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.

An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours.

BACKGROUND: Cixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours. METHODS: In this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10mg/kg) for 1h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon's optimum 2-stage design was applied (PFR at 12 weeks P0=20%, P1=40%, α=0.10, ß=0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2. RESULTS: A total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n=17), 14% for leiomyosarcoma (n=22), 32% for adipocytic sarcoma (n=37), 18% for synovial sarcoma (n=17) and 11% for Ewing family of tumours (n=18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%). CONCLUSIONS: Patients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia.

The impact of induction duration and the number of high-dose cycles on the long-term survival of women with metastatic breast cancer treated with high-dose chemotherapy with stem cell rescue: an analysis of sequential phase I/II trials from the Dana-Farber/Beth Israel STAMP program.

Although high-dose chemotherapy (HDC) with stem cell rescue for the treatment of women with metastatic breast cancer (MBC) is currently a controversial strategy, we report the long-term outcomes of women undergoing high-dose therapy for MBC over the past 12 years while participating in a sequence of research studies transitioning between a single to a double intensification approach. Univariate and multivariate analyses provide a framework to understand the prognostic factors important for event-free and overall survival. Between May 1988 and April 1998, we enrolled 188 women with MBC into 3 trials of previously reported sequential transplantation strategies. Trial I (long induction/single transplantation) accepted 62 women in partial or complete response to an unspecified induction therapy and treated them with high-dose CTCb (cyclophosphamide, thiotepa, and carboplatin) supported by marrow or peripheral blood progenitor cells (PBPC). Trial II (long induction/double transplantation) accepted 68 women in partial or complete response to an unspecified induction therapy, and mobilized stem cells with 2 cycles of AF (doxorubicin and 5-fluorouracil) with granulocyte colony-stimulating factor (G-CSF). These women then received 1 cycle of high-dose single-agent melphalan followed 3 to 5 weeks later by CTCb, each with marrow or PBPC support. Trial III (short induction/double transplantation) enrolled 58 women prior to chemotherapy treatment for metastatic disease. Induction/mobilization consisted of 2 cycles given 14 days apart of doxorubicin and G-CSF. In contrast to trials I and II, patients with stable disease or better response to induction were eligible to proceed ahead with 2 cycles of HDC, 1 being CTCb and the other being dose escalated paclitaxel together with high-dose melphalan (TxM). These 2 HDC regimens were administered 5 weeks apart. TxM was given first in 32 patients and CTCb was given first in 26 patients. The median follow-up periods for trials I, II, and III were 98, 62, and 39 months from the initiation of induction chemotherapy and 92, 55, and 36 months from last high-dose therapy, respectively. The patient characteristics upon entry into these trials were similar. Important differences were that only those patients achieving a partial response or better to induction therapy were enrolled and analyzed for trials I and II, but all patients were analyzed on an intent-to-treat basis for trial III, including those who did not receive intensification. The median event-free survival (EFS) times from induction chemotherapy were 13, 19, and 27 months for trials I, II, and III, respectively (III versus I + II, P = .0004; III versus I, P = .0005; III versus II, P = .005; II versus I, P = .25). The median overall survival (OS) times from induction chemotherapy were 30, 29, and 57 months for trials I, II, and III, respectively (III versus I + II, P = .002; III versus I, P = .003; III versus II, P = .009; II versus I, P = .47). By multivariate Cox regression, participation in the short induction/double transplantation trial III and having no prior adjuvant chemotherapy remained favorable prognostic factors for both EFS and OS. The presence of visceral disease shortened EFS, and hormone sensitivity was of borderline significance. No substantive differences in the characteristics of the patient populations between the 3 trials appeared to interact with outcomes. In conclusion, we found that single transplantation in responding patients after long induction achieves a small cohort of long-term survivors, similar to the results reported by other transplantation centers. Adding a cycle of single-agent high-dose melphalan in this context delayed median time to relapse but did not affect long-term EFS or OS. The double transplantation approach using CTCb and TxM early in the course of treatment was associated with the best EFS and overall survival and was safe, feasible, and tolerable. Treatment duration was only 14 weeks, and this treatment option eliminated lengthy induction chemotherapy. Although selection biases may have in part contributed to this effect, a randomized comparison of standard therapy versus short induction/double transplantation is warranted.

A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer: sequential phase I/II studies.

Two cycles of high-dose chemotherapy with stem cell support (HDC) may increase the total dose delivered and dose intensity. A brief induction phase and different non-cross-resistant agents for each HDC cycle were used to avoid drug resistance. Twenty-six women with metastatic BC had induction and stem cell mobilization with two cycles of doxorubicin/G-CSF given every 14 days. Patients with stable disease or better after induction received HD CTCb followed by HD melphalan and dose-escalated paclitaxel. At 475 mg/m(2) of paclitaxel by 24-h infusion, dose-limiting transient peripheral sensory neuropathy was encountered. No toxic deaths occurred. Complete and near complete response after completion of therapy was achieved in 22 (85%) of 26 patients. The median EFS was 38 months. The median OS has not yet been reached. At a median follow-up of 33 (25-43) months, actuarial EFS and OS were 54% (95% confidence interval (CI), 39-69%) and 69% (95% CI, 56-79%), respectively. This double transplant approach lasts only 14 weeks and is feasible, safe, and tolerable. Whilst selection biases may in part contribute to favorable EFS and OS, a randomized comparison of standard therapy vs double transplant in both metastatic and locally advanced breast cancer is warranted.

A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer.

A single cycle of high-dose chemotherapy with stem cell support (HDC) in women with responsive metastatic breast cancer (BC) consistently achieves over 50% complete and near complete response (CR/nCR). This significant cytoreduction results in a median event-free survival (EFS) of 8 months, and approximately 20% 3-year and 16% 5-year EFS in selected patients. To improve long-term outcomes, new strategies to treat minimal residual tumor burden are needed. Increased total dose delivered can be achieved with two cycles of HDC. Critical design issues include shortening induction chemotherapy to avoid development of drug resistance and the use of different agents for each HDC cycle. We have determined the maximum tolerated dose (MTD) for paclitaxel combined with high-dose melphalan in the context of a double transplant and explored the impact of a short induction phase. Between June 1994 and August 1996, we enrolled 32 women with metastatic BC on to this phase I double transplant trial. Induction consisted of doxorubicin 30 mg/m2/day days 1-3 given for 2 cycles every 14 days with G-CSF 5 microg/kg s.c. days 4-12. Stem cell collection was performed by leukapheresis in each cycle when the WBC recovered to above 1000/microl. Patients with stable disease or better response to induction were eligible to proceed with HDC. HDC regimen I (TxM) included paclitaxel with dose escalation from 0 to 300 mg/m2 given on day 1 and melphalan 180 mg/m2 in two divided doses given on day 3. HDC regimen II was CTCb (cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 total doses) delivered by 96-h continuous infusion. At the first dose level of 150 mg/m2 paclitaxel by 3 h infusion, four of five patients developed dose-limiting toxicity consisting of diffuse skin erythema and capillary leak syndrome. Only two of these five completed the second transplant. Subsequently, paclitaxel was delivered by 24-h continuous infusion together with 96 h of dexamethasone and histamine receptor blockade. This particular toxicity was not observed again. No toxic deaths occurred and dose-limiting toxicity was not encountered. Three patients were removed from study prior to transplant: one for insurance refusal and two for disease progression. All others completed both cycles of transplant. Complete and near complete response (CR/nCR) after completion of therapy was achieved in 23 (72%) of 32 patients. The median EFS is 26 months. The median overall survival has not yet been reached. At a median follow-up of 58 months, EFS and overall survival are 41% and 53%, respectively. This double transplant approach is feasible, safe, and tolerable. Treatment duration is only 14 weeks and eliminates lengthy induction chemotherapy. The observed event-free and overall survivals are promising and are better than expected following a single transplant. Whilst selection biases may in part contribute to this effect, a much larger phase II double transplant trial is warranted in preparation for a potential randomized comparison of standard therapy vs single vs double transplant.

High dose chemotherapy with stem cell rescue for breast cancer: current status and future directions.

Dose intensification of particular chemotherapy agents can produce high, complete and overall response rates in women with locally advanced or metastatic breast cancer. High dose chemotherapy with stem cell rescue is currently a controversial strategy, not only as a component of the standard of care, but even as an investigative field. This review covers the preclinical and clinical underpinnings of high dose therapy for breast cancer, including selected phase II trials and the phase III trials reported to date in both metastatic and locally advanced breast cancer. Proof of principle for the clinical utility of this approach requires further maturation of data and completion of ongoing randomized trials. Nonetheless, the clinical results are sufficiently compelling to support ongoing research and grants, particularly in the effort to develop multicycle high dose approaches and to integrate new agents and new modalities, such as immunotherapy, into the framework of high dose therapy.

Status of high-dose chemotherapy for breast cancer: a review.

The purpose of this review is to analyze the current status of high-dose chemotherapy (HDCT) with autologous stem cell transplantation for patients with breast cancer. Current results from the major prospective phase 2 and phase 3 trials in metastatic breast cancer (MBC) and high-risk primary breast cancer (HRPBC) are reviewed. Prognostic factors and future research directions are also discussed. The encouraging results of phase 2 trials suggested a benefit for HDCT in HRPBC and some categories of patients with MBC. Some investigators have argued that patient selection might have been a critical factor in those studies. Recently reported randomized trials in patients with chemosensitive MBC have included only small numbers of patients in complete remission and thus have not adequately addressed the relative value of HDCT versus maintenance standard-dose chemotherapy in this patient subset. Although initial results of 2 studies have been reported, most randomized phase 3 studies of HDCT in HRPBC require longer follow-up before definitive conclusions can be made about its efficacy in this setting. We conclude that the role of HDCT for HRPBC or MBC patients has not yet been fully defined. Longer follow-up of the ongoing randomized trials is necessary, and their mature results will help clarify this important question. In the meantime, it is imperative that research continues, to enhance the efficacy of the procedure. This may come through incorporating more active drugs into HDCT regimens and combining HDCT with novel strategies aimed at eradication of posttransplantation minimal residual disease.

Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population.

Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.

Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.

High-dose therapy for adult soft tissue sarcoma: dose response and survival.

The role for high-dose therapy in the treatment of sarcomas is controversial and limited. Numerous trials in soft tissue sarcomas have suggested dose-response relationships for doxorubicin (and epirubicin) and ifosfamide. Low doses of these agents are associated with lower response rates than aggressive doses that do not require cellular support. There is little evidence that doses high enough to require hematopoietic stem cell support achieve higher response rates. Complete responses remain rare, and no survival advantage has been documented. New drugs are needed urgently, particularly those with dose-response relationships and those achieving complete responses. In their absence, transplant therapy does not yet play a role in the treatment of soft tissue sarcomas, although further phase II trials could be performed to assess consolidation therapy for complete responders, patients requiring neoadjuvant therapy, and those with resectable oligometastatic disease. High-dose therapy has been evaluated more extensively in patients with pediatric histologies like Ewing's sarcoma, rhabdomyosarcoma, and osteosarcoma. Many more agents suited to transplant regimens have substantial activity against these histologies. Results from certain trials demonstrate improved, long-term, relapse-free survival compared with historical controls, whereas others suggest that selection biases may account for such "improvements." Development of new agents is needed. Carefully designed randomized trials to evaluate the role of high-dose therapy with cellular support should be strongly encouraged in these histologies.

Small cell lung cancer: state-of-the-art therapy in 1996.

Small cell lung cancer (SCLC) occurs almost exclusively in smokers and represents 15 to 25% of all lung cancer histologic findings. It is distinguished from non-small cell lung cancer by its rapid tumor doubling time, high growth fraction, and early development of widespread metastases. Since patients with SCLC usually present with disseminated disease, treatment strategies have focused on systemic therapy. Single-agent and combination chemotherapy, as well as combined-modality therapy, have produced high response rates (80 to 100% for limited disease; 60 to 80% for extensive disease), but these tend to be short-lived (median duration, 6 to 8 months). Survival beyond 5 years occurs in only 3 to 8% of all patients with SCLC. At least 15 to 20 different chemotherapeutic agents have shown major activity against SCLC in both the untreated and relapsed settings, including etoposide, teniposide, cisplatin, carboplatin, ifosfamide, cyclophosphamide, vincristine, and doxorubicin. This paper reviews state-of-the-art treatment strategies being employed in the treatment of SCLC, including those incorporating high-dose intensive therapy, salvage therapy, new agents, thoracic radiotherapy, prophylactic cranial radiotherapy, surgical resection, and biologic response modifiers.

Ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer: update and preliminary survival analysis.

The primary objective of this study was to define the maximum tolerated dose and toxicity profile of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given as a 24-hour infusion, in conjunction with ifosfamide/carboplatin/etoposide (ICE) chemotherapy in patients with advanced lung cancer. Paclitaxel was escalated from 75 to 225 mg/m2 in 25-mg/m2 increments. All patients received granulocyte colony-stimulating factor 5 microg/kg/d from day 4 until the neutrophil count was > or = 10,000/microL. The study population consisted of 41 patients with a median age of 60 years and a median follow-up of 20.7 months. Stage distribution included 5% stage IIIA, 46% stage IIIB, and 49% stage IV. Histology consisted of 61% adenocarcinoma, 12% squamous cell carcinoma, 10% large cell carcinoma, 15% small cell carcinoma, and 2% mixed. The predominant toxicity was hematologic; 63% of patients experienced grade 4 neutropenia and 49% developed grade 4 thrombocytopenia. Fever and neutropenia occurred in 34% of patients. Hematologic toxicity was, in all cases, short-term and reversible and was not dose related. With few exceptions, nonhematologic toxicity was not clinically important. Among 39 patients evaluable for response, 36% achieved a remission (8% complete, 28% partial, 41% had stable disease, and 23% experienced disease progression). Among 33 patients with non-small cell lung cancer, the response rate was 27% (one complete response, eight partial responses, 15 had stable disease, and nine had progressive disease). Among six patients with small cell carcinoma, the response rate was 83% (two complete responses, three partial responses, and one had stable disease). The median survival of all 41 patients was 13.6 months. Survival was almost identical between stage IIIA and stage IV subsets. We conclude that it is possible to safely administer full-dose single-agent paclitaxel with granulocyte colony-stimulating factor support in conjunction with full-dose ifosfamide/carboplatin/etoposide chemotherapy. While response rates observed were not particularly notable, median survival is considerably longer than that usually achieved with combination chemotherapy in advanced lung cancer.

Future directions in lung cancer research and therapeutics.

Although immune and genetic approaches do not yet have substantial clinical exposure in NSCLC, it is hoped that the future will bring less toxic, more specific, and more effective methods to prevent the development of end-stage NSCLC. The principles of multitargeted and multimodality therapy to overcome tumor heterogeneity and resistance, and drug delivery issues have been developed over years of effort using chemotherapy. The lessons learned should not be forgotten, because they will remain applicable to newer biologic and genetic modalities.

Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC).

INTRODUCTION: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92. METHODS: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy. RESULTS: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery. CONCLUSIONS: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.

Sources and sequelae of bacterial contamination of hematopoietic stem cell components: implications for the safety of hematotherapy and graft engineering.

BACKGROUND: It is important to compare the incidence of bacterial contamination of components collected from the peripheral blood or bone marrow (BM), as well as of components processed with or without cell selection or depletion, and to evaluate the sequelae of such contamination. STUDY DESIGN AND METHODS: Bacterial contamination rates were compared in 1380 untreated autologous peripheral blood progenitor cells (PBPCs), 291 untreated autologous BM samples, 916 monoclonal antibody (MoAb)-treated autologous and allogeneic BM samples, and in 45 autologous PBPC components from which the CD34+ cells were selected. Bacterial cultures were performed at sequential time points during the processing of MoAb-treated BM. RESULTS: Bacterial contamination was documented in 44 of 2632 components from 1593 patients (1.67% of components, 2.76% of patients) before cryopreservation. Although only 0.65% of untreated PBPCs were contaminated before cryopreservation, each patient was more likely to have given a contaminated PBPC component than a contaminated BM component (2.41% vs. 0%, p < 0.01). Bacterial contamination of MoAb-treated BM was greater during or after manipulation than it was before (2.33% vs. 0.77%, p < 0.05). At thawing, contamination was documented in 42 (1.97%) of 2136 components cultured. Ten (13.7%) of 73 patients who received hematopoietic progenitor cells that were contaminated before cryopreservation or at thawing developed fever or positive blood cultures within 48 hours of transfusion. Fever was associated with bacteremia in two cases, but no irreversible clinical sequelae were noted. CONCLUSION: These studies suggest that, despite careful attention to sterile procedures, low-level contamination of hematopoietic stem cell components can be introduced before or during manipulation as well as at thawing, and that standards for monitoring of the procedures for collection, processing, cryopreservation, thawing, and transfusion of hematopoietic progenitor cells are necessary.

Patterns of disease failure after trimodality therapy of nonsmall cell lung carcinoma pathologic stage IIIA (N2). Analysis of Cancer and Leukemia Group B Protocol 8935.

BACKGROUND: The impact of sequential trimodality therapy on the pattern of first site disease failure in pathologic Stage IIIA (N2) nonsmall cell lung carcinoma (NSCLC) was analyzed. METHODS: Seventy-four eligible patients with histologically documented Stage IIIA (N2) NSCLC underwent sequential trimodality therapy on Cancer and Leukemia Group B (CALGB) Protocol 8935. Treatment consisted of 2 cycles of induction cisplatin at 100 mg/m2 intravenously (i.v.) (Days 1 and 29) and vinblastine at 5 mg/m2 i.v. weekly for 5 weeks followed by surgery. Surgery included a thoracotomy with resection of the primary tumor and hilar lymph nodes and a mediastinal lymph node dissection. Patients with resected disease then received an additional a cycles of cisplatin at 100 mg/m2 i.v. and vinblastine at 5 mg/m2 i.v. biweekly for 2 total of 4 doses followed by consolidative thoracic irradiation. Patients with completely resected disease received 54 Gray (Gy) whereas those with incompletely resected disease received 59.4 Gy at 1.8 Gy/fraction (fx) once a day. Patients with unresectable disease underwent thoracic radiation therapy (TRT) treatments only to 59.4 Gy at 1.8 Gy/fx without any additional chemotherapy. Disease recurrence was determined by clinical, radiographic, or histologic criteria. Pattern of disease failure was identified by site of involvement at first recurrence as indicated by the CALGB Respiratory Follow-Up Form. RESULTS: Sixty-three of the 74 patients completed the induction chemotherapy as planned. Forty-six of the 63 patients underwent resection of disease whereas the remaining 17 were unresectable. Thirty-three of the 46 resected patients completed the entire adjuvant postoperative chemoradiation treatment as planned. Ten of 17 patients with unresectable disease completed postsurgical TRT. At a median follow-up interval of 27 months (range, 4-43), the 3-year overall survival and failure-free survival were 23% and 18%, respectively, for all 74 eligible patients. Overall, disease failure has occurred in 52 (70%) of the 74 eligible patients: local only: 13 (25%); distant only: 16 (31%); and both local and distant: 23 (44%), (P = not significant [NS]). Ten patients progressed during induction chemotherapy: local only: six patients; and both local and distant failure: four patients. Twenty-eight of 46 resected patients recurred: local only: 1 (4%); both local and distant failure: 11 (39%); and distant only: 16 (57%); (P < 0.001). Disease progression occurred in 14 of 17 patients with unresectable disease: local only: 6; both local and distant sites: 8. Among the 52 total patients experiencing disease relapse, isolated or combined local failure occurred commonly among patients during induction chemotherapy (n = 10, [28%]), in those with unresectable disease (n = 14, [39%]), or in those with resected disease (n = 12, [33%]), (P = NS). However, isolated or combined distant failure was more likely to occur among patients with resected disease (n = 27, [69%]) than either during induction chemotherapy (n = 4, [10%]) or in those with unresected disease (n = 8, [21%]), (P < 0.05). Among patients who relapsed, brain metastases occurred in 13 of 52 (25%) patients overall and in 12 of 28 (43%) patients with resected disease. CONCLUSIONS: Overall, disease failure was just as likely to occur in local, distant, or combined sites on CALGB Protocol 8935 using sequential trimodality therapy in the treatment of pathologic Stage IIIA (N2) NSCLC: Isolated or combined local failure occurred commonly during sequential tri-modality therapy whereas isolated or combined distant relapse was prevalent among patients with resected disease. In addition, isolated local failure was rare among patients with resected disease. The pattern of disease failure on CALGB Protocol 8935 reflects the biology of locoregional NSCLC as much as the therapeutic impact of trimodality therapy.

Kinetics of peripheral blood mononuclear cell mobilization with chemotherapy and/or granulocyte-colony-stimulating factor: implications for yield of hematopoietic progenitor cell collections.

BACKGROUND: Peripheral blood progenitor cells (PBPCs) are commonly collected and used to reconstitute hematopoiesis after high-dose chemotherapy. However, strategies for optimal collection and assessment of leukapheresis components are not standardized. STUDY DESIGN AND METHODS: Hematopoietic progenitor cell assays were performed on 369 leukapheresis components collected from 95 patients who had received doxorubicin-based chemotherapy and/or granulocyte-colony-stimulating factor (G-CSF). Precollection patient hematologic values, leukapheresis collection values, component hematopoietic progenitor cell assays, and patient outcome measures were summarized. The kinetics of mononuclear cell (MNC) and PBPC mobilization were assessed among four patient groups. RESULTS: Patient group was a significant predictor of the peripheral blood MNC count on the day of collection (p<0.0001), and that value was a significant predictor of granulocyte-macrophage--colony-forming unit (CFU-GM) yield (p<0.0001). This relationship between the peripheral blood MNC count on the day of collection and CFU-GM yield differed according to patient group (p<0.0001). CFU-GM made up a larger fraction of peripheral blood MNCs collected from patients who received chemotherapy plus G-CSF than collected from those who received G-CSF alone. Moreover, the peripheral blood MNC count and the corresponding CFU-GM yield increased significantly on consecutive days of collection in patient groups receiving chemotherapy and G-CSF but were unchanged or decreased in patients receiving G-CSF alone. CONCLUSION: The relationship between peripheral blood MNC count and leukapheresis component CFU-GM yield differed significantly between patients who received chemotherapy and G-CSF and those who received G-CSF alone for the mobilization of PBPCs. Patient peripheral blood MNC count and component CFU-GM yield are useful for both assessing and suggesting revisions to PBPC mobilization and collection strategies.

A phase I study of ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer.

A phase I study was conducted to define the maximally tolerated dose and toxicity profile of the ifosfamide/carboplatin/etoposide/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (ICE-T) regimen in advanced lung cancer. This chemotherapy program uses paclitaxel given as a 24-hour continuous infusion in conjunction with full-dose ICE chemotherapy with growth factor support. The dosage of paclitaxel was escalated from 75 to 225 mg/m2. Thirty-four patients have been accrued to date onto this study. Because hematologic dose-limiting toxicity was defined in terms of neutropenia and/or thrombocytopenia exceeding 7 days' duration, no patient demonstrated what was defined by the protocol as dose-limiting toxicity. Nonetheless, substantial hematologic toxicity was observed. Overall, 26% had fever and neutropenia, 56% had grade 4 neutropenia, and 26% had grade 4 thrombocytopenia. In all cases, hematologic toxicity was short term and reversible. While grade 3 and 4 myelosuppression was frequently observed, it was not dose related (in terms of paclitaxel dosage). Nonhematologic toxicity also was not dose related and, with only a few exceptions, was not clinically significant. Among 27 patients evaluable for response, 41% achieved an objective response, including 15% with a complete response. All of five patients with small cell lung cancer responded (including two with a complete response). Among 22 patients with non-small cell lung cancer, 27% achieved an objective response (also including two with a complete response). The results of this study suggest that with growth factor support, it is possible to safely administer full-dose, single-agent paclitaxel in conjunction with full-dose ICE chemotherapy. We will soon be initiating a phase II study of the ICE-T regimen using paclitaxel at 225 mg/m2 as a 24-hour continuous infusion in advanced lung cancer. We will also conduct a phase I study of ICE-T, with paclitaxel administered as a 3-hour continuous infusion.

Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic.

Cytotoxic chemotherapy remains the principal modality of treating advanced or unresectable sarcomas of soft tissue. Certain drugs, such as doxorubicin and ifosfamide, are able to induce clinically useful antitumor effects as single agents, and combination chemotherapy regimens have been tested based upon these results. This article summarizes the results of single agent and combination chemotherapy trials for soft tissue sarcomas.