Absolute Improvement In Survival Research Articles

Receipt of RhD-positive whole blood for life-threatening bleeding in female children: A survey in alloimmunized mothers regarding minimum acceptable survival benefit relative to risk of maternal alloimmunization to anti-D.

Low-titer group O whole blood (LTOWB) for treatment of hemorrhagic shock sometimes necessitates transfusion of RhD-positive units due to short supply of RhD-negative LTOWB. Practitioners must choose between using RhD-positive LTOWB when RhD-negative is unavailable against the risk to a female of childbearing potential of becoming RhD-alloimmunized, risking hemolytic disease of the fetus and newborn (HDFN) in future children, or using component therapy with RhD-negative red cells. This survey asked females with a history of red blood cell (RBC) alloimmunization about their risk tolerance of RhD alloimmunization compared to the potential for improved survival following transfusion of RhD-positive blood for an injured RhD negative female child. A survey was administered to RBC alloimmunized mothers. Respondents were eligible if they were living in the United States with at least one red cell antibody known to cause HDFN and if they had at least one RBC alloimmunized pregnancy. Responses from 107 RBC alloimmmunized females were analyzed. There were 32/107 (30%) with a history of severe HDFN; 12/107 (11%) had a history of fetal or neonatal loss due to HDFN. The median (interquartile range) absolute improvement in survival at which the respondents would accept RhD-positive transfusions for a female child was 4% (1%-14%). This was not different between females with and without a history of severe or fatal HDFN (p = .08 and 0.38, respectively). Alloimmunized mothers would accept the risk of D-alloimmunization in a RhD-negative female child for improved survival in cases of life-threatening bleeding.

Association between admission to a cardiac arrest centre and survival to hospital discharge for adults following out-of-hospital cardiac arrest: A multi-centre observational study

AimThis study examined the association between admission to a cardiac arrest centre and survival to hospital discharge for adults following out-of-hospital cardiac arrest (OHCA). MethodsWe undertook a multicentre retrospective observational study of patients transferred to hospital after OHCA of presumed cardiac aetiology in three ambulance services in England. We used propensity score matching to compare rates of survival to hospital discharge in patients admitted to OHCA centres (defined as either 24/7 PPCI availability or >100 OHCA admissions per year) to rates of survival of patients admitted to non-centres. ResultsBetween January 2017 and December 2018, 10,650 patients with OHCA were included in the analysis. After propensity score matching, admission to a hospital with 24/7 PPCI availability or a high volume centre was associated with an absolute improvement in survival to hospital discharge of 2.5% and 2.8%, respectively. The corresponding odds ratios and 95% confidence intervals were 1.69 (1.28–2.23) and 1.41 (1.14–1.75), respectively. The results were similar when missing values were imputed. In subgroup analyses, the association between admission to an OHCA centre and improved rates of survival was mainly seen in patients with OHCA due to shockable rhythms, with no or minimal potential benefit for patients with OHCA and asystole as first presenting rhythm. ConclusionFollowing OHCA, admission to a cardiac arrest centre is associated with a moderate improvement in survival to hospital discharge. A corresponding bypass policy would need to consider the resulting increased workload for OHCA centres.

The Impact of Adjuvant Postoperative Radiation Therapy and Chemotherapy on Survival After Esophagectomy for Esophageal Carcinoma.

The objective of this study was to analyze the impact on overall survival (OS) from the addition of postoperative radiation with or without chemotherapy after esophagectomy, using a large, hospital-based dataset. Previous retrospective studies have suggested an OS advantage for postoperative chemoradiation over surgery alone, although prospective data are lacking. The National Cancer Data Base was queried to select patients diagnosed with stage pT3-4Nx-0M0 or pT1-4N1-3M0 esophageal carcinoma (squamous cell or adenocarcinoma) from 1998 to 2011 treated with definitive esophagectomy ± postoperative radiation and/or chemotherapy. OS was analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was used to identify covariates associated with OS. There were 4893 patients selected, of whom 1153 (23.6%) received postoperative radiation. Most patients receiving radiation also received sequential/concomitant chemotherapy (89.9%). For the entire cohort, postoperative radiation was associated with a statistically significant but modest absolute improvement in survival (hazard ratio 0.77; 95% CI, 0.71-0.83; P < 0.001). On subgroup analysis, postoperative radiation was associated with improved OS for patients with node-positive disease (3-yr OS 34.3 % vs 27.8%, P < 0.001) or positive margins (3-yr OS 36.4% vs 18.0%, P < 0.001). When chemotherapy usage was incorporated, sequential chemotherapy was associated with the best survival (P < 0.001). Multivariate analysis revealed that the addition of chemotherapy to radiation therapy, whether sequentially or concurrently, was a strong prognostic factor for OS. In this hospital-based study, the addition of postoperative chemoradiation (either sequentially or concomitantly) after esophagectomy was associated with improved OS for patients with node-positive disease or positive margins.

PL05.05: Chemotherapy

PL05.05: Chemotherapy

Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data

SummaryBackgroundResults from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis.MethodsFor this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel).FindingsWe identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68–0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5–14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58–0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12–19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69–1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61–0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5–10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79–0·98]; p=0·025), which translates to 5% (1–8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83–1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (−3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89–1·18]; p=0·724) or zoledronic acid (0·98 [0·82–1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials.InterpretationThe addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small.FundingMedical Research Council UK.

PWE-325 Do we practice what we preach with complete responders in rectal cancer?

Introduction There is a lack of conclusive long-term studies evaluating risk and benefit in the surgical management of complete pathological response to rectal cancer. The trend in practice is becoming increasingly conservative, especially with an ageing population with increasing comorbidity, with recent data supporting a ‘watch and wait’ approach to complete responders. A recently published article utlilsing decision-analytical modelling predicted no difference in survival in 60 year old male patients between those managed conservatively and operatively. More interestingly they predicted a significant improvement in absolute survival in 80 year olds managed conservatively. Given the trend of the current evidence we aimed to determine the regional practice in Merseyside. We questioned whether increased age and/or comorbidity influenced surgeon decision when complete pathological response was detected. Method A questionnaire was submitted to all the colorectal cancer surgeons within the greater Merseyside region, in the north west of England, United Kingdom. The participants were asked for their practice in managing 3 patient cohorts (60, 70, 80 years of age) with complete pathological response and of varying comorbid status. They were then asked for their preference should they be faced with the same clinical scenario personally. Results 10 colorectal cancer units with 33 colorectal surgeons were surveyed. The response rate was 23/33 (70%). 5% of surgeons would offer surgery to 70–80 year old patients with multiple comorbidities, whereas 22% would if the patient was 60 years of age. 27% of surgeons would offer surgery to patients who were 80 years of age who had no medical comorbidities, and 55% would if they were 60 years of age with no comorbidities. 66% of surgeons would not want any surgery if they personally had a completely responding rectal cancer. 44% would want different treatment from what they would offer their patients. One surgeon would not routinely offer surgery but would personally want one. Conclusion Patients with complete pathological response get different treatment according to surgeon preference in Merseyside. 44% of surgeons would advise their patients something they would not choose should they be faced with the same scenario. More study into the long-term risk and benefit of surgical vs. conservative management of complete responders is required, in order that surgeons can offer a more evidence based treatment for the patient, a treatment they would wish upon themselves. Disclosure of interest None Declared.

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.

To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Effect of early versus late or no tracheostomy on mortality of critically ill patients receiving mechanical ventilation: a systematic review and meta-analysis

Delay of tracheostomy for roughly 2 weeks after translaryngeal intubation of critically ill patients is the presently recommended practice and is supported by findings from large trials. However, these trials were suboptimally powered to detect small but clinically important effects on mortality. We aimed to assess the mortality benefit of early versus late or no tracheostomy in critically ill patients who need mechanical ventilation. We systematically searched PubMed, CINAHL, Embase, Web of Science, DOAJ, the Cochrane Library, references of relevant articles, scientific conference proceedings, and grey literature up to Aug 31, 2013, to identify randomised controlled trials comparing early tracheostomy (done within 1 week after translaryngeal intubation) with late (done any time after the first week of mechanical ventilation) or no tracheostomy and reporting on mortality or incidence of pneumonia in critically ill patients under mechanical ventilation. Our primary outcomes were all-cause mortality during the stay in the intensive-care unit and incidence of ventilator-associated pneumonia. We calculated pooled odds ratios (OR), pooled risk ratios (RR), and 95% CIs with a random-effects model. All but complications analyses were done on an intention-to-treat basis. Analyses of 13 trials (2434 patients, 800 deaths) showed that all-cause mortality in the intensive-care unit was significantly lower in patients assigned to the early versus the late or no tracheostomy group (OR 0·72, 95% CI 0·53-0·98; p=0·04). This finding represents an 18% reduction in the relative risk of death, translating to a 5% absolute improvement in survival (from 65% to 70%). This result persisted when we considered only trials with a low risk of bias (663 deaths; OR 0·68, 95% CI 0·49-0·95; p=0·02; eight trials with 1934 patients). There was no evidence of a difference between the compared groups for 1-year mortality (788 deaths; RR 0·93, 95% CI 0·85-1·02; p=0·14; three trials with 1529 patients). The synthesised evidence suggests that early tracheostomy is associated with lower mortality in the intensive-care unit than late or no tracheostomy; a finding that might question the present practice of delaying tracheostomy beyond the first week after translaryngeal intubation in mechanically ventilated patients. However, the scarcity of a beneficial effect on long-term mortality and the potential complications associated with tracheostomy need careful consideration; thus, further studies focusing on long-term outcomes are warranted. None.

Efficacy of a Low-Cost Bubble CPAP System in Treatment of Respiratory Distress in a Neonatal Ward in Malawi

BackgroundRespiratory failure is a leading cause of neonatal mortality in the developing world. Bubble continuous positive airway pressure (bCPAP) is a safe, effective intervention for infants with respiratory distress and is widely used in developed countries. Because of its high cost, bCPAP is not widely utilized in low-resource settings. We evaluated the performance of a new bCPAP system to treat severe respiratory distress in a low resource setting, comparing it to nasal oxygen therapy, the current standard of care.MethodsWe conducted a non-randomized convenience sample study to test the efficacy of a low-cost bCPAP system treating newborns with severe respiratory distress in the neonatal ward of Queen Elizabeth Central Hospital, in Blantyre, Malawi. Neonates weighing >1,000 g and presenting with severe respiratory distress who fulfilled inclusion criteria received nasal bCPAP if a device was available; if not, they received standard care. Clinical assessments were made during treatment and outcomes compared for the two groups.Findings87 neonates (62 bCPAP, 25 controls) were recruited. Survival rate for neonates receiving bCPAP was 71.0% (44/62) compared with 44.0% (11/25) for controls. 65.5% (19/29) of very low birth weight neonates receiving bCPAP survived to discharge compared to 15.4% (1/13) of controls. 64.6% (31/48) of neonates with respiratory distress syndrome (RDS) receiving bCPAP survived to discharge, compared to 23.5% (4/17) of controls. 61.5% (16/26) of neonates with sepsis receiving bCPAP survived to discharge, while none of the seven neonates with sepsis in the control group survived.InterpretationUse of a low-cost bCPAP system to treat neonatal respiratory distress resulted in 27% absolute improvement in survival. The beneficial effect was greater for neonates with very low birth weight, RDS, or sepsis. Implementing appropriate bCPAP devices could reduce neonatal mortality in developing countries.

Adjuvant Chemotherapy for Stage II Colon Cancer: Less Complicated Than We Thought

TO THE EDITOR: In his recent editorial, Mayer agreed with the conclusion of Tournigand et al that there is no benefit for the inclusion of oxaliplatin in adjuvant chemotherapy regimens for patients with standard or indeed high-risk stage II colon cancer. Mayer then posed the question as to whether these patients, with a generally favorable prognosis, merit any adjuvant treatment at all. The virtues of prolonged clinical trial follow-up to provide mature survival data were extolled, but it surprised us greatly that no mention was made of Quasar (Quick and Simple and Reliable) 1 (A UKCCR[United Kingdom Coordinating Committee on Cancer Research] Study of Adjuvant Chemotherapy for Colorectal Cancer), the only trial in this field to show a survival benefit for patients with stage II colon cancer. In the Quasar 1 study, 2,291 patients with colon cancer were randomly assigned to receive chemotherapy with fluorouracil and leucovorin or to undergo observation. After a median follow-up of 5.5 years, the trial demonstrated that although the absolute improvements are small, the relative risk of death that was observed translates into a significant absolute improvement in survival of 3.6% (95% CI, 1.0 to 6.0; P .04). This is by far the largest and therefore the most informative trial of chemotherapy ever undertaken for this disease, and it is the only trial to show a significant survival benefit. The fluorouracil-based chemotherapy was well tolerated, and we believe that these results are sufficient to mandate an informed discussion with all patients with stage II colon cancer so that at least the offer of treatment might be made. Furthermore, we have worked with colleagues from the National Surgical Adjuvant Breast and Bowel Project, the Cleveland Clinic, and Genomic Health to develop a polymerase chain reaction– based prognostic gene signature that has now been validated in more than 5,000 patients. This can be used to define the risk of recurrence with greater precision than conventionally accepted high-risk criteria, and therefore can inform and influence the outcome of the physicianpatient consultation. We believe that there are data and validated tools that support rational and informed decision making on the utility of adjuvant fluorouracil-based therapy for patients with stage II colon cancer, and that matters are not necessarily as nihilistic as Mayer implies.

Use of iPad technology to determine cancer patient-reported preferences for and understanding of pharmacogenetic testing (PGT).

319 Background: PGT in oncology can be used to predict the efficacy and toxicity of a particular treatment in an individual. Previous work by our group has demonstrated that among cancer patients willing to undergo chemotherapy, &gt;98% wanted PGT testing if it could identify patients who would respond to chemo. However, in the original study using a paper questionnaire, 22% of patients did not understand the concept of PGT and its clinical implications. Therefore, we have devised a simpler, more visual questionnaire in electronic format using iPad technology and simple animations. We are assessing if patient understanding using this format is increased and also if patients prefer completing the survey with this novel technology. Methods: An interim analysis of a broad cross-section of cancer patients using an iPad was performed. PGT questions related to hypothetical efficacy, toxicity, time to test results, willingness to pay as well as understanding of PGT scenarios were assessed. Results: 135 cancer patients (87% adjuvant, 12% metastatic; 27% breast, 25% colon, 22% heme malignancy, 23% other) attending Princess Margaret Hosptial participated. 85% of patients accepted chemo that had a 5% absolute improvement in survival and &lt;10% chance of side effects. 94% of patients chose to have PGT if it could identify subsets of patients who would benefit from chemo. The median that patients were willing to pay for PGT was $250 (range $0-$5,000), however the median that patients felt was a reasonable price was $100 ($0-$5,000). 11% of patients admitted that they did not understand the concept of PGT and its clinical implications. Conclusions: Almost all patients who were willing to undergo chemo were also willing to accept PGT. Fewer patients in this study compared with our original paper directed questionnaire described themselves as lacking an understanding of PGT (11% versus 22% respectively), suggesting that survey administration on an iPad with a visual characterization of question scenarios improved understanding. Final data from over 300 patients will be analyzed in the fall, which would include data on patient attitudes on use of such technology for communication and decision making.

Aromatase inhibitors: what is the true cost?

The major tenets of systemic anti-cancer therapy should be to improve either or both overall survival and quality of life with acceptable cost–benefit. In this issue of the Journal, Vitry et al. discuss the rising costs associated with the use of aromatase inhibitors (AIs) in the treatment of breast cancer.1 As they point out, this class of drugs is now the preferred choice in Australia despite the lack of evidence of improvement in overall survival and the cost being six times that of the alternative drug, tamoxifen. Tamoxifen, a selective oestrogen receptor modulator, has a proven survival benefit in the adjuvant setting, along with a well-understood side-effect profile that includes hot flushes (common) as well as deep vein thrombosis and uterine cancer at a combined rate of 0.2% per decade among women on treatment for 5 years.2 An overview of randomized trials of tamoxifen has shown an absolute improvement in survival of 9.2% at 15 years after diagnosis compared with no tamoxifen.2 For individual women the magnitude of benefit will vary with the risk of recurrence. The AIs prevent the synthesis of oestrogen from adrenal produced androgen by blocking the aromatase enzyme. They are suitable only for postmenopausal women. Their side effects include hot flushes and arthralgia; the latter can affect 15–25% of women.3 AIs can cause a fall in bone mineral density (BMD) and a subsequent increased risk of fracture during treatment. This increased risk resolves after stopping treatment.3 Patients on an AI should have their BMD measured at baseline and every 2 years while on treatment. A fall in BMD or a low baseline can be treated with an oral or i.v. bisphosphonate, with their inherent toxicities and costs. Adjuvant AI therapy has consistently been shown to be superior to tamoxifen in terms of disease-free survival (delaying recurrence) but has not been shown to improve overall survival.4 Ten-year survival data for 5 years of tamoxifen compared with 5 years of the AI anastrozole, the most mature AI trial to date, have recently been published. The absolute reduction in recurrence with anastrozole compared with tamoxifen was 4.3% at 10 years. There was no improvement in overall survival. The number of deaths after breast cancer recurrence in the anastrozole arm of the trial was reduced. However, the increase in the number of deaths from other cancers and other causes in those without breast cancer recurrence resulted in similar overall survival to tamoxifen.5 Letrozole, another AI compared with tamoxifen in the adjuvant setting, now has 6-year data.6 An earlier interim analysis had shown an improvement in disease-free survival and subsequent unblinding allowed cross-over to the AI arm. Intention-to-treat analysis has not shown a significant improvement in survival. Subgroup analyses excluding patients who were allowed to cross-over are underpowered and post-hoc but do show a small advantage in this group.6 It may be that a true survival advantage exists but is likely now never to be proven. This will be an ongoing problem in oncology as primary outcomes other than overall survival are now frequent and these early results often prompt cross-over in trials. Vitry et al. discuss the cost to the Pharmaceutical Benefits Scheme of the increase in prescribing of AIs. The true total cost of this treatment must include the cost of measuring, preventing and treating the effects on BMD, including the costs borne by patients of calcium and vitamin D supplementation and analgesia for arthralgia. This would seem likely to be more than the cost of managing the side effects of tamoxifen. We know from the chemotherapy published work that breast cancer patients will accept side effects for even very small advantages in survival, but it is less clear whether they accept this for delayed recurrence alone. Certainly, the compliance with any adjuvant hormone therapy is known to be poor. Aromatase inhibitors are not cheap. They offer a choice to women and their oncologists with regard to side-effect profile and have a role in delaying recurrence. They are just one example of new cancer treatments, often expensive, which provide improvements in disease-free survival in the adjuvant setting or progression-free survival in the metastatic setting but have no clear overall survival benefit. As a society, are we prepared to continue to bear the cost of these medications, or should we adopt a more hardline stance and only accept expensive new drugs if there is an improvement in quality of life and/or a clear and meaningful overall survival advantage?

Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer

Since our individual patient data (IPD) meta-analysis of supportive care and chemotherapy for non-small cell lung cancer (NSCLC), published in 1995, many trials have been completed. We have carried out an updated IPD meta-analysis to assess newer regimens and determine conclusively the effect of chemotherapy. To assess the effect on survival of supportive care and chemotherapy versus supportive care alone in advanced NSCLC. All randomised controlled trials (RCTs), published or unpublished. We searched bibliographic databases, trials registers, conference proceedings and reference lists of relevant trials. Searches were completed to November 2009. Trials had to have commenced accrual on or after 1 January 1965 and should have included patients with NSCLC who had received either chemotherapy and supportive care or supportive care alone. Patients should have not received any previous chemotherapy or had any prior malignancy. For trials included in 1995 we sought updated follow up. For new trials we sought survival and baseline characteristics for all patients. We combined results from RCTs to calculate individual and pooled hazard ratios (HRs). We obtained data on 2714 patients from 16 RCTs. There were 1293 deaths among 1399 patients assigned supportive care and chemotherapy and 1240 among 1315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR = 0.77; 95% CI 0.71 to 0.83, P < 0.0001), equivalent to a relative increase in survival of 23%, an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29% or an absolute increase in median survival of 1.5 months (from 4.5 months to six months). There was no clear evidence that this effect was influenced by the drugs used (P = 0.63) or whether they were used as single agents or in combination (P = 0.40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = 0.77). There was no clear evidence of a difference in the relative effect of chemotherapy across patient subgroups. Quality of life could not be formally assessed. All trials were of good methodological quality with no risk of bias. This meta-analysis of chemotherapy in the supportive care setting demonstrates that chemotherapy improves overall survival in all patients with advanced NSCLC. Patients who are fit enough and wish to receive it should be offered chemotherapy.

Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data

SummaryBackgroundMany randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy.MethodsWe included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat.FindingsThe first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0·86, 95% CI 0·81–0·92, p<0·0001), with an absolute increase in survival of 4% (95% CI 3–6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0·88, 95% CI 0·81–0·97, p=0·009), representing an absolute improvement in survival of 4% (95% CI 1–8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup.InterpretationThe addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy.FundingUK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Adjuvant therapy of melanoma with interferon: lessons of the past decade.

The effect of interferon alpha (IFNα2) given alone or in combination has been widely explored in clinical trials over the past 30 years. Despite the number of adjuvant studies that have been conducted, controversy remains in the oncology community regarding the role of this treatment.Recently an individual patient data (IPD) meta-analysis at longer follow-up was reported, showing a statistically significant benefit for IFN in relation to relapse-free survival, without any difference according to dosage (p = 0.2) or duration of IFN therapy (p = 0.5). Most interestingly, there was a statistically significant benefit of IFN upon overall survival (OS) that translates into an absolute benefit of at least 3% (CI 1–5%) at 5 years. Thus, both the individual trials and this meta-analysis provide evidence that adjuvant IFNα2 significantly reduces the risk of relapse and mortality of high-risk melanoma, albeit with a relatively small absolute improvement in survival in the overall population.We have surveyed the international literature from the meta-analysis (2006) to summarize and assimilate current biological evidence that indicates a potent impact of this molecule upon the tumor microenvironment and STAT signaling, as well as the immunological polarization of the tumor tissue in vivo. In conclusion, we argue that there is a compelling rationale for new research upon IFN, especially in the adjuvant setting where the most pronounced effects of this agent have been discovered. These efforts have already shed light upon the immunological and proinflammatory predictors of therapeutic benefit from this agent – that may allow practitioners to determine which patients may benefit from IFN therapy, and approaches that may enable us to overcome resistance or enhance the efficacy of IFN. Future efforts may well build toward patient-oriented therapy based upon the knowledge of the unique molecular features of this disease and the immune system of each melanoma patient.

Chemotherapy in Addition to Supportive Care Improves Survival in Advanced Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data From 16 Randomized Controlled Trials

Purpose Since our individual patient data (IPD) meta-analysis (MA) of supportive care and chemotherapy for non–small-cell lung cancer (NSCLC), published in 1995, many trials have been completed. An updated, IPD MA has been carried out to assess newer regimens and determine conclusively the effect of chemotherapy. Methods Systematic searches for randomized controlled trials (RCTs) were undertaken, followed by central collection, checking, and reanalysis of updated IPD. Results from RCTs were combined to calculate individual and pooled hazard ratios (HRs). Results Data were obtained from 2,714 patients from 16 RCTs. There were 1,293 deaths among 1,399 patients assigned supportive care and chemotherapy and 1,240 among 1,315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI, 0.71 to 0.83; P ≤ .0001), equivalent to a relative increase in survival of 23% or an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29%. There was no clear evidence that this effect was influenced by the drugs used (P = .63) or whether they were used as single agents or in combination (P = .40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = .77). There was no clear evidence of a difference or trend in the relative effect of chemotherapy across patient subgroups. Conclusion This MA of chemotherapy in the supportive care setting demonstrates conclusively that chemotherapy improves overall survival in all patients with advanced NSCLC. Therefore, all patients who are fit enough and wish to receive chemotherapy should do so.

Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study

The aim of the QUASAR trial was to determine the size and duration of any survival benefit from adjuvant chemotherapy for patients with colorectal cancer at low risk of recurrence, for whom the indication for such treatment is unclear. After apparently curative resections of colon or rectal cancer, 3239 patients (2963 [91%] with stage II [node negative] disease, 2291 [71%] with colon cancer, median age 63 [IQR 56-68] years) enrolled between May, 1994, and December, 2003, from 150 centres in 19 countries were randomly assigned to receive chemotherapy with fluorouracil and folinic acid (n=1622) or to observation (with chemotherapy considered on recurrence; n=1617). Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil (370 mg/m2) with high-dose (175 mg) L-folinic acid or low-dose (25 mg) L-folinic acid. Until 1997, levamisole (12 courses of 450 mg over 3 days repeated every 2 weeks) or placebo was added. After 1997, patients who were assigned to receive chemotherapy were given fluorouracil and low-dose folinic acid only. The primary outcome was all-cause mortality. Analyses were done by intention to treat. This trial is registered with the International Clinical Trial Registry, number ISRCTN82375386. At the time of analysis, 61 (3.8%) patients in the chemotherapy group and 50 (3.1%) in the observation group had missing follow-up. After a median follow-up of 5.5 (range 0-10.6) years, there were 311 deaths in the chemotherapy group and 370 in the observation group; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70-0.95; p=0.008). There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67-0.91; p=0.001). Treatment efficacy did not differ significantly by tumour site, stage, sex, age, or chemotherapy schedule. Eight (0.5%) patients in the chemotherapy group and four (0.25%) in the observation group died from non-colorectal cancer causes within 30 weeks of randomisation; only one of these deaths was deemed to be possibly chemotherapy related. Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer, although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death seen here translates into an absolute improvement in survival of 3.6% (95% CI 1.0-6.0).

Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review

Although surgery offers the best chance of cure for patients with non-small cell lung cancer (NSCLC), the overall 5-year survival rate is modest, and improvements are urgently needed. In the 1990s, much interest was generated from two small trials that reported striking results with neo-adjuvant chemotherapy, and therefore our intergroup randomised trial was designed to investigate whether, in patients with operable non-small cell lung cancer of any stage, outcomes could be improved by giving platinum-based chemotherapy before surgery. Patients were randomised to receive either surgery alone (S), or three cycles of platinum-based chemotherapy followed by surgery (CT-S). Before randomisation, clinicians chose the chemotherapy that would be given from a list of six standard regimens. The primary outcome measure was overall survival, which was analysed on an intention-to-treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN25582437. 519 patients were randomised (S: 261, CT-S: 258) from 70 centres in the UK, Netherlands, Germany, and Belgium. Most (61%) were clinical stage I, with 31% stage II, and 7% stage III. Neo-adjuvant chemotherapy was feasible (75% of patients received all three cycles of chemotherapy), resulted in a good response rate (49% [95% CI 43%-55%]) and down-staging in 31% (25%-37%) of patients, and did not alter the type or completeness of the surgery (lobectomy: S: 56%, CT-S: 60%, complete resection: S: 80%, CT-S: 82%). Post-operative complications were not increased in the CT-S group, and no impairment of quality of life was observed. However, there was no evidence of a benefit in terms of overall survival (hazard ratio [HR] 1.02, 95% CI 0.80-1.31, p=0.86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1507 patients, HR 0.88, 95% CI 0.76-1.01, p=0.07), equivalent to an absolute improvement in survival of 5% at 5 years Although there was no evidence of a difference in overall survival with neo-adjuvant chemotherapy, the result is statistically consistent with previous trials, and therefore adds considerable weight to the current evidence.

Cytotoxic chemotherapy in advanced non-small cell lung cancer

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Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—Long-term results of phase III RTOG 85-31: Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, Hug EB, Asbell SO, Grignon D, University of California, Los Angeles, School of Medicine, Los Angeles, CA

Radiation Therapy Oncology Group protocol 85–31 was designed to evaluate the effectiveness of adjuvant androgen suppression, using goserelin, in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy (RT). Eligible patients were those with palpable primary tumor extending beyond the prostate (clinical Stage T3) or those with regional lymphatic involvement. Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement was documented histologically. Stratification was based on histologic differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either RT and adjuvant goserelin (Arm I) or RT alone followed by observation and application of goserelin at relapse (Arm II). In Arm I, the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression. Between 1987 and 1992, when the study was closed, 977 patients were entered: 488 to Arm I and 489 to Arm II. As of July 2003, the median follow-up for all patients was 7.6 years and for living patients was 11 years. At 10 years, the absolute survival rate was significantly greater for the adjuvant arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year local failure rate for the adjuvant arm was 23% vs. 38% for the control arm (p < 0.0001). The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24% vs. 39% (p < 0.001) and 16% vs. 22% (p = 0.0052), respectively, both in favor of the adjuvant arm. In a population of patients with unfavorable prognosis carcinoma of the prostate, androgen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival. The improvement in survival appeared preferentially in patients with a Gleason score of 7−10.