Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.

Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030).

BACKGROUND: The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ≥70 years and <60 years were compared in SWOG0030. METHODS: Twenty-nine unresectable colorectal cancer patients were stratified to either ≥70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared. RESULTS: Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ≥70 years patients (P<0.05). No difference in 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females. CONCLUSION: Increases in capecitabine Cmax and AUC was observed in patients ≥70 years when compared with younger patients who were >60 years.

Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.

BACKGROUND: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. METHODS: We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. FINDINGS: In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. INTERPRETATION: 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. FUNDING: Cancer Research UK; British Heart Foundation; UK Medical Research Council.

Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence.

BACKGROUND: We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer. METHODS: We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo. RESULTS: Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours. CONCLUSION: Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.

1-beta-D-arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum(II) and modification of platinum-induced DNA interstrand cross-linking.

1-beta-D-Arabinofuranosylcytosine (ara-C) and hydroxyurea (HU) were investigated as possible inhibitors for the repair of cis-diamminedichloroplatinum(II) (DDP)-induced DNA damage. HU and ara-C were chosen for their known ability to inhibit DNA excision repair following UV irradiation. Work by several groups has suggested that the repair of DDP-induced DNA damage may involve an excision-repair mechanism. The cytotoxic effects of dose, exposure duration, and sequence for the three drugs was studied in a human colon cancer cell line (HT-29) by colony formation assays. Significant synergistic cytotoxicity was seen whether HU + ara-C were given prior to, or following DDP exposure. Cytotoxic synergy was also seen between HU + ara-C themselves. The effect of the combined antimetabolites on the level and persistence of DDP-induced DNA interstrand cross-links was assessed by DNA alkaline elution. These were measured as an indicator of DDP-DNA adduct formation and removal. When HU + ara-C exposure preceded or followed DDP treatment, higher levels of interstrand cross-linking were found at late time points than were seen with DDP alone, suggesting repair inhibition. We conclude that the combination of HU, ara-C, and DDP shows synergistic cytotoxicity, and that this effect may be due in part to inhibition of DDP-induced DNA adduct repair. The concentrations of drugs used in vitro are achievable in humans. On the basis of these results, a Phase I/II clinical trial of the three agents in combination has been initiated.

Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience.

We analyzed the 2,531-patient Southwest Oncology Group extensive-stage non-small-cell lung cancer (ENSCLC) data base from 1974 to 1988 to (1) assess the interactions of host- or tumor-related prognostic factors and therapy using Cox modeling and recursive partitioning and amalgamation (RPA) to determine whether each independently predicts outcome, and (2) use RPA to define prognostic subsets with different survival potentials. Good performance status (PS), female sex, and age greater than or equal to 70 years were significant independent predictors in a Cox model applied to the entire population. In a second Cox model for patients with good PS enrolled on recent studies, hemoglobin level greater than or equal to 11.0 g/dL, normal lactate dehydrogenase (LDH), normal calcium, and a single metastatic site were significant favorable factors. The use of cisplatin was an additional independent predictor of improved outcome in both Cox models after adjustments for year of accrual and all prognostic variables. The favorable effect of cisplatin was observed in each of six RPA-derived subgroups from the entire population. A second RPA of 904 patients from recent trials (nearly all received cisplatin-based therapy) resulted in three distinct prognostic subsets based on PS, age, hemoglobin, and LDH; greater than or equal to 1-year survivals were 27%, 16%, and 6% (P less than .0001). The best survival occurred for patients with a good PS who had a hemoglobin level greater than or equal to 11 g/dL and who were older than 47 years. This analysis suggests that although several factors were independent variables in the Cox models, three important prognostic subgroups were easily defined through RPA. Together with other analyses, our results suggest the need to modify the stage IV category in NSCLC.

Determinants of improved outcome in small-cell lung cancer: an analysis of the 2,580-patient Southwest Oncology Group data base.

We analyzed the 2,580-patient Southwest Oncology Group (SWOG) small-cell lung cancer data base from 1976 to 1988 in order to (1) determine the prognostic value of favorable demographic and tumor-related factors and therapy programs using Cox multivariate analyses in limited- and extensive-stage disease (LD, ED), and (2) define patient subgroups with significantly different survivals using recursive partitioning and amalgamation (RPA) analysis to refine the current two-stage system. Cox multivariate models were applied to 1,363 patients in six LD trials: good performance status, female sex, age less than 70 years, white race, and normal lactate dehydrogenase (LDH) were significant favorable independent predictors. Concurrent chemoradiotherapy was also a strong independent predictor of survival. For 1,217 patients in four ED trials, a normal LDH, treatment with an intensive multidrug regimen, and a single metastatic lesion were favorable independent variables in the Cox model. RPA analysis of 1,137 patients in recent LD and ED trials resulted in a regression tree in which the most important prognostic split was LD versus ED. Normal or abnormal LDH, absence or presence of a pleural effusion, and age less than 70 or greater than or equal to 70 years were important in LD, but only LDH was significant in ED. The terminal nodes of the regression tree were amalgamated to form four distinct prognostic subgroups with median survivals of 19.0, 12.5, 10.5, and 6.3 months (P less than .0001). The best survival occurred for younger patients with "true" LD: no effusion and normal LDH. The two intermediate patient subgroups had either LD or ED but still lived significantly longer than those patients with true ED (elevated LDH). This analysis suggests that although several factors were independent prognostic variables in LD in the Cox models, a smaller number of variables can be used to form important prognostic subgroups through RPA. The LDH emerged as a highly significant factor, but performance status and sex did not. A refinement of the current staging system should be made if our results can be confirmed with a combined-group data base analysis.

Treatment of limited small-cell lung cancer with concurrent etoposide/cisplatin and radiotherapy followed by intensification with high-dose cyclophosphamide: a Southwest Oncology Group study.

Between March 1986 and May 1988, the Southwest Oncology Group enrolled 58 previously untreated patients with limited small-cell lung cancer on a treatment program that administered high-dose cyclophosphamide (150 mg/kg) as late intensification. Treatment consisted of induction chemo-radiotherapy, (weeks 1 to 11), consolidation chemotherapy (weeks 11 to 18), and intensification (week 18). Median age was 61.5 years. Eighty-nine percent of patients had a Southwest Oncology Group (SWOG) performance status of 0-1. Twenty-one patients completed all prescribed treatments. There were seven treatment-related deaths, four as a result of intensification. Fifty-six patients are available for response analysis. Thirty-two patients achieved a complete remission (CR) (57%) and fifteen achieved a partial remission (PR) (26%). Median survival for all patients is 11.1 months. Among the 21 patients who received intensification, nine remain alive in a CR with a median survival of 27 months. This sequence of treatments was not associated with a survival advantage for the group as a whole, possibly because of the toxicity of induction and consolidation treatment and the delayed administration of high-dose cyclophosphamide.

A phase I trial of high-dose diaziquone and autologous bone marrow transplantation: an Illinois Cancer Council study.

Diaziquone (AZQ), a synthetic quinone with demonstrated activity against acute nonlymphocytic leukemia (ANLL), primary CNS tumors, and non-Hodgkin's lymphoma (NHL), is virtually devoid of nonhematopoietic toxicity at conventional doses. As a prelude to its inclusion into bone marrow transplant (BMT) preparative regimens, a phase I study of high-dose AZQ with autologous BMT (ABMT) was performed. Patients with refractory solid tumors and lymphomas were treated with a single 24-hour infusion of AZQ at 50 to 355 mg/m2 in dose escalations of 20%. Fifty-six patients received 69 courses. Those receiving greater than 60 mg/m2 had nadir granulocyte and platelet counts less than 500/microL and 20,000/microL, respectively. Nausea, vomiting, stomatitis, and diarrhea were mild, transient, and not dose-related. Transient minimal elevations of liver function tests were seen in five patients and were also not dose-related. The maximally tolerated dose (MTD) of high-dose AZQ was found to be 245 mg/m2, with nephrotoxicity being dose-limiting. Significant azotemia was seen in four of 12 patients treated at 295 and 355 mg/m2, including fatal anuric renal failure in three of these patients. Reversible proteinuria also occurred in 24 of 26 courses above 150 mg/m2, including nephrotic range proteinuria in eight courses, all at doses of 205 to 355 mg/m2. The proteinuria was also associated with multiple proximal tubular defects including generalized aminoaciduria and proximal renal tubular acidosis. There were six early deaths including two of early renal failure (295 and 355 mg/m2), two of sepsis (205 and 245 mg/m2), one of a pulmonary embolus (85 mg/m2), and one of progressive disease (60 mg/m2). Of 50 patients who were assessable for response, there were seven responses including two of 10 with primary CNS tumors, one of 12 with malignant melanoma, one of five with non-small-cell lung carcinoma, two of two with breast carcinoma, and one of one with ovarian carcinoma. Because of its activity in ANLL and NHL and its unique toxicity spectrum, high-dose AZQ may improve the efficacy of current BMT preparative regimens without significantly increasing their nonhematopoietic toxicity.

Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7.

Clinical, histologic, and cytogenetic features in 63 patients with a therapy-related myelodysplastic syndrome (t-MDS) or acute nonlymphocytic leukemia (t-ANLL) following cytotoxic chemotherapy or radiotherapy for a previous disease were analyzed. Eleven patients had received only radiotherapy for the primary disorder. In most cases, high doses had been administered to treatment ports that included the pelvic or spinal bone marrow. Twenty-one patients had received only chemotherapy for their primary disease, all for more than 1 year and all but one with an alkylating agent, either alone or in combination with other drugs. Thirty-one patients had received both radiotherapy and chemotherapy, either concurrently or sequentially. A clonal chromosomal abnormality was observed in marrow or blood cells from 61 of the 63 patients (97%). Fifty-five patients (87%) had a clonal abnormality of chromosomes no. 5 and/or 7 consisting of loss of all or part of the long arm of the chromosome. The critical chromosome region that was consistently deleted in all 17 patients with del(5q) comprised bands q23 to q32. In addition to nos. 5 and 7, five other chromosomes (no. 1, 4, 12, 14, and 18) were found to be nonrandomly involved. Both t-MDS and t-ANLL are late complications of cytotoxic therapies that have distinctive clinical and histologic features and are associated with characteristic aberrations of chromosomes no. 5 and 7. It seems likely that these two chromosomes contain genes involved in the pathogenesis of these hematopoietic neoplasms.

Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer.

PURPOSE: A phase II study was conducted by the Southwest Oncology Group (SWOG) to assess the efficacy and toxicity of concurrent carboplatin, etoposide, and thoracic radiation (XRT) in a defined population of poor-risk patients with stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III NSCLC were eligible if they were excluded from cisplatin-based protocols because of poor pulmonary or renal function, history of congestive heart failure, hearing loss, peripheral neuropathy, or weight loss. Carboplatin 200 mg/m2 daily intravenously days 1, 3, 29, and 31 and etoposide 50 mg/m2 daily intravenously days 1 through 4 and 29 through 32 were administered. Beginning day 1, XRT was delivered at 1.8 to 2.0 Gy daily to a total dose of 61 Gy. RESULTS: Within a period of 1 year, 63 patients were registered and 60 were eligible. Patient characteristics were age 47 to 79 years, performance status 0 to 1 (82%) and 2 (18%), and stages IIIA (60%) and IIIB (40%) NSCLC. The most common grades 3 and 4 toxicities included leukopenia (50%), thrombocytopenia (23%), and esophagitis (15%). There were no treatment-related deaths. The overall confirmed response rate was 29%, and median overall survival was 13 months (95% confidence interval, 11 to 14 months). The 2-year survival rate was 21%. CONCLUSION: This chemoradiotherapy regimen is well tolerated in poor-risk patients and yields a median survival similar to that of good-risk patients who received cisplatin-based chemoradiotherapy. This chemoradiotherapy regimen will be compared with XRT alone in poor-risk patients with stage III NSCLC in a randomized phase III trial.

Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805.

PURPOSE: To assess the feasibility of concurrent chemotherapy and irradiation (chemoRT) followed by surgery in locally advanced non-small-cell lung cancer (NSCLC) in a cooperative group setting, and to estimate response, resection rates, relapse patterns, and survival for stage subsets IIIA(N2) versus IIIB. PATIENTS AND METHODS: Biopsy proof of either positive N2 nodes (IIIAN2) or of N3 nodes or T4 primary lesions (IIIB) was required. Induction was two cycles of cisplatin and etoposide plus concurrent chest RT to 45 Gy. Resection was attempted if response or stable disease occurred. A chemoRT boost was given if either unresectable disease or positive margins or nodes was found. RESULTS: The median follow-up time for 126 eligible patients [75 stage IIIA(N2) and 51 IIIB] was 2.4 years. The objective response rate to induction was 59%, and 29% were stable. Resectability was 85% for the IIIA(N2) group eligible for surgery and 80% for the IIIB group. Reversible grade 4 toxicity occurred in 13% of patients. There were 13 treatment-related deaths (10%) and 19 others (15%) died of causes not related to toxicity or tumor. Of 65 relapses, 11% were only locoregional and 61% were only distant. There were 26 brain relapses, of which 19 were the sole site or cause of death. There was no survival difference (P = .81) between stage IIIA(N2) versus stage IIIB (median survivals, 13 and 17 months; 2-year survival rates, 37% and 39%; 3-year survival rates, 27% and 24%). The strongest predictor of long-term survival after thoracotomy was absence of tumor in the mediastinal nodes at surgery (median survivals, 30 v 10 months; 3-year survival rates, 44% v 18%; P = .0005). CONCLUSION: This trimodality approach was feasible in this Southwest Oncology Group (SWOG) study, with an encouraging 26% 3-year survival rate. An Intergroup study is currently being conducted to determine whether surgery adds more to the risk or to the benefit of chemoRT.

Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: Cisplatin has played a major role in the treatment of non-small-cell lung cancer (NSCLC). This randomized trial was performed by the Southwest Oncology Group (SWOG) to determine whether the combination of vinorelbine and cisplatin has any advantage with regard to response rate, survival, and time to treatment failure over single-agent cisplatin in the treatment of patients with advanced NSCLC. METHODS: Between October 1993 and April 1995, 432 patients with advanced stage NSCLC were randomized to receive arm I (cisplatin 100 mg/m2 every 4 weeks) or arm II (cisplatin 100 mg/m2 every 4 weeks and vinorelbine 25 mg/m2 weekly). All patients were chemotherapy-naive, had performance status (PS) 0 or 1, and had adequate hematologic, renal, and hepatic function. RESULTS: Four hundred fifteen patients were eligible and assessable. On arm I (cisplatin), there was a 12% partial response rate. Arm II (cisplatin and vinorelbine) had a 26% response rate (2% complete responses and 24% partial responses, P = .0002). There was a statistically significant advantage with regard to progression-free survival (median, 2 v 4 months; P = .0001) and overall survival (median, 6 v 8 months; P = .0018) for the cisplatin and vinorelbine arm. One-year survival was 20% for cisplatin alone and 36% for the combination arm. There was more hematologic toxicity on arm II of the study (81% grades 3 and 4 granulocytopenia v 5% on arm I). Other toxicities, such as renal insufficiency, ototoxicity, and nausea and vomiting, and neuropathy were similar. CONCLUSION: The results of this study indicate that the combination of cisplatin and vinorelbine is a superior treatment when compared with single-agent cisplatin in the treatment of advanced NSCLC. Cisplatin and vinorelbine is the new standard for SWOG against which new therapies will be evaluated.

American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel.

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. METHODS: An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected physicians, members of the American Society of Clinical Oncology (ASCO) Health Services Research Committee, and the ASCO Board of Directors. RESULTS: Bisphosphonates have not had an impact on the most reliable cancer end point: overall survival. The benefits have been reductions in skeletal complications, ie, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Intravenous (IV) pamidronate 90 mg delivered over 1 to 2 hours every 3 to 4 weeks is recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. For women with only an abnormal bone scan but without bony destruction by imaging studies or localized pain, there is insufficient evidence to suggest starting bisphosphonates. Starting bisphosphonates in patients without evidence of bony metastasis, even in the presence of other extraskeletal metastases, is not recommended. Studies of bisphosphonates in the adjuvant setting have yielded inconsistent results. Starting bisphosphonates in patients at any stage of their nonosseous disease, outside of clinical trials, despite a high risk for future bone metastasis, is currently not recommended. Oral bisphosphonates are one of several options which can be used for preservation of bone density in premenopausal patients with treatment-induced menopause. The panel suggests that, once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient's general performance status. The panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events. Symptoms in the spine, pelvis, or femur require careful evaluation for spinal cord compression and pathologic fracture before bisphosphonate use and if symptoms recur, persist, or worsen during therapy. The panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. IV pamidronate is recommended in women with pain caused by osteolytic metastasis to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, since it was associated with a modest pain control benefit in controlled trials. CONCLUSION: Bisphosphonates provide a meaningful supportive but not life-prolonging benefit to many patients with bone metastases from cancer. Further research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost-benefit consequences.

Influence of patient characteristics, socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment in women enrolled in adjuvant breast cancer studies: an analysis of two intergroup trials.

PURPOSE: To investigate the frequency of breast-sparing treatment among breast cancer patients subsequently enrolled in national cooperative group studies of adjuvant chemotherapy. PATIENTS AND METHODS: A data base was formed of 5,172 patients randomized onto two intergroup trials. Lumpectomy rates were analyzed within study-defined risk strata and across geographic regions. Significant predictors of lower lumpectomy usage were determined in multivariate analyses with variables that described patient and disease characteristics, systemic risk strata, geographic region, and socioeconomic indicators based on zip code of residence. RESULTS: Breast-conservation rates were 30% in the node-negative and 15% in the node-positive trials, with a wide geographic variation within each study (range, 14% to 49% and 9% to 31%, respectively). Lumpectomy use declined with increasing tumor size and did not exceed 40% even for tumors < or = 1 cm with negative nodes. With increasing risk of systemic relapse, frequency of lumpectomy declined (rates for five strata in order of increasing systemic risk: 41%, 33%, 24%, 18%, and 11%), even though these strata were not known at the time of the surgical decision. A logistic model confirmed the joint significance of geographic region and systemic risk. An exploratory model that adjusted for all important variables identified the following significant predictors of lower lumpectomy use: positive nodes; many positive nodes, increased systemic risk; tumor size > or = 2.0 cm; older age; South, Central or non-New England regions; and either lack of college degree or lower income levels. CONCLUSION: Breast-sparing therapy was used in the minority of women subsequently accrued to two national adjuvant breast cancer studies, even though this cohort and their referring surgeons represented a select population. Although multiple concrete factors were independent predictors of lower lumpectomy rates, prospective research is needed into how patients and their physicians approach the mastectomy versus lumpectomy decision.

Breast cancer outcome and predictors of outcome: are there age differentials?

Several questions were addressed regarding breast cancer outcome, predictors of outcome, and young age at diagnosis. Is there evidence that outcome is worse in younger women compared with other age groups? Do younger patients have a greater frequency of adverse prognostic factors? If younger age is associated with a poor outcome, is it an intrinsic independent adverse predictor, or is the outcome worse due to poor prognostic factor profiles? Several methods were used to answer these questions and applied to those reports in which age categories were carefully defined: 1) detailed review of population-based breast cancer outcome literature, 2) synthesis of published cooperative group and single institution univariate and multivariate analyses, and 3) a new analysis of the 8738-patient San Antonio database. Overall, epidemiologic studies suggested that younger women have the worst survival outcome, when matched with similarly staged older cohorts. Univariate trends analyses confirmed that younger women more often had more positive lymph nodes, larger tumors, and negative steroid hormone receptors. Significantly more cancers in women less than 35 years of age had high S-phase fractions and abnormal expression of p53. Multivariate modeling confirmed that young age was an independent adverse predictor when a few standard factors were considered in the model, but other descriptors such as tumor grade or high S-phase fraction were more important when available. These data support the conclusion that "young age" serves as a surrogate for a greater frequency of adverse prognostic factor profiles and suggest important questions for future study.

Cytotoxic synergy of cisplatin with concurrent hydroxyurea and cytarabine: summary of an in vitro model and initial clinical pilot experience.

Cytarabine and hydroxyurea in combination are known to inhibit the DNA excision repair system. Given this system is responsible for repair of cisplatin-DNA adducts, we hypothesized that combining cytarabine, hydroxyurea, and cisplatin in an appropriate schedule might inhibit adduct repair, increase the number of DNA lesions, and produce synergistic cell kill. In vitro experiments using clinically achievable doses and schedules of these antimetabolites demonstrated cytotoxic synergy with the three-drug combination, but little or no such synergy with either antimetabolite plus cisplatin. The inclusion of hydroxyurea was necessary to achieve maximum synergy. Increased levels and persistence of cisplatin-induced DNA interstrand cross-links were observed, suggesting repair inhibition may have occurred. The dose of cisplatin required to inhibit colony formation by 90% was reduced approximately one third, even after normalization for the cytotoxic component(s) of hydroxyurea, cytarabine, and hydroxyurea plus cytarabine. Using one of the two optimal in vitro schedules for the three-drug combination, we performed a clinical pilot study in two patient cohorts (with and without prior systemic therapy). Administration of the program was feasible, and resulted in dose-limiting thrombocytopenia only in the cohort with prior chemotherapy. Azotemia was treatment-limiting in responding patients. Responses were observed in patients with a variety of solid tumors, including several patients who had previously failed cisplatin therapy. Modifications of this program are discussed, which have, to date, significantly decreased the toxicity concerns raised by the first trial. Phase II trials are planned in patients with a variety of cisplatin-responsive and nonresponsive neoplasms.

Aggressive large cell lymphoma of the ileum after long-term cyclophosphamide therapy for breast carcinoma.

A middle-aged woman was treated for breast carcinoma with postoperative adjuvant chest wall irradiation, followed four and seven years later with therapy to spinal ports for palliation of metastatic disease. For the next three and a half years, she received oral cyclophosphamide on a daily basis to a total of more than 110 g. Twelve years after diagnosis and five years after the start of chemotherapy, an aggressive, large cell lymphoma of the ileum developed, with poor response to conventional therapy. This may represent the first patient with breast carcinoma in whom a treatment-induced non-Hodgkin's lymphoma has developed.