proctopathy.³⁹ Radiation enteropathy is associated with chronic inflammation of the bowels, leading to malabsorption and malnutrition, not unlike bowel inflammatory disease. Radiation proctopathy is associated with mucosal atrophy and telangiectasia and decreased capacity of the rectal vault due to fibrosis. This could manifest as increased stool frequency and rectal bleeding. Preventative interventions include agents that could counteract the oxidative injury of radiation to these organs, such as vitamin E and analogs, superoxide dismutase and mimetics, and amifostine; and agents that modulate pathophysiological responses to radiation injury, such as immune-modulating drugs (misoprostol), enterotrophic agents, and compounds that modulate intraluminal contents (sucralfate, somatostatin). These interventions are either investigational, of poor practicality, or of uncertain safety or effectiveness.³⁸ Thus, preventative strategies remain largely limited to decreasing radiation dose to small bowels and the rectum, which entails improvement of radiation delivery.^40,41 Compensatory and supportive strategies include dietary modification and nutritional supplementation.⁴²

Two studies primarily investigated genitourinary function. Gargiulo et al reported urinary incontinence to be common but rarely disabling at 36 months.²⁵ Conversely, Katepratoom et al,²⁰ using the UDI, found lower urinary tract symptoms to remain prevalent (77%), stress incontinence being the most common, among survivors at 6 years. Importantly, lower urinary tract dysfunction was present in 60%. Fokdal et al reported rates of mild to moderate and severe to life-threatening urinary morbidity to be 57.5 and 5.1% respectively, in a cohort treated entirely with 3DCRT or IMRT, and IGBT, at 27 months. Documented end points were similar, with frequency, incontinence, and cystitis occurring most frequently. Radiotherapy dose-volume constraints were proposed for the prevention of urinary morbidity.⁴³ Parasympathetic nerve damage and sympathetic denervation, as well as radiation injury leading to fibrosis and sclerosis, have been associated with these complications following typical treatment regimens.⁴⁴ Other proposed preventative strategies include identifying co-existing anatomical abnormalities prior to treatment and implementing preventive pelvic floor muscle exercises to maintain muscle strength.^45,46 Pharmacologic interventions, such as non-steroidal anti-inflammatory drugs (ibuprofen, solifenacin) for dysuria, antispasmodics (oxybutynin, tolterodine) for detrusor instability, or local vaginal estrogen can also be prescribed.^42,47 Early identification and management of related complications, (UTI, ureteral strictures, and fistulae), and urogynecologic referral are recommended compensatory and supportive strategies.⁴⁷

Three studies investigated primarily sexual function. Rai et al reported sexual inactivity to remain prevalent, and dyspareunia and vaginal tightness and shortening to persist among LACC survivors at 12 months.²³ Even in a cohort of only Stage IIB cervical cancer survivors, Ljuca and Marošević reported that overall sexual function remained unimproved at 12 months, despite improved vaginal function.²⁶ Furthermore, Daga et al reported that sexual function impairment was prevalent on follow-up beyond 2 years.³¹ Kirchheiner et al have proposed radiation dose-volume parameters to prevent vaginal toxicity⁴⁸ and, in an abstract-only article, they reported sexual QoL outcomes in their updated cohort.⁴⁹ At 36 months, sexual activity was reported in more than half. Among these, compromised sexual enjoyment was reported in nearly half, and sexual function problems in around one-third. Supportive strategies for vaginal dryness or stenosis include lubricants and estrogen creams, and vaginal dilators.³¹ In addition to vaginal toxicity, pelvic radiotherapy results in ovarian dysfunction and onset of menopausal symptoms, such as hot flashes and fatigue,⁵⁰ which could in turn contribute to diminished sexual desire, arousal, and satisfaction. Management includes hormone replacement therapy to decrease symptoms and improve QoL.²² Among survivors with sexual function issues, the presence of symptoms of distress, anxiety, depression or other psychological concerns needs to be evaluated.⁴²

One study investigated primarily symptoms of distress. Conway et al reported that, while most psychological symptoms (pain, drowsiness, depression, anxiety) improved at 12 and 24 months, tiredness and a lack of sense of well-being tended to worsen.²¹ Furthermore, Kirchheiner et al reported a decline in role and social function at 36 months,¹⁹ and Prasongvej et al reported prevalent physical and role function impairment at 4 years.²⁷ Patient education could alleviate distress, anxiety, and depression, improve their sense of empowerment, and foster a more active and collaborative role in their own management, which has been shown to improve QoL. Social reintegration and opportunities for employment and engagement could foster a sense of well-being, purpose, and belongingness. The National Cancer Comprehensive Network has published patient education resources for cancer survivors.⁵¹

Several late toxicities are worth further discussing: peripheral neuropathy, lymphedema, and insufficiency fractures.

Peripheral neuropathy was reported to develop early and persist at 12 months,²² highlighting the long-term effects of platinum therapy. Further, the recognition of cisplatin-related ototoxicity has been well-documented for head-and-neck cancers, but less so for cervical cancers.⁵²

Lymphedema was noted to develop more gradually.¹⁹ Lower-limb and perineal lymphedema is a documented complication of both surgery (surgical nodal staging and therapeutic lymphadenectomy) and radiotherapy for cervical cancer.⁵³ Ferrandina et al⁵⁴ noted early worsening of lymphedema, both in early cervical cancer patients who underwent surgery and in LACC patients treated with CRT followed by surgery. However, lymphedema among the latter tended to peak higher (28.3% relative to baseline) compared with the former (14.6%), highlighting the combined effect of the two modalities. The increasing use of positron emission tomography scan in staging has led to diminished use of surgical nodal staging. On the other hand, the increasing use of nodal boost, as well as ICISBT, may lead to higher lymphedema rates. In a cohort treated entirely by 3DCRT or IMRT and IGBT, and that utilized nodal boosts as indicated, Najjari et al⁵⁵ reported an incidence rate of 22.2% at 27 months, and obesity and invasive nodal staging to be significant determinants. On the other hand, an extended EBRT field was associated with a non-significant correlation, and nodal boost, no correlation, with lymphedema. The burden of lymphedema could be alleviated by early identification, self-care management, supportive interventions (compression garments, manual drainage), and rehabilitative interventions (range-of-motion exercises).⁴²

Musculoskeletal events, specifically insufficiency fractures, although uncommon, have been reported on longer-term follow-up,²¹ supporting the practice of limiting radiation doses to the femurs, as well as the importance of vitamin D supplementation, osteoporosis screening, and hormonal replacement therapy.⁴²

Limitations

The number and quality of studies included in our review reflect the relative paucity of high-quality literature on long-term QoL among LACC survivors. Of the nine papers included in this review, one¹⁹ is a multinational study; six^{20,21,22,25,26,27} come from upper-middle or high income countries, namely, Brazil, Canada, Italy, Bosnia and Herzegovina, and Thailand; and two^23,31 come from a lower-middle income country, India.⁵⁶ The studies include three small (<50) cross-sectional studies,^20,27,31 one (n = 67) retrospective study,²¹ and three small (<60) prospective studies.^23,25,26 Only the multinational study¹⁹ reported multiple QoL assessments beyond the first year after completion of therapy, while only two cross-sectional studies from Thailand^20,27 provide QoL data beyond 3 years of survivorship.

Given these, information on determinants for QoL or its domains that could be derived from this review are limited. Age was a determinant for body image, sexual activity, and menopausal symptoms.²² Age, stage, and baseline symptom distress levels were determinants for long-term symptom distress.²¹ Baseline physical condition, which was measured using the EORTC QLQ-C30 functioning scale, predicted the development of dyspnea.¹⁹ Age and baseline physical condition impact QoL domains among survivors differently. Aside from age-related differences in physical, social, and sexual functional demands, CRT exposure at a younger age could lead to premature menopause. This could mean increased burden of menopausal symptoms and risks for cardiovascular and skeletal events. Among the elderly, the late effects of CRT compound the already complex interactions of co-existing comorbidities.

Recommendation

The multinational, mostly European, group has published updated, outcome-specific analyses directed toward identifying optimal radiotherapy dose-volume parameters, based on their growing prospective observational cohort.^15,40,50,55 The group has also published a review article on systematic assessment and registration of morbidity outcomes.⁵⁷ This demonstrates the feasibility of establishing collaborative regional prospective registries to generate meaningful data that are appropriate to each region or locality and could inform clinical decision-making, both in the active treatment and post-treatment surveillance, toward improving QoL outcomes among LACC survivors.

Conclusion

Advances in the delivery of definitive CRT for LACC have resulted in improved disease control and survival, and QoL and survivorship have become paramount. Published quality data on QoL are limited. Cohorts that employ advanced EBRT and BRT techniques find overall QoL to improve in the first 3 years from treatment completion. Nevertheless, gastrointestinal, genitourinary, sexual, and psychosocial function impairment persist on the long-term. Other late toxicities worth noting include peripheral neuropathy, lower limb edema, and insufficiency fractures. Collaborative prospective registries could generate data that could clarify determinants of QoL and inform treatment and surveillance strategies toward improving QoL among LACC survivors.