Risk Factors For Severe Toxicity Research Articles

Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.

Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95). Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

P14.13 Severe hematological toxicity during chemoradiation for glioblastoma: Identification of clinical and pharmacological risk factors and consequences for the individual patient

Abstract BACKGROUND Besides early tumour progression, standard first-line radiation with concurrent and adjuvant temozolomide in de novo glioblastoma patients is abrogated frequently by severe haematological toxicity. This leads to treatment delays with unknown effect on efficacy and to more hospital visits with increased disease burden. In the present study, we identified clinical and pharmacological risk factors for temozolomide induced severe hematological toxicity. Furthermore, we describe the burden of toxicity for patients and evaluate the effect of severe toxicity on prognosis. METHODS A retrospective cohort study of adult patients with a histological confirmed glioblastoma (n=363), treated with standard treatment regimen at the Brain Tumor Center Amsterdam between 2000 and -2020. Severe haematological toxicity was defined as a CTCAE (version 5.0) grade ≥3. We used Pearson Chi-Square test to analyze differences in patient characteristics between the groups (no vs. severe toxicity) and paired samples T- Test to analyze fluctuations in cell counts. Univariate and multivariate logistic regression were used to identify patient- and treatment characteristics associated with severe hematological toxicity. Cox Proportional Hazards models were used to estimate Hazard Ratio’s for the association between survival and severe hematological toxicity. RESULTS Female gender (OR 8.05, 95%CI 2.96–21.89, p&amp;lt;0.001) and older age (age &amp;gt; 70 years; OR 2.44, 95%CI 1.12–5.31, p=0.025) were independent risk factors for severe toxicity. Concurrent and adjuvant temozolomide was discontinued in respectively 56% and 35% of the patients. In general, patients with severe hematological toxicity had a treatment delay of 22 ± 48 days. Of all patients with severe hematological toxicity during chemoradiation, 96% developed toxicity after ≥4 weeks of treatment (p&amp;lt;0.001). Females who received highest temozolomide-doses (4th quartile) had a longer survival than females with low cumulative temozolomide doses (1st quartile). Patients, who developed severe toxicity had much more hospital visits (20; range 12–26), and were admitted more frequently to the hospital. Severe haematological toxicity was not related to survival (HR 1.04; 95%CI 0.74–1.45). CONCLUSION Female gender and age &amp;gt;70 years are risk factors for severe hematological toxicity. Severe hematological toxicity relates to temozolomide exposure and results in a significant treatment burden for patients. Low temozolomide exposure results in decreased survival. Patient tailored therapy may result in better treatment outcomes.

Gastrointestinal Toxicity of High-Dose Melphalan in Autologous Stem-Cell Transplantation: Identification of Risk Factors and a Benchmark for Experimental Therapies

Gastrointestinal (GI) adverse effects are the dose limiting toxicity of high-dose melphalan (HDM), and despite prophylactic measures, continue to have a significant impact on morbidity, length of stay, and quality of life. There are limited contemporary data on gastrointestinal toxicity associated with HDM. Our objective was to characterize the GI toxicity of HDM and identify risk factors for severe toxicity in a cohort of patients.We conducted a retrospective study on 100 consecutive patients with multiple myeloma, amyloidosis, or lymphoma who underwent autologous stem-cell transplant at Columbia University Irving Medical Center using HDM, either alone or in combination with other chemotherapeutic agents. Gastrointestinal adverse events, use of rescue medications, infectious complications, and length of stay were collected from electronic medical records. CTCAE (Common Terminology for Adverse Events) grading for GI events was conducted daily. Risk factors for GI toxicity were identified using linear regression and then examined in a multivariable model.Patients (median age 56 years, range 20-73) had myeloma (42%), lymphoma (42%), or amyloidosis (16%). Melphalan dose was 200 (40%), 140 (59%), or 100 mg/m2 (1%). Ninety-seven percent of patients experienced diarrhea ranging 1 - 18 daily bowel movements (Figure 1) and lasting 0 - 17 days (median 7). Nausea and vomiting of any grade occurred in 88% and 61% of patients, respectively. Sixty-two percent developed grade≥2 diarrhea, and grade≥2 nausea and vomiting was observed in 35% and 7%, respectively. The mean total number of bowel movements during a 14-day period post-transplant was 39 (maximum 67). Rescue loperamide was given 10 doses on average overall (range 0-43). Eighteen percent experienced weight loss of more than 10% and 38% dropped albumin level by at least 1g/dL.Patients with grade≥2 diarrhea had a higher incidence of hypokalemia, hypoalbuminemia, required greater electrolyte repletions (Figure 2), utilized more rescue medications, and had prolonged diarrhea (average 8.7 v. 5 days, p<0.0001) compared to patients with grade 1 diarrhea. Patients with grade≥2 diarrhea were also more likely to stay in the hospital more than 23 days (p=0.07). Of the entire cohort, eleven percent had at least one episode of incontinence and 15% had an infection identified in stool studies. To rule out further complications, 31% of patients had CT scans of the abdomen and pelvis but only 8% showed evidence of colitis.Grade≥2 diarrhea was independently associated with age>50 years (p=0.04), creatinine clearance <60 ml/min (p=0.05), and female sex (p=0.04). Female sex was also associated with developing grade≥1 nausea (p=0.05) and vomiting (p=0.09). Melphalan dose, underlying disease, and HDM v. BEAM (BCNU, Etoposide, Ara-C, Melphalan) were not significantly associated with diarrhea severity, although numerically there were more patients with grade≥2 diarrhea in the HDM 200 mg/m2 compared to 140 mg/m2 (70% vs. 59%).Diarrhea remains a very common side effect of HDM with no improvement over historical rates and no known prophylactic measures. Female sex, a low creatinine clearance, and age over 50 years portend a higher risk for severe diarrhea, and female sex for nausea and vomiting. Novel therapies for chemotherapy-induced diarrhea are critically needed for patients undergoing stem-cell transplantation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma

ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity.A retrospective cohort study was conducted in 194 CRC patients.In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4.85; p = 0.03); GSTP1 G-allele (OR = 3.01; p = 0.005) and MTHFR rs1801133 T allele (OR = 2.51; p = 0.03) with respiratory toxicity; GSTP1 G-allele with cardiovascular toxicity (OR = 4.05; p = 0.01); ERCC1 rs11615 GG genotype with neurological toxicity (OR = 3.98; p = 0.01) and with asthenia (OR = 2.91; p = 0.08); XRCC1 rs1799782 T allele (OR = 0.31; p = 0.03) and GSTP1 G-allele (OR = 1.81; p = 0.01) with cutaneous toxicity. In second line treatment, XRCC1 rs1799782 T-allele was associated with asthenia (OR = 0.17; p = 0.03) and XRCC1 rs25487 T-allele with gastrointestinal toxicity (OR = 3.03; p = 0.005). After stratifying by treatment, in the 5-Fluorouracil group, the DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 2.76; p = 0.003), ABCB1 rs1045642 T-allele with the need of treatment adjustment due to toxicity (OR = 3.06; p = 0.01), and rs1045642 CC genotype with gastrointestinal toxicity (OR = 5.80; p = 0.03). In the capecitabine group, the MTHFR rs1801131 CC genotype was associated with asthenia (OR = 3.48; p = 0.009). In the oxaliplatin group, rs1045642 TT genotype was associated with the need to adjust treatment (OR = 0.32; p = 0.02), ERCC1 rs11615 GG genotype with asthenia (OR = 3.01; p = 0.01) and rs1615 GSTP1 GG genotype with respiratory toxicity (OR = 5.07; p = 0.009).ABCB1 rs1045642 T-allele reduces the need for treatment modification with both 5FU and oxaliplatin. Although several biomarkers predicted different toxic effects, they cannot be considered as risk factors for severe toxicity.

Selected Articles from This Issue

Malignant pleural mesothelioma (MPM) is an incurable cancer associated with exposure to asbestos, and there remains a critical need for effective front-line therapeutics. Inhibition of heatshock protein 90 (Hsp90) has shown promise in preclinical studies. Fennell and colleagues conducted a dose-escalation study of pemetrexed and cisplatin/carboplatin plus ganetespib, an Hsp90 inhibitor, in patients with chemotherapy-naiïve MPM. At the maximum-tolerated dose, 56% showed a partial response, while 83% showed disease control; median progression-free survival was 6.3 months. Patients with tumors harboring epithelioid histology and global loss of heterozygosity benefitted most from this combination. These results support the further development of combination therapies including ganetespib for patients with MPM.The prognosis of advanced gastric cancer remains dismal, with most patients with advanced disease surviving less than one year. In a multicenter phase II study, Shah and colleagues assessed cabazitaxel, a next generation taxoid, in patients with metastatic gastric cancer. Modest antitumor activity was observed in both taxane-naï;ve and taxane-pretreated patients as 2nd- and 3rd-line therapy. Genomic analyses associated elevated HER2 levels and an M2 tumor-associated macrophage signature with improved survival in patients with metastatic gastric cancer treated with cabazitaxel. Additional study is needed to further elucidate these signatures as prognostic markers for gastric cancer therapy.Multiple factors present prior to chimeric antigen receptor T (CAR T) cell infusion influence the development of immune-mediated toxicities. Faramand and colleagues assessed risk factors for severe toxicity or treatment related death in a cohort of 75 patients with large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), a standard of care CD19-targeted CAR T therapy. An association was identified between a pro-inflammatory tumor microenvironment—specifically, elevated interleukin 6 levels—and severe cytokine release syndrome (CRS) and neurotoxicity. Furthermore, elevated peak noradrenaline levels were observed in patients developing severe CRS. Analysis of pretreatment patient tumor biopsies revealed an association of myeloid markers with higher toxicity as well. The role of myeloid cells and the tumor microenvironment on mediating toxicities is an evolving concep. and warrants further investigation in a clinical trial.Recent advances in the subtyping of pancreatic adenocarcinoma (PDAC) have revealed two major subtypes of the disease: basal and classical. In an analysis of the COMPASS trial, O'Kane and colleagues assessed the contribution of subtype to response to modified FOLFIRINOX (mFFX) in patients with PDAC. Patients with basal-like tumors showed resistance to mFFX and a shorter median overall survival when compared with patients with classical PDAC. GATA6 and Keratin 5 expression correlated with classifier status: low GATA6 expression and high Keratin 5 expression correlated with the basal subtype. Further analysis of these markers is necessary to assess their utility as surrogate markers for transcriptional subtyping.

154 - Gastrointestinal Toxicity of High-Dose Melphalan in Autologous Stem-Cell Transplantation: Identification of Risk Factors and a Benchmark for Experimental Therapies

Gastrointestinal (GI) adverse effects are the dose limiting toxicity of high-dose melphalan (HDM), and despite prophylactic measures, continue to have a significant impact on morbidity, length of stay, and quality of life. There are limited contemporary data on gastrointestinal toxicity associated with HDM. Our objective was to characterize GI toxicity of HDM and identify risk factors for severe toxicity in a cohort of patients. We conducted a retrospective study on 100 consecutive patients with multiple myeloma, amyloidosis, or lymphoma who underwent autologous stem-cell transplant at Columbia University Medical Center using HDM, either alone or in combination with other chemotherapeutic agents. Patients (median age 56 years, range 20-73) had myeloma (42%), lymphoma (42%), or amyloidosis (16%). Melphalan dose was 200 (40%), 140 (59%), or 100 mg/m2 (1%). Ninety-seven percent of patients experienced diarrhea ranging 1 – 18 daily bowel movements (Figure 1) and lasting 0 – 17 days (median 7). Nausea and vomiting of any grade occurred in 88% and 61% of patients, respectively. Sixty-two percent developed grade ≥ 2 diarrhea, and grade ≥ 2 nausea and vomiting was observed in 35% and 7%, respectively. The mean total number of bowel movements during a 14-day period post-transplant was 39 (maximum 67). Rescue loperamide was given 10 doses on average overall (range 0-43). Eighteen percent experienced weight loss of more than 10% and 38% dropped albumin level by at least 1g/dL. Patients with grade ≥ 2 diarrhea had a higher incidence of hypokalemia, hypoalbuminemia, required greater electrolyte repletions (Figure 2), utilized more rescue medications, and had prolonged diarrhea (average 8.7 v. 5 days, P < .0001). Patients with grade ≥ 2 diarrhea were also more likely to stay in the hospital more than 23 days (P = .07). Eleven percent had at least one episode of incontinence and 15% had an infection identified in stool studies. To rule out further complications, 31% of patients had CT scans of the abdomen and pelvis but only 8% showed evidence of colitis. Grade ≥ 2 diarrhea was independently associated with age > 50 years (P = .04), creatinine clearance <60 ml/min (P = .05), and female sex (P = .04). Female sex was also associated with developing grade ≥ 1 nausea (P = .05) and vomiting (P = .09). Melphalan dose, underlying disease, and HDM v. BEAM, were not significantly associated with diarrhea severity, although numerically there were more patients with grade ≥ 2 diarrhea in the HDM 200 mg/m2 compared to 140 mg/m2 (70% vs. 59%). Diarrhea remains a very common side effect of HDM. Female sex, a low creatinine clearance, and age over 50 years portend a higher risk for severe diarrhea, and female sex for nausea and vomiting. Novel therapies for chemotherapy-induced diarrhea are critically needed for patients undergoing stem-cell transplantation.

Dihydropyrimidine Dehydrogenase Deficiency: Homozygosity for an Extremely Rare Variant in DPYD due to Uniparental Isodisomy of Chromosome 1.

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C>T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.

A Systematic Literature Review on Salvage Radiotherapy for Local or Regional Recurrence After Previous Stereotactic Body Radiotherapy for Lung Cancer.

Purpose:The purpose of this review article was to summarize available data on the efficacy and safety of salvage radiotherapy for isolated local or regional recurrence after prior stereotactic body radiotherapy for lung cancer.Methods:Studies were systematically searched on PubMed, following which suitable papers were selected. Reported outcomes and toxicities were qualitatively reviewed.Results:Nineteen papers, which were retrospective studies based on single institution experiences, were selected. Sixteen papers were on salvage radiotherapy for local tumor recurrence, and the remaining 3 papers evaluated radiotherapy for regional failures after stereotactic body radiotherapy for lung cancer. Patient cohorts in the selected papers seemed very frail with 2-year survival of 30% to 40% after the salvage. Local control was reported to be approximately 60% to 70%, which is worse than that after primary stereotactic body radiotherapy. Reported rates of toxicity grade 3 or worse were considered acceptable. Larger target volume and central tumor localization were suggested as risk factors for severe toxicities. Dosimetric data on patients having toxicities were found to help with considering dose constraints for organs at risk.Conclusion:Based on data from a limited number of articles, salvage radiotherapy is a reasonable treatment option for select patients with local or regional tumor recurrence after prior stereotactic body radiotherapy for lung cancer. Optimal patient selection and dose prescription can be clarified with a larger study that include more data on experiences with salvage radiotherapy.

Biomphalaria alexandrina as a bioindicator of metal toxicity

Heavy metals are common environmental pollutants to the aquatic ecosystems. Several aquatic species have been used as bioindicators and biomonitoring subjects for heavy metals pollution. In the present study, the effects of cadmium (Cd) and manganese (Mn) on the survival, attachment, locomotion, and feeding behaviours of the gastropod snail Biomphalaria alexandrina were determined. The short-term (96 h) LC50 for Cd and Mn were found to be 0.219 and 154.2 mg/l, respectively. Long-term exposures (16–20 days) to ascending concentrations of Cd (0.01–1 mg/l) and Mn (50–500 mg/l) also caused gradual decreases in the survival rate of B. alexandrina in a dose-dependent manner. Attachment, locomotion and feeding behaviours of snails exposed to lethal and sublethal concentrations of Cd and Mn at acute (96 h) and chronic exposure (24 days) intervals, respectively, were also recorded. Compared to controls, a significant decrease (p ≤ 0.05) was recorded in the different behaviours of exposed snails. These changes in behaviour would potentially impact the snail’s ability to survive in the wild. Although Cd caused a more severe decline in snail survivorship than Mn, the behavioural effects of Mn were much more severe than Cd when the metals were roughly matched for lethality. In sum, the present study demonstrates B. alexandrina to be a sensitive bioindicator and model organism to assess heavy metals risk factors for severe toxicity in freshwater ecosystems.

Toxicity of intraperitoneal chemotherapy and risk factors for severe toxicity in optimally debulked ovarian cancer patients

ObjectiveTo assess the effect and toxicity of intraperitoneal (IP) chemotherapy for epithelial ovarian cancer and to determine the risk factors for severe toxicity. Materials and methodsPatients who received IP chemotherapy after optimal debulking surgery for ovarian cancer between 2006 and 2012 were retrospectively reviewed. Clinical characteristics were compared between patients with none/Grade 1 or Grade 2 toxicity and those with Grade 3 or Grade 4 toxicity. ResultsIn 41 patients, the mean number of IP cycles administered was 5.6 and most patients (80.5%) completed at least six cycles. The reasons for discontinuation were catheter-related problems (30%), disease progression (20%), or drug-related adverse effects (30%). Grade 3 or Grade 4 toxicity was observed in 30 patients (73.2%). The rate of neoadjuvant chemotherapy was higher in the patients with Grade 3 or Grade 4 toxicity (37%) than in the patients without Grade 3 or Grade 4 toxicity (9%), however, this difference was not significant (p = 0.128). During a mean follow-up period of 33.6 months, tumor recurrence occurred in 20 (48.8%) patients and the median progression-free survival was 30.0 months. ConclusionDespite the high rate of adverse events, IP chemotherapy can be delivered with a high completion rate and manageable toxicity to patients with optimally debulked ovarian cancer. Toxicity should be closely monitored in patients who have received neoadjuvant chemotherapy until a large prospective study can be performed to determine its influence.

Evaluation of UGT1A1 genotyping for predicting individual toxicity of irinotecan plus platinum analog regimens: Interim safety analysis of a prospective observational study.

11049 Background: Irinotecan (IRI)+platinum (Pt) therapy works synergistically and is widely used for solid carcinomas. Although UGT1A1 genotyping has been implemented in daily practice since long, recommended doses of IRI+Pt therapy according to UGT1A1 genotyping remain undetermined. Risk factors for severe toxicities of IRI+Pt regimens remain uncertain. We conducted a prospective observational study to examine the correlation between UGT1A1 genotyping and toxicity/efficacy in IRI+Pt regimens (NCT 01040312). Methods: During October 2009 and March 2012, 321 patients were enrolled. Eligible patients had histologically confirmed SCLC, non-SCLC, cervical, ovarian, or gastric cancer; had PS 0-2; and were receiving IRI+Pt (cisplatin, carboplatin, and nedaplatin) regimen, following UGT1A1 genotyping: hetero (*1/*6, *1/*28) and homo (*6/*6, *6/*28, *28/*28). Primary endpoint was to evaluate overall toxicity profile during first 3 cycles of treatment. In this interim analysis, incidences of grade 3/4 toxicities were compared among UGT1A1 phenotypes, and logistic regression models were used to identify independent risk factors for these toxicities. Results: At the time of abstract writing, toxicity data from 137 patients were available. There were 110 (80%) hetero and 27 (20%) homo genotypes. Combination therapy of IRI (57.2 ± 12.2 mg/m2 for average initial dose) and Pt analogs (cisplatin, 63%; carboplatin, 20%; nedaplatin, 17%) was administered. Incidences of grade 3/4 toxicities during first 3 cycles of treatment in hetero and homo were as follows: leukocytopenia, 38% and 59%; neutropenia, 55% and 67%; thrombocytopenia, 7% and 22%; and diarrhea, 9% and 7%. Overall grade 3/4 hematological toxicity was 50% (55/110) in hetero and 78% (21/27) in homo; the adjusted odds ratio was 3.379 (p = 0.0185) in homo compared with hetero. Conclusions: A higher rate of grade 3/4 hematological toxicity in homo than in hetero was confirmed with IRI+Pt therapy. Thus, UGT1A1 genotyping could be a potential biomarker of toxicity with individualized chemotherapy using low-dose IRI regimens. At the presentation, analysis of &gt;250 patients’ data will be shown. Clinical trial information: NCT01040312.

Safety and feasibility of adjuvant chemotherapy with S-1 in Korean patients with curatively resected advanced gastric cancer.

121 Background: Adjuvant chemotherapy with S-1 has been proven effective for patients with curatively resected advanced gastric cancer with D2 lymph node dissection in Japan. We assessed the safety and feasibility of adjuvant S-1 chemotherapy in Korean patients with stage II, III or IV(M0) gastric cancer. Methods: A total of 305 patients with stage II, III or IV(M0) gastric cancer received adjuvant S-1 chemotherapy following curative gastrectomy with D2 lymph node dissection in Asan Medical Center between October 2007 and December 2009. Adjuvant chemotherapy with S-1 was started 3-6 weeks after surgery and it was administered orally twice daily at the dose of 40 mg/m2 for 4 weeks followed by 2 weeks of rest, every 6 weeks 8 times for 1 year. We retrospectively reviewed the medical records of the patients and evaluated the safety and feasibility of adjuvant S-1 chemotherapy in Korean patients. Results: Among the 305 patients, 248 (81.3%) and 198 (64.9%) patients completed 4 and 8 cycles of adjuvant chemotherapy, respectively. The most common reasons for discontinuation of treatment were adverse event (43.9%) and recurrence (26.2%). Among the 305 patients, 75 (24.6%) patients required dose reduction because of toxicities. The most common grade 3/4 toxicities were neutropenia (12.8%), diarrhea (5.3%), abdominal pain (3.8%), and anemia (3.3%). Multivariate analysis showed that total gastrectomy (H.R. 2.50; 95% C.I. 1.32-4.72, p=0.005) and female gender (H.R. 1.95; 95% C.I. 1.03-3.66, p=0.039) were independent risk factors for grade 3/4 hematologic toxicities, and old age (&gt;65 years) (H.R. 2.92; 95% C.I. 1.50-5.69, p=0.002) was an independent risk factor for grade 3 non-hematologic toxicities. Conclusions: Adjuvant chemotherapy with S-1 for 1 year was safe and feasible in Korean patients. Old age, female gender, and total gastrectomy were independent risk factors for severe toxicities of adjuvant S-1 chemotherapy.

Predictors of toxicity of weekly docetaxel in chemotherapy-treated non-small cell lung cancers

Weekly docetaxel seems to be safe and effective compared with traditional tri-weekly docetaxel as a second-line treatment for non-small cell lung cancer. However, the risk factors for severe toxicity of weekly docetaxel in this group of patients are not well-described. Patients with advanced non-small cell lung cancer receiving weekly docetaxel as second- or third-line treatment at a medical center between 1999 and 2003 were identified from cancer registry and pharmacy records. The clinical characteristics, prior chemotherapy regimens, docetaxel administration schedules, and treatment efficacy were collected. Logistic regression was performed to identify risk factors for adverse outcomes and Cox's proportional hazards model was used to analyze cumulative-dose related adverse events. A total of 155 patients were analyzed for treatment effect and toxicity. The overall response rate of weekly docetaxel was 5.2% and the median survival was 8.1 months. The incidence of treatment withdrawal due to adverse events was 43.2% and was significantly related to previous anthracycline use (odds ratio, 4.582; p=0.0144) and chronic hepatitis B or C virus infection (odds ratio, 3.928; p=0.0058). The incidence of grade 3 or 4 neutropenia was 23.2% and was significantly associated with old age (odds ratio, 7.232; p<0.001), lower baseline white blood cell counts (odds ratio, 5.57; p<0.05), and chronic hepatitis B or C virus infection (odds ratio, 3.25; p<0.05). The incidence of fluid retention was 41.3% and the median cumulative dose of docetaxel at onset was 327 mg/m(2). Abnormal liver function status significantly increased the risk for fluid retention (odds ratio, 2.368; p<0.05); while pre-medication with steroids (odds ratio, 0.184; p<0.01), elevated albumin (odds ratio, 0.237; p<0.01), and previous surgical resection (odds ratio, 0.341; p<0.05) decreased the risk. Weekly docetaxel given as second- or third-line chemotherapy to patients with advanced non-small cell lung cancer harbors significant side effects. It should be given cautiously in elderly patients and in patients with chronic viral hepatitis or low white blood cell counts.

Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial

Cancer is most common in older age groups, but little information is available with regard to the impact of age on chemotherapy toxicity. This study was undertaken to determine if age is an independent risk factor for 5-fluorouracil (5-FU) toxicity. Toxicity data from a prospective, randomized, multiinstitution trial of 5-FU-based treatment for advanced colorectal cancer were analyzed. Toxicity for each organ system was graded. Individual organ toxicity proportions were compared using chi-square analysis. A logistic regression was performed using age (younger than 70 years vs. 70 years or older), sex, treatment arm, performance status, and length of therapy as model parameters to predict severe toxicity. Toxicity in 331 patients was analyzed. Advanced age was significantly associated with the occurrence of any severe toxicity (58 vs. 36%, P < 0.001), leukopenia (24 vs. 10%, P < 0.005), diarrhea (24 vs. 14%, P = 0.01), vomiting (15 vs. 5%, P = 0.01), severe toxicity in more than 2 organ systems (10 vs. 3%, P = 0.02), and treatment mortality (9 vs. 2%, P = 0.01). By univariate analysis, age (P < 0.001) and sex (P < 0.0001) were independent predictors of severe toxicity. Twenty-two of 27 women age 70 years or older had severe toxicity. Age 70 years or older and sex are risk factors for severe toxicity from 5-FU-based chemotherapy. Advanced age does not contraindicate the use of this type of chemotherapy, but close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are required. Dosing decisions in older patients are difficult and must integrate assessments of organ function, comorbidities, overall physical status, and goals of treatment, in an effort to ensure the best possible outcome for these patients.