Incidence Of Treatment-related Death Research Articles

Outcomes of adolescents with acute lymphoblastic leukaemia.

Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Incidence of Serious Adverse Events, Pneumonitis, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for multiple pathways in B cells and is important for B cell survival, proliferation and metabolism. Hence, PI3K inhibitors have become an attractive therapeutic option for treatment of B cell malignancies. Two prominent PI3K inhibitors, (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and have shown to improve survival in recent trials with notable toxicities. We analyzed phase 3 trials to assess the incidence of serious adverse events, pneumonitis, infection and sepsis associated with PI3K inhibitors in this susceptible population. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention serious adverse events, pneumonitis, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included in analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The incidence of serious adverse events was 479 (73.69%) in study group vs 252 (44.92%) in control group (RR, 1.58; 95% CI: 1.37 - 1.83; P < 0.0001 and RD, 0.26; 95% CI: 0.13 - 0.40; P = 0.0002). Pneumonitis was noted in 20 (3.07%) vs 1 (0.18%) in control group with RR of 6.53 (95% CI: 1.74 -24.53; P = 0.005) and RD of 0.02 (95% CI: 0.01 - 0.04; P = 0.0004). The incidence of any-grade pneumonia was 107 (16.46%) in study group vs 54 (9.63%) in control group (RR, 1.61; 95% CI: 1.00 - 2.58; P = 0.05). High-grade pneumonia was reported in 81 (12.46%) in idelalisib arm versus 35 (6.24%) in control group with RR of 1.84 (95% CI: 0.82 - 4.13; P = 0.14). Pneumocystis jiroveci pneumonia (PJP) rate was 2.24% higher in study group compared to control arm (RR, 3.87; 95% CI: 1.22 - 12.29; P = 0.02). Any-grade upper respiratory tract infection (URTI) was 14% in study group versus 7.84% in control arm (RR, 1.65; 95% CI: 1.17 - 2.34; P = 0.005). Sepsis rate was 2.88% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.68 (95% CI: 1.19 - 6.04, P = 0.02). Treatment-related deaths were 64 (11.85%) in study arm vs 28 (6.17%) in control arm according to analysis of 3 trials. The pooled RR was also statistically significant at 1.87 (95% CI: 1.21 -2.88; P = 0.005). Conclusions: Our meta-analysis showed that the incidence of serious adverse events, pneumonitis, PJP pneumonia, any-grade URTI and sepsis was significantly higher in PI3K inhibitors group with RR of 1.58 for serious adverse events, RR of 6.53 for pneumonitis, RR of 3.87 for PJP pneumonia and RR of 2.68 for sepsis respectively. Moreover, patients on PI3K inhibitors experienced 5.68% higher incidence of treatment-related deaths with RR of 1.87, compared to control arm. Since treatment-related serious toxicities and deaths are higher amongst patients treated with these agents, extra caution should be observed and recommended with their use. Disclosures No relevant conflicts of interest to declare.

Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10–14 years as compared with those aged 15–17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study

BackgroundAdolescents (aged 10–17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. MethodsWe retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10–17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10–14 and 15–17 years. FindingsCompared with younger children (aged 1–9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10–14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15–17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. InterpretationFurther prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15–17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis

BackgroundThe future of combined immunotherapy (a PD-1/PD-L1 plus a CTLA-4 antagonist) is very bright. However, besides improving efficacy, combined therapy increases treatment-related adverse events (TRAEs). Also, the clinical application is limited in some solid tumors.MethodsThis paper purports to investigate the TRAEs for the combined immunotherapy aiming for a more appropriate utilization of immune checkpoint inhibitors (ICIs) in clinical practice through a meta-analysis.ResultsA total of 17 eligible studies covering 2626 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The incidence rates of any grade and grade 3 or higher TRAEs were 88% (95%CI, 84–92%) and 41% (95%CI, 35–47%), respectively. The overall incidence of any grade TRAEs leading to discontinuation of treatment was 20% (95%CI, 16–24%). The incidence rate of treatment related deaths was 4.3‰ (95%CI, 1.4‰-8.4‰). Analysis showed that NIVO1 + IPI3 cohort had higher incidences of grade 3 or higher TRAEs (RR = 1.77, 95%CI, 1.34–2.34, p < 0.0001) and any grade TRAEs leading to discontinuation of treatment (RR = 1.81, 95%CI, 1.08–3.04, P = 0.02), compared with NIVO3 + IPI1 regimen.ConclusionsThe combined therapy had high TRAEs. The TRAEs, especially grade 3 or higher, led to discontinuation of the treatment. Furthermore, the incidence of treatment-related deaths was rare. Moreover, the NIVO3 + IPI1 regimen, regardless of efficacy, is more recommended because of better tolerance and lower adverse events.

Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis.

Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitor therapy is showing marked efficacy in advanced non-small cell lung cancer (NSCLC). Meanwhile, it is concomitant with distinctive immune-related adverse effects. We aim to describe the incidence of pneumonitis and other rare but severe immune-related adverse effects (IRAEs), as well as treatment related deaths. In addition, we analyze the differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitors and standard-of-care chemotherapy. PubMed was searched up to 24 March 2017 for clinical trials of PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) in treatment of NSCLC. Besides, references of relevant articles were screened. Finally, 22 trials were included in our study, 14 with data of pneumonitis, 19 with other severe IRAEs or treatment related deaths and 5 with control groups. Incidence of all-grade pneumonitis was 2.9% (95% CI, 2.0-4.8%) and grade 3 or higher pneumonitis 2.0% (95% CI, 1.0-2.0%). Incidence of all-grade pneumonitis in PD-1 and PD-L1 inhibitor therapy (n=1,313) was significantly higher than that in chemotherapy (n=918) (OR=2.35, 95% CI, 1.32-4.20, P=0.004), but had no significance in grade 3-5 pneumonitis. Incidence of cardiorespiratory arrest (n=537) was 1.0% (95% CI, 0-2.0%), cardiac failure (n=214) 2.0% (95% CI, 1.0-5.7%), myocardial infarction (n=402) 1.0% (95% CI, 0-3.8%), stroke (n=135) 2.0% (95% CI, 0-13.0%), disease progression (n=391) 1.0% (95% CI, 0-2.9%), pancreatitis (n=700) 1.0% (95% CI, 0-2.0%) and severe skin reactions (n=836) 2.0% (95% CI, 1.0-3.8%). Incidence of treatment related deaths was 0.7%. Immune related adverse effects can on occasion be life-threatening even though usually rare. Incidence of pneumonitis in PD-1 and PD-L1 inhibitors was significantly higher than that in chemotherapy. More studies should be conducted to investigate the incidence of these rare but life-threatening IRAEs.

Emerging Role for Bevacizumab in Combination With Chemotherapy for Patients With Platinum-Resistant Ovarian Cancer

each of these three studies, AURELIA observed a statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to chemotherapy, with an absolute 3.3-month improvement in median PFS from 3.4 months in the chemotherapy-alone arm to 6.7 months in the chemotherapy plus bevacizumab arm (hazard ratio, 0.48; 95% CI 0.38 to 0.60; P , .001). This margin of benefit is similar to those reported in the GOG 218, ICON7, and OCEANS studies, which suggests a remarkable consistency in the observed effects of combining bevacizumab with chemotherapy in several different settings in ovarian cancer. However, as with the other randomized phase III studies, no overall survival (OS) benefit was observed in the chemotherapy plus bevacizumab arm in AURELIA. Similar to the OCEANS trial, the combination of bevacizumab and chemotherapy in AURELIA also significantly improved the overall response rate (ORR) from 11.8% to 27.3% ( P 5 .001), as assessed by RECIST criteria. No new safety signals were observed in the chemotherapy plus bevacizumab arm, with the incidence of $ grade 2 hypertension and proteinuria being similar to that of other studies. The incidence of $ grade 2 GI perforation was 2.2% in the chemotherapy plus bevacizumab arm compared with 0% in the chemotherapy-alone arm; again, this is consistent with the findings of other studies. Interestingly, the incidence of hand-foot syndrome and peripheral sensory neuropathy was greater in the chemotherapy plus bevacizumab arm compared with chemotherapy alone, which most likely relates to the longer duration of time that patients received either PLD or paclitaxel in the combination arm (because patients remained on chemotherapy for a longer period of time without disease progression). The incidence of treatment-related death was 2.8% in each arm. Importantly, AURELIA also studied PROs as a separate preplanned end point and found that more patients in the chemotherapy plus bevacizumab arm achieved a $ 15% improvement in abdominal/GI symptom PROs (as assessed by the Quality of Life Questionnaire–OV28 abdominal/GI symptom subscale) at week 8 or 9 (21.9% v 9.3%; P 5 .002). 4 This may represent an underestimate of the PRO improvement with chemotherapy plus bevacizumab, given that only 65% of patients in this trial had sufficient symptoms at baseline for a difference to be detectable. It is noteworthy that AURELIA is the first study incorporating bevacizumab in ovarian cancer to report an improvement in PROs. In the setting of platinum-resistant ovarian cancer, in which therapy is palliative, improvement in PROs is of potential importance even in the absence of an OS benefit. In contrast, in the studies incorporating bevacizumab into first-line and subsequent maintenance treatment, GOG 218 did not demonstrate an improvement in PROs, and ICON7 demonstrated a slight worsening in PROs. 8,9 Perhaps it is not surprising that PROs were not improved and were possibly compromised by introducing bevacizumab into the first-line setting, where most patients experience relatively few disease-related symptoms once chemotherapy begins, and when the magnitude of median PFS prolongation with bevacizumab is modest. In the relapsed setting, OCEANS did not include a PRO end point. 7 Although the results reported in these studies add to our experience with bevacizumab in ovarian cancer, interpreting the data from these reports is not straightforward. AURELIA differs from GOG 218 and OCEANS in that it is an open-label study without a placebo

Risk Factors for Severe Adverse Effects and Treatment-related Deaths in Japanese Patients Treated with Irinotecan-based Chemotherapy: A Postmarketing Survey†

ObjectivesThis analysis was conducted to clarify risk factors for severe adverse effects and treatment-related deaths reported during a postmarketing survey of irinotecan.MethodsThe survey covered all patients treated with irinotecan in Japan between April 1995 and January 2000. The patient background data and adverse drug reactions were collected through case report forms. Univariate and multivariate logistic regression analyses including 14 explanatory variables were performed to determine the risk factors for grade 3–4 leukopenia, thrombocytopenia and diarrhea for all patients and subgroups with five major cancers. Treatment-related deaths were also analyzed.ResultsCase report forms of 13 935 patients (94.1% of 14 802 patients registered) treated with irinotecan-based chemotherapy were collected. Major grade 3–4 adverse drug reactions were leukopenia (34.8%), thrombocytopenia (12.4%) and diarrhea (10.1%). Multivariate analysis revealed that the risk factors (odds ratio ≥1.5) common for all these three adverse drug reactions were performance status (≥3), infection and renal dysfunction before starting irinotecan therapy. Additionally, the risk factors for leukopenia were being female and prior radiotherapy, those for thrombocytopenia were age (≥65 years), while those for diarrhea were pleural effusion and watery stool. The risk factors in each cancer were also identified. The incidence of treatment-related death was 1.3% (176). Myelosuppression-related deaths accounted for 70% and interstitial lung disease for 11% of all treatment-related deaths. Being male, age, performance status ≥3, massive ascites and infection and renal dysfunction were identified as risk factors for treatment-related death.ConclusionsTo ensure the safety of irinotecan therapy, it is important to select appropriate patients by considering the risk factors.

Phase II study of preoperative chemotherapy with S‐1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancers (JCOG0210)

We conducted a phase II study to evaluate the safety and efficacy of preoperative chemotherapy with S-1 + cisplatin followed by gastrectomy in patients with linitis plastica (type 4) or large ulcero-invasive-type (type 3) gastric cancer. Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinically resectable gastric cancer of type 4 or type 3. Patients received two 28-day courses of preoperative chemotherapy of S-1 (80-120 mg/body, p.o., days 1-21) and cisplatin (CDDP; 60 mg/m(2), i.v., day 8). Primary endpoints were completion of protocol treatment and incidence of treatment-related death (TRD). Among the 49 eligible patients with the median age of 61 years, 36 completed the protocol treatment comprising two courses of preoperative chemotherapy and R0/1 resection (73.5% completion, 80% CI, 63.7-81.7%). One TRD was observed during the first course of chemotherapy. Median survival and 3-year overall survival were 17.3 months and 24.5%, respectively. Preoperative chemotherapy with S-1 + CDDP followed by gastrectomy is a safe and promising treatment for type 4 and large type 3 gastric cancers. Based on the results of this study, we are now conducting a phase III study (JCOG0501) to confirm the superiority of this treatment.

Time trend in treatment-related deaths of patients with advanced non-small-cell lung cancer enrolled into phase III trials of systemic treatment

PurposeDespite recent improvements in supportive care, treatment-related death (TRD) remains a serious problem for lung cancer patients undergoing systemic chemotherapy. However, few studies have formally assessed possible changes in the TRD rate over the past two decades. Patients and methodsWe searched phase III trials to address the role of systemic treatment of advanced non-small-cell lung cancer (NSCLC). Time trend was assessed using linear regression analysis. ResultsThe overall incidence of TRD was calculated from 119 trials including 263 chemotherapy arms (46477 patients), with information about the causes of deaths available for 197 arms (75%, 30147 patients). Cisplatin-based regimens were the most frequently investigated. The crude TRD rate in the overall cohort of 119 trials was 1.26% and has been notably consistent over the investigated time (P = 0.762). The most common cause of death was febrile neutropenia, with no significant change in its incidence over the years (P = 0.139). In contrast, deaths due to renal toxicity decreased significantly (P = 0.042), whereas deaths due to pulmonary disorder increased significantly (P = 0.007). Among the pharmacological agents investigated, docetaxel (Taxotere) and epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) were associated with relatively high rates of deaths from pulmonary disorders, but EGFR-TKIs were not associated with death from any other cause. ConclusionsDespite of potential confounders in our results, the overall TRD rate has remained low, but not negligible, in phase III trials for advanced NSCLC, over the past two decades. Notably, the incidence and pattern of TRD stratified by cause have changed considerably.

Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia

In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications. We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92 and ALL-2000 protocols. Fifty-five TRDs were identified among the 1,645 ALL-92 patients and 33 among the 1,090 ALL-2000 patients. There was no significant difference in the incidence of TRDs between the two protocols (3.4% vs. 3.2%). Five patients died before initiation of therapy (0.2%), and the overall subsequent risk of induction death and death in first complete remission (CR1) was 1.2% and 1.8%, respectively. Infections were the major cause of death comprising 72% of all cases including 9 deaths from Pseudomonas aeruginosa and 11 deaths from fungal infections. Other causes of death included bleeding or thrombosis (eight patients), tumour burden related toxicities (seven patients) and organ toxicity (seven patients). Female gender (hazard ratio (HR): 2.2, 95% confidence interval (95% CI): 1.4-3.4), high white blood cell count (≥ 200 × 10(9) /L) at diagnosis (HR: 3.5, 95% CI: 1.7-7.1), T-cell disease (HR: 1.9, 95% CI: 1.01-3.7), Down syndrome (HR: 7.3, 95% CI: 3.6-14.9) and haematopoietic stem cell transplantation in CR1 (HR: 8.0, 95% CI: 3.3-19.5) were identified as independent risk factors for TRD. Several TRDs were potentially preventable and future efforts should be directed towards patients at risk.

Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer

Locally advanced gastric cancer with extensive lymph node metastasis is usually considered unresectable and so treated by chemotherapy. This trial explored the safety and efficacy of preoperative chemotherapy followed by extended surgery in the management of locally advanced gastric adenocarcinoma. Patients with gastric cancer with extensive lymph node metastasis received two or three 28-day cycles of induction chemotherapy with irinotecan (70 mg/m(2) on days 1 and 15) and cisplatin (80 mg/m(2) on day 1), and then underwent gastrectomy with curative intent with D2 plus para-aortic lymphadenectomy. Primary endpoints were 3-year overall survival and incidence of treatment-related death. The study was terminated because of three treatment-related deaths when 55 patients had been enrolled (mortality rate above 5 per cent). Two deaths were due to myelosuppression and one to postoperative complications. Clinical response and R0 resection rates were 55 and 65 per cent respectively. The pathological response rate was 15 per cent. Median overall survival was 14.6 months and the 3-year survival rate 27 per cent. This multimodal treatment of locally advanced gastric cancer provides reasonable 3-year survival compared with historical data, but at a considerable cost in terms of morbidity and mortality.

A phase II study of preoperative chemotherapy (CX) with S-1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancer: JCOG 0210

4609 Background: Prognosis of both linitis plastica (type 4) and large ulcero-invasive type (type 3) gastric cancer is poor even after curative resection. We conducted a phase II study to evaluate the safety and efficacy of preoperative CX with S-1 and cisplatin followed by gastrectomy in patients (pts) with these tumors. Methods: Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinically resectable gastric cancer of type 4 or type 3 of =8 cm; cN0–2; cM0; PS 0–1; 20–75 years old. Pts received two 28-day cycles of induction CX of S-1 (80–120 mg/body, po, day 1–21) and cisplatin (60mg/m2, iv, day 8). Gastrectomy with D2/3 dissection was performed within 3 to 5 weeks after CX. No adjuvant therapy was added until recurrence after the curative gastrectomy. Primary endpoints were the proportion of protocol achievement and incidence of treatment related death (TRD). Sample size was determined to reject the rate of 45% under the expectation of 60% with power of 80% and alpha of 10%. Results: Fifty pts, 29 males and 21 females with a median age of 61 years (range: 32–75), were entered in this study between 03/2003 and 12/2003. Type 3/4 ratio was 20/30. Surgical exploration was carried out in 48 pts (96%). Among 49 eligible pts, 36 pts (73%; 95% CI, 59–85%) received two cycles of induction CX and R0 resection. One TRD was observed during the first course of CX due to uncontrollable hemorrhage from the primary tumor. Median survival time and the 3- year OS were 1.44 years (95% CI, 1.26–1.98) and 26.0% (95% CI, 14.9–38.6%), respectively. Pathological response, defined as disappearance of more than one third of the primary tumor, was confirmed in 24 pts (48%) and pathological complete response was seen in 1 pts (2%). During the CX, grade 3/4 neutropenia and anorexia occurred in 7 pts (14%), respectively. Postoperative morbidity included pneumonia in 2 pts, pancreatic leakage in 4, and intraperitoneal abscess in 3, without any mortality. Conclusions: Preoperative CX with S-1 and cisplatin followed by gastrectomy was safe and promising for type 4 and large type 3 gastric cancer. The results of ongoing phase III study to evaluate this treatment are awaited. No significant financial relationships to disclose.

Late treatment mortality and secondary cancers after autologous stem cell transplant for relapsed or refractory Hodgkin lymphoma (HL)

8016 Background: Late treatment-related mortality and second cancers have an important influence on the long-term outcome of patients (pts) with HL. The incidence of treatment failure and causes of death were evaluated in pts with advanced HL receiving high-dose therapy and ASCT, to understand the impact of late events on overall survival (OS). Methods: From Dec 1986 to Nov 2005, 323 pts with relapsed/refractory HL after primary chemotherapy (plus radiation [RT]: 32%) received salvage chemotherapy to best response, followed by etoposide 60 mg/kg day -4 and melphalan 160–180 mg/m2 day -3 supported by autologous bone marrow (46%), mobilized peripheral blood stem cells (49%) or both (5%)on day 0; 24% received involved field RT post-ASCT. Risk of treatment failure and second cancer was estimated using competing risks methods. Results: Patient Characteristics: male: 61%; median age 33 years (range16–67). Number of salvage regimens pre-ASCT: 1: 72%; 2: 25%. Disease status post-salvage chemotherapy: CR 28%, PR 66%. After a median follow-up of 4.7 years post-ASCT (range 1–17), 174 pts (54%) have experienced treatment failure (relapse or treatment related death) and 154 pts (48%) have died, 75% following relapse and 20% from toxicity without relapse. Of the 30 deaths without relapse, 30% occured &gt;5 years post-ASCT. Failure free survival at 3 and 10 years is 50% (95% CI, 44–55%) and 40% (33–46), and overall survival is 68% (63–73) and 39% (33- 46), respectively. There have been 29 second cancers (17 AML/MDS, 12 solid tumors) in pts alive without relapsed HL. The probability of a second cancer is 4.9% (2.8–7.8) at 3 years and 12% (8–17%) at 10 years. The hazard rates for second malignancy, leukemia and solid tumors for each 10-year age increment are 1.9 (p=0.0001), 1.9 (0.001) and 1.8 (0.03), respectively. Only 4 pts have relapsed beyond 5 years post- ASCT but the cumulative incidence of treatment-related death (from toxicity or second cancers) continues to increase from 9% (6–13) at 3 years to 15% (11–20) 10 yrs post-ASCT. Conclusions: In this single-institution series of uniformly treated patients with relapsed/refractory HL, late relapse of disease is uncommon, but late toxicities have a significant and ongoing impact on failure-free survival. No significant financial relationships to disclose.

Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI).

In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment-related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Down's syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.

Risk factors of treatment-related death in chemotherapy and thoracic radiotherapy for lung cancer

We retrospectively analysed the incidence and risk factors of treatment-related death in the treatment of chemotherapy- and thoracic radiotherapy-naı̈ve patients with lung cancer. Between July 1992 and December 1997, 1799 patients were diagnosed as having lung cancer in our hospital and 926 patients received chemotherapy and/or thoracic radiotherapy. 25 patients (2.7%) died from toxicity of the treatment, 10 from pneumonia, 7 from radiation pneumonitis, 6 from sepsis, 1 from perforation of the small intestine and 1 for an unknown reason. 18 patients (2.3%) died from chemotherapy-related toxicity. The incidence of treatment-related death (TRD) from chemotherapy was highly correlated with the performance status (PS), PS 0: 0.7%, PS 1: 2.2%, PS 2: 4.0%, PS 3: 7.7% and PS 4: 25% ( P=0.004). 7 patients (1.6%) died from pneumonitis after thoracic radiotherapy. Multivariate analyses demonstrated that poor PS (relative risk (RR): 1.95, 95% confidence interval (CI): 1.05–3.65, P=0.034) and chemotherapy using the cisplatin+vindesine+mitomycin C regimen (RR: 9.36, 95% CI: 1.29–68.0, P=0.027) are associated with treatment-related death from chemotherapy. Pulmonary fibrosis identified on a plain chest X-ray film (RR: 165.7, 95% CI: 8.79–3122, P<0.001), the combination of cisplatin+irinotecan (RR: 120.5, 95% CI: 2.90–4993, P=0.012), advanced age (RR: 1.17, 95% CI: 1.002–1.37, P=0.047), and elevated lactate dehydrogenase (LDH) (RR: 10.4, 95% CI: 1.20–90.2, P=0.033) were also associated with treatment-related death from thoracic radiotherapy. The administration of mitomycin C in addition to cisplatin-based regimens for patients with lung cancer should be carefully considered.

Pretreatment surgical staging of patients with cervical carcinoma: the case for lymph node debulking.

The routine use of extraperitoneal surgical staging prior to radiation therapy in patients with bulky or locally advanced cervical carcinoma remains controversial. A review was performed of 266 patients with cervical carcinoma who underwent extraperitoneal pelvic and paraaortic lymphadenectomy prior to receiving radiotherapy. Patients were divided into groups based on their lymph node status. Group A had negative lymph nodes; Group B had resected, microscopic lymph node metastases; Group C had macroscopically positive lymph nodes that were resectable at the time of surgery; and Group D had unresectable lymph nodes. All patients received standard radiotherapy utilizing external beam and brachy-therapy. Patients with lymph node metastases received extended field irradiation. Survival probabilities were computed by the Kaplan-Meier product limits method with statistical significance determined by the Mantel-Cox log rank test. Lymph node metastases were detected in 50% of patients. Five- and 10-year disease free survival rates were similar for all patients in Groups B and C. All patients in Group D recurred. There was a 10.5% incidence of severe radiation-related morbidity and a 1.1% incidence of treatment-related deaths. Pretreatment extraperitoneal staging of patients with bulky or locally advanced cervical carcinoma may afford a survival benefit via the debulking of macroscopically positive lymph nodes without significantly increasing treatment-related morbidity or mortality.