Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology–Gynecologic Oncology Group protocol 240)

Summary Background GOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer signiﬁ cantly improves overall and progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240. Methods Eligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0–1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m² intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m² intravenously over 24 h or 175 mg/m² intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m² over 3 h on day 1) and topotecan (0·75 mg/m² for 30 min on days 1–3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred ﬁ rst. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov, number NCT00803062. Findings Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not diﬀ er signiﬁ cantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not diﬀ er signiﬁ cantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI –4·1 to 1·7; p=0·30). overall survival and progression-free survival bevacizumab cervical cancer


Introduction
Around 500 000 new cases of cervical cancer and 250 000 cervical cancer-related deaths occur worldwide every year. 1 Although screening with cytology and high-risk human papillomavirus DNA testing have reduced the incidence and mortality of this disease, women who do not have access to health care and those living in resource-poor areas remain at high risk of death from cervical cancer. Prophylactic human papillomavirus vaccination is an important preventive approach, but also one that needs access to health care. Although early-stage disease can be cured by radical surgery and locally advanced disease by chemoradiotherapy, women with metastatic and non-operable recurrent disease have previously had few treatment options. 1 Platinumbased chemotherapy in this setting is palliative and is associated with median overall survival of 8-12 months. 2 Vascular endothelial growth factor (VEGF) has emerged as an important therapeutic target in many solid tumours. 5 Gynecologic Oncology Group (GOG) protocol 240 (GOG 240) was a randomised phase 3 clinical trial that showed that, compared with chemotherapy alone, chemotherapy plus bevacizumab (a monoclonal antibody that binds VEGF) signifi cantly increased overall survival from 13·3 months to 17·0 months (hazard ratio [HR] 0·71 [98% CI 0·54-0·95], p=0·004) in patients with advanced cervical cancer. 6 The triplet regimens used in the study (cisplatin, paclitaxel and bevacizumab, and topotecan, paclitaxel and bevacizumab) were quite well tolerated but were both associated with a 6% incidence of fi stula and 8% incidence of thromboembolism (compared with fi stula <1% and thromboembolism 1% for either chemotherapy regimen alone without bevacizumab). On Aug 14, 2014, under the US Food and Drug Administration's (FDA) Priority Review programme (which makes promising therapies rapidly available to patients), both of these bevacizumab-containing triplet regimens were approved for the treatment of advanced cervical cancer.
In the advanced cervical cancer setting, quality of life must be measured to balance potential toxicities with treatment effi cacy; it is important to simultaneously assess quality of life while measuring progression-free and overall survival. Before GOG 240, progression-free and overall survival increases in cervical cancer treatments were modest, with little benefi t or diff erence in health-related quality of life. [7][8][9][10] In view of the poor prognosis for patients with advanced cervical cancer, we should strive to identify treatments that prolong life but do not create additional toxicities that would further compromise quality of life. With the typically marginal benefi t provided by the addition of new agents to combination chemotherapy, it was anticipated that short of an overall survival benefi t, clinical benefi t would have to be demonstrated by the additional benefi t of patient-reported outcomes to a progression-free survival advantage. Therefore, a major aim of GOG 240 was to establish whether or not the addition of bevacizumab to chemotherapy aff ected healthrelated quality of life. To establish whether or not baseline health-related quality of life in this population was associated with survival was an exploratory endpoint, since earlier published studies have indicated that quality of life at study entry is a prognostic indicator for survival.

Study design and participants
Entry criteria for this international, phase 3, multicentre, randomised controlled trial have been described previously. 6 Briefl y, eligible adult participants (≥18 years of age) were enrolled from participating National Cancer Institute GOG institutions in the USA and the Spanish cooperative group, Grupo Español de Investigation en Cancer de Ovario (GEICO) participating institutions in Spain. All participants had primary stage IVB or metastatic, recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0-1 (where 0 indicates that the person is fully active, and 1 indicates that the person is ambulatory but restricted in physically strenuous activities). No previous chemotherapy for recurrence was allowed, and no previous paclitaxel or topotecan with prior radiation was permitted. Patients had to have adequate renal, hepatic, and bone marrow function. Patients treated with chemotherapy for recurrence, and those with nonhealing wounds, active bleeding conditions, or inadequately anticoagulated thrombo embolism were ineligible. Patients with recurrent tumours that could be salvaged by pelvic exenteration were also not allowed to enroll in this study.
The trial was done through the GOG and GEICO, with funding from the National Institutes of Health and bevacizumab (Genentech, San Francisco, CA, USA/ Roche, Basel, Switzerland) supplied by the National Cancer Institute (NSC number 704865, Investigational New Drug number 113912), with central institutional review board approval and registration. All patients provided written informed consent before enrolment.

Randomisation and masking
Web-based permuted block randomisation, with a block size of 4, was done by the GOG Statistical and Data Center, with use of a 2 × 2 factorial design. The randomisation ratio was 1:1 for each level of each factor (subsitution of cisplatin with topotecan [ie, non-platinum chemotherapy doublet] and use of anti-angiogenesis therapy [bevacizumab]) or 1:1:1:1 for each treatment group. Random assignment to one of the four groups was balanced within disease status (recurrent or persistent vs stage IVB primary), GOG performance status (0 vs 1), and previous platinum therapy as a radiation sensitiser (eg, no previous cisplatin-based chemoradiotherapy vs previous cisplatin-based chemoradiotherapy). Treatment assignment was concealed to everyone at randomisation and became open-label when each patient was registered to the trial (which was immediately upon web-based registration with the National Cancer Institute and before the administration of any treatment).

Procedures
Briefl y, patients were randomly assigned to paclitaxel (135 mg/m² intravenously over 24 h or 175 mg/m² intravenously over 3 h on day 1) plus cisplatin 50 mg/m² intravenously on days 1 or 2, with or without bevacizumab 15 mg/kg intravenously on days 1 or 2; or paclitaxel 175 mg/m² over 3 h on day 1 with topotecan 0·75 mg/m² for 30 min on days 1-3, with or without bevacizumab 15 mg/kg intravenously on day 1. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred fi rst. To reduce the risk of neurotoxicity, paclitaxel infusions could also be given on non-platinum days. Disease was assessed by physical examination and chest radiography, and by abdomen and pelvic CT or MRI within 28 days before the study treatment was initiated. In patients without disease progression, imaging was repeated every other cycle. Tumour measurements according to the Response Evaluation Criteria in Solid Tumors (RECIST; version 1), were made within 1 week before the next planned cycle. After discontinuation of treatment, disease was assessed every 3 months for 2 years, followed by assessment every 6 months for 3 years until disease progression was documented. Safety, as assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, was monitored during each cycle. Patientreported outcomes, including health-related quality of life, were assessed for all treatment regimens at fi ve timepoints: at baseline (before randomisation), before cycles 2 and 5, and at 6 and 9 months since the start date of treatment cycle 1.

Outcomes
The primary endpoints of the GOG 240 trial were overall survival and the frequency and severity of toxicity, with progression-free survival and tumour response as secondary endpoints. Health-related quality of life and patient-reported outcomes were tertiary (exploratory) endpoints.
The health-related quality-of-life measures used in this trial were the Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) Trial Outcome Index (TOI), on which a higher score indicates better health-related quality of life; the FACT/GOG-Neurotoxicity four-item subscale (FACT/ GOG-Ntx-4), on which a higher score indicates less neurotoxicity; and the Brief Pain Inventory (BPI) single item assessing worst pain in the past 24 h, for which a higher score indicates more pain. These previously validated, self-reported measures were selected on the basis of previous justifi cation that quality of life, neurotoxicity, and pain are all sensitive to change in randomised clinical trials of advanced cervical cancer. All scales are available in English and Spanish; both language versions were used in this trial. 11,12 The FACT-Cx is the FACT-G plus a cervical cancerspecifi c subscale. 11 The FACT-G is a 27-item self-reported quality-of-life measure that includes four subscales (physical wellbeing, social wellbeing, functional wellbeing, and emotional wellbeing). Each scale produces a score, and the scores can be summed to produce a total quality-of-life score. The FACT-Cx endpoint for this trial focuses on aspects of health-related quality of life that are most sensitive and responsive in clinical trials. This FACT-Cx TOI is the summation of the physical wellbeing, functional wellbeing, and cervical cancer subscales.
FACT-Cx TOI was selected as the primary quality-of-life endpoint and consists of two subscales from the FACT-G: physical wellbeing (seven items) and functional wellbeing (seven items), plus the cervix cancer-specifi c subscale (15 items). 11,12 Four items from the 11-item FACT/GOG-Neurotoxicity (FACT/GOG-Ntx) subscale were included to assess this important side-eff ect (neurotoxicity) that is associated with many of the chemotherapy agents in this trial. These four questions are for sensory peripheral neuropathy and include, "I have numbness/tingling in my hands"; "I have numbness/tingling in my feet"; "I have discomfort in my hands"; and "I have discomfort in my feet") also explain more than 50% of the variation in the total Ntx score. 13,14 The BPI is a 23-item, self-reported measurement to assess pain in cancer and other diseases. 15 To limit patient burden, we selected the most frequently used endpoint Administrative error 6 (5%) 10 (9%) 6 (5%) 9 (8%) Lost to follow-up 7 (6%) 6 (5%) 7 (6%) 8 (7%) Other 5 (4%) 6 (5%) 8 (7%) 5 (5%) ( Table 1 continues on next page) from the BPI, which is the single item assessing "worst pain" in the past 24 h, on a 0-10 scale. Each item in the FACT-Cx TOI and FACT/GOG-Ntx4 subscale is scored on a fi ve-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The range of possible scores is 0-116 for the FACT-Cx TOI and 0-16 for the FACT/GOG-Ntx4 subscale. For all Functional Assessment of Chronic Illness Therapy (FACIT) patientreported outcome scales, a higher score indicates better quality of life or fewer symptoms or toxicity. Collection of the later patient-reported outcome data, at 6 and 9 months after the fi rst cycle, was needed irrespective of whether or not participants had experienced progressive disease, and participants had to fi ll out responses on their own (they were not allowed to be helped). Validation of the prognostic signifi cance of patient-reported outcomes in this trial was an exploratory endpoint.

Statistical analysis
Patients who completed baseline assessment and at least one follow-up self-reported outcome assessment were judged eligible for evaluation in this fi nal analysis. The association between baseline FACT-Cx TOI score and overall survival and progression-free survival was analysed with a proportional hazards model stratifi ed by prognostic factors, assignment of bevacizumab, and treatment with cisplatin or topotecan. 16 The median follow-up for survival was 20·8 months (IQR 14·0-27·4 months). 6 The presence of neurotoxic symptoms was defi ned as an Ntx score lower than 16. The severity of reported neurotoxic symptoms was established as the mean Ntx score that was less than 16. The distribution of the Ntx subscale score tended to show clumping at 16 (no neurotoxicity) and was skewed to the left. The distribution of BPI score tended to cluster at 0 (no pain) and was skewed to the right. To analyse these data, we used a mixed-eff ects mixed-distribution model. This model contains two components: the fi rst is a logistical model to estimate the odds of reporting a non-zero value (<16 for Ntx scores) and the second component models the possibly truncated distribution of the non-zero scores (again, <16 for Ntx scores). Random eff ects are used to account for the correlation of repeating measures within an individual. This model also allows for a correlation of the random eff ects from the two components of the model. 17 We did all analyses on the whole intention-totreat population using SAS/STAT software version 9.4. We assessed the diff erence in FACT-Cx TOI using the linear mixed model, adjusting for patient's pretreatment score, performance status, assignment of bevacizumab, treatment with cisplatin or topotecan, and age at enrolment. We treated the assessment timepoints as categorical since they are not equally spaced. We assumed the covariance matrix to be unstructured. To represent the observed covariance pattern of the TOI scores, the empirical variance was used to estimate the precision of parameter estimates. The denominator degrees of   freedom were approximated as described by Kenward and Roger. 14 The independence eff ect of two factors on quality of life (interaction between bevacizumab and topotecan or cisplatin) was tested fi rst, and the interactions between assessment timepoints and treatment assignments were then tested fi rst for diff erential eff ects of treatments on TOI scores over time. If the inter action eff ect was signifi cant, we estimated the treatment diff erences for each assessment timepoint. Otherwise, we estimated the overall treatment eff ect using a weighted average of estimates from each timepoint.
The sample size was ascertained by the primary clinical objective. 6 Because the original study design tested two independent hypotheses (eff ect of bevacizumab, and substitution of topotecan for cisplatin), to control the overall type 1 error at 5%, the signifi cance level was set to 0·0125 for the FACT-Cx TOI and the FACT/GOG-Ntx subscale, and 0·05 for the BPI worst pain score for exploratory purposes. According to previous studies, the correlation between repeated measures made on the same participant ranged from 0·3 to 0·8. With the assumption that at least 80% of eligible patients were evaluable for the analysis (ie, they completed baseline and at least one follow-up assessment), the study was expected to have at least 86% power to detect an eff ect size of 0·35 in FACT-Cx TOI scores between treatment groups. Treatment eff ect size was calculated as the ratio of the treatment diff erence to the baseline standard deviation in the control group. The minimum clinically important diff erence (ie, that perceived by patients as important, and by clinicians to require a change in the patients' management) for FACT-Cx TOI is believed to range from 5·8 to 8·7 points. 13 Every eff ort was made to avoid missing data and the reasons for missing assessments were collected at each assessment timepoint and documented in the analysis. The assessment compliances were compared across assigned groups with a generalised estimating equation. Additionally, multiple imputation for missing values was done using data from those patients who were still alive at assessment time. The results from multiple imputation were consistent with the original analysis. This study is registered with ClincialTrials.gov, number NCT00803062.

Role of the funding source
The funders had no role in the study design, conduct, analysis, interpretation of the data, or writing of the report. Only the statistician (HQH) had access to the raw data, according to GOG policy. The corresponding author had fi nal responsibility for the decision to submit for publication.

Results
Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial and assigned to the four treatment groups: 114 (25%) to cisplatin plus paclitaxel; 115 (25%) to cisplatin, paclitaxel, and bevacizumab; 111 (25%) to topotecan plus paclitaxel; and 112 (25%) to topotecan, paclitaxel, and bevacizumab. 426 (94%) of 452 patients completed the baseline qualityof-life assessment (table 1). Compliance to quality-of-life analysis (including in those who had progressive disease, since patients were followed for survival) dropped to 372 (84%) of 443 patients at pre-cycle 2 assessment, 322 (78%) of 412 at pre-cycle 5 assessment, 245 (67%) of 368 at 6 months post-cycle 1, and 193 (63%) of 307 at 9 months post-cycle 1 follow-up. Compliance did not diff er signifi cantly between treatment regimens (p=0·78; data not shown) and reasons for noncompliance were similar in the four treatment groups (table 1) outcome assessments (33 in the cisplatin and paclitaxel group, 36 in the cisplatin and paclitaxel plus bevacizumab group, 36 in the topotecan and paclitaxel group, and 38 in the topotecan and paclitaxel plus bevacizumab group), 14 patients (three in the cisplatin and paclitaxel group, three in the cisplatin and paclitaxel plus bevacizumab group, three in the topotecan and paclitaxel group, and fi ve in the topotecan and paclitaxel plus bevacizumab group) completed none. Additionally, 12 patients did not complete baseline quality-of-life assessments and 36 patients did not complete any follow-up assessments. These 62 patients were not evaluable for patient-reported outcomes and were therefore not included in the fi nal analysis. 390 patients completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes.
Clinical features of the 390 evaluable patients were similar in groups treated with chemotherapy with and without bevacizumab, and in those treated with cisplatin versus topotecan (table 2; appendix p 1). Overall, 153 (39%) of 390 had performance status 1, 322 (83%) had recurrent or persistent disease, and 286 (73%) had received previous platinum therapy. This study encouraged all patients to complete the patient-reported outcome, irrespective of their disease progression status. At 9 months, 104 (68%) of 153 of patients without disease progression and 83 (64%) of 129 with disease progression completed patient-reported outcomes (appendix p 2).
The baseline FACT-Cx TOI scores did not diff er signifi cantly between patients who received bevacizumab versus those who did not (p=0·27). Analyses of follow-up FACT-Cx TOI scores suggested no interaction between bevaci zumab and topotecan (p=0·31), or between assessment time and assignment of bevacizumab (p=0·29). Patients who received bevacizumab reported, on average across all timepoints, FACT-Cx TOI scores that were 1·2 points lower (98·75% CI -4·1 to 1·7) than did those receiving chemotherapy alone (p=0·30; fi gure 1A). After adjustment for baseline score and patients' age, those who received cisplatin and paclitaxel plus bevacizumab reported FACT-Cx TOI scores that were 2·1 points lower (95% CI -1·2 to 5·3) on average across all timepoints than those treated with cisplatin and paclitaxel alone (p=0·20; fi gure 1B). Patients who received topotecan and paclitaxel plus bevacizuamb reported 0·1 points higher scores (95% CI -3·1 to 3·2) on average across all timepoints on the FACT-Cx TOI than did those who were given topotecan and paclitaxel alone (p=0·96; fi gure 1C).

Discussion
This phase 3 study of the integration of anti-angiogenesis therapy for advanced cervical cancer showed that signifi cant improvements in overall survival, progressionfree survival, and the proportion of patients achieving an objective response conferred by the addition of bevacizumab to chemotherapy did not come at the cost of a concomitant deterioration of health-related quality of life as defi ned by the FACT-Cx TOI (panel). Specifi cally, the fi tted mixed model estimates for the FACT-Cx TOI scores shows that the addition of bevacizumab did not adversely aff ect quality of life. The eff ect of substitution of cisplatin with topotecan did not change quality of life, nor did it abrogate neurotoxic symptoms. Both triplet regimens of cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab have been granted regulatory approval by the US FDA for fi rst-line treatment of metastatic and recurrent cervical cancer and both triplets have been designated as Category 1 interventions in the National Comprehensive Cancer Network's Cervical Cancer Treatment Guidelines. This report confi rms the tolerability of these new combinations.
This study showed that baseline FACT-Cx TOI as a continuous variable is associated with both overall survival and progression-free survival. Clearly, baseline health-related quality of life is strongly predictive of survival in this population. 18,19 Importantly, to further explore the eff ect of health-related quality of life on survival, our quartiles analysis of the FACT-Cx TOI score indicate that the estimated HR of death for patients in the highest health-related quality-of-life quartile was much lower than for patients in the lowest quartile.
Baseline predictors of overall survival and progressionfree survival have clear clinical relevance, since they allow future studies to potentially pursue stratifi cation based on baseline scores to further establish diff erential treatment responses and, importantly, also provide an upfront opportunity to monitor and remediate symptoms that might be contributing to the decline in quality of life.
The 2·1-points lower FACT-Cx TOI measured in the cisplatin-paclitaxel-bevacizumab group than in the cisplatin-paclitaxel alone group after adjustment for baseline score and patients' characteristics could be regarded as an improvement, although it did not reach our prespecifi ed 5·8 points for clinically signifi cant improvement for the FACT-Cx TOI. This could be interpreted as encouraging for the development of combination of bevacizumab with the less toxic and equally eff ective carboplatin-paclitaxel com bination. However, carboplatin-related haemato logical toxicity can be substantial when patients have previously been treated with chemo radiotherapy, and this treatment approach should not yet be viewed as standard.
Several possible reasons exist for the recorded trend that patients receiving bevacizumab were less likely to report neurotoxic symptoms than were those who received chemotherapy alone, including secondary gains from increased tumour shrinkage, better health, or increased activity levels. 15,18,20 Conversely, the myalgias of bevacizumab-as perhaps documented in the BPI score-could function as a counter-irritant so-called distraction from neurotoxicity symptoms. 12 This idea is consistent with the gate theory of pain proposed by Melzack and Wall in 1965. 21 This theory suggests that physical pain is not a direct result of activation of pain receptor neurons, but rather its perception is modulated by interaction of a network of neurons and complex central processing. In addition to inducing angiogenesis and lymphangiogenesis, VEGF is also directly involved in neuroplasticity and nerve bundle maturation, and exerts protective eff ects on neurons. VEGF protects dorsal root ganglion neurons against paclitaxel-induced neuro toxicity. 22 Although factors such as disease site, histology, and intrinsic and acquired drug resistance mechanisms could ultimately decide which patients respond to anti-VEGF therapy, diff erential expression of the VEGF transcript should also be taken into account. 23,24 In GOG 240, patients who responded and ultimately benefi ted from treatment on the bevacizumab-containing regimens might have comprised an enriched population who express high amounts of the target. Such patients would also be expected to experience and report less severe neurotoxicity. However, predictive factors have not yet been defi ned. Notably, the absence of a proven diff erence in neurotoxicity between cisplatin-paclitaxel and topotecan-paclitaxel suggests that we have not yet identifi ed the appropriate methods to assess neurotoxicity with suffi cient sensitivity. In successive phase 3 randomised trials done by the GOG in patients with advanced cervical cancer, eligibility criteria have become stricter; 2-4 this is especially the case in GOG 240, in which the inclusion of an antiangiogenic agent undoubtedly contributed to a change in population demographics. The study needed patients to have better renal function than previous studies before enrolment, and excluded patients with a GOG perfor mance status of 2. Given that this population is mostly underserved with scarce resources, it was not uncommon in previous studies to have very ill patients enrolled in trials. Median survival in the preceding phase 3 protocol (GOG 204) was 12 months for patients who received the cisplatinpaclitaxel doublet, 3 which is closer to the real-world population of patients with advanced cervical cancer, who have a likely median survival time of 7 months or shorter-closer to the GOG phase 3 experiences from the 1990s. 2,4 Therefore, the 17 months median overall survival reported in GOG 240 associated with the groups in which anti-angiogenesis therapy was administered with chemo therapy represents a new benchmark that is more than double the median survival experienced off protocol and one that represents a degree of selection bias. 6 Further more, investigators were required to medically optimise their patients (address nutritional needs and correct renal dysfunction) in order for them to participate in this trial, and clinicians have become proactive with nephrostomies and ureteral stents, correcting anaemia and electrolyte abnormalities, and aggressively improving nutritional status. Although it cannot be quantifi ed, the contribution of medical optimisation to maintenance of quality of life in GOG 240 is implicit, and the general isability of study data necessitates that improve ments in supportive care be taken into account in consideration of the historical context.
Fatigue is the dominant symptom in patients with cancer. 25 Achievement of antiangiogenic blockade with tyrosine kinase inhibitors is associated with more fatigue than is reported with bevacizumab. The favourable side-eff ect and quality-of-life profi le of bevacizumab suggests it is one of the better novel biologics to use to achieve clinical benefi t, 26 which prompts the question as to whether fewer cycles of chemo therapy with maintenance bevacizumab is a good future strategy. Ongoing analyses are assessing whether or not it is possible to predict which patients are at risk of fi stula or gastro intestinal perforation, and whether these adverse events can be avoided.
Patients with cervical cancer often experience quality-oflife disruptions from physical symptoms including pain; bowel, bladder, and sexual dysfunction; and lymphoedema. 20 Additional key psychological and physical health factors have been identifi ed, which contribute substantially to poor quality of life subsequent to defi nitive cancer treatment. 27 Most of these factors are amenable to supportive care inter ventions, and could be assessed at the time of primary treatment.