Relapse-free Survival Benefit Research Articles

The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis.

The association between PIK3CA mutation and resistance to anti-HER2 therapy (AHT) is not precisely defined. This meta-analysis intended to explore the clinical utility of PIK3CA mutation in HER2-positive breast cancer treated with AHT. Literature search identified 19 eligible studies. There were 1720 patients with advanced, 828 with early and 1290 patients treated in the neoadjuvant setting. In metastatic breast cancer, AHT showed no differential objective response benefit between the wild type (WT) and the mutated type (MT) PIK3CA subgroups (odds ratio [OR] = 1.09; 95 % CI 0.60-2.00; P = 0.78). AHT favorable affected progression-free survival (PFS) irrespective of PIK3CA mutation. There was no PFS difference between WT and MT regardless of the offered therapy. In early breast cancer, trastuzumab combined with the same chemotherapy conferred consistent relapse-free survival benefit in WT and MT subgroups (WT: HR = 0.59; 95 % CI 0.44-0.80; P < 0.001 vs. MT: HR = 0.42; 95 % CI 0.24-0.74; P < 0.001). In the neoadjuvant setting, AHT-based therapy produced a 72 % higher pathologic complete response (pCR) rate in WT as compared with that in MT PIK3CA tumors (OR = 1.72; 95 % CI 1.29-2.13; P < 0.001). In that setting, there was no disease-free or overall survival difference based on PIK3CA mutational status. In this meta-analysis, AHT did not achieve differential benefit according to PIK3CA mutation in HER2-positive metastatic or early breast cancer; however, in the neoadjuvant setting, patients harboring WT PIK3CA tumors attained a higher pCR rate.

Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia

AbstractIn this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.

Abstract P1-12-02: Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial

Abstract Background: Whether administration of LHRH analog during CT in premenopausal patients with early-stage, hormone receptor-positive disease would reduce CT-induced premature ovarian failure (POF) is still controversial. Moreover, whether LHRH analog would influence the prognosis of patients is unknown yet. This randomized study is to evaluate whether administration of LHRH analog during CT would reduce POF and effect the prognosis of breast cancer. Methods: This is arandomized, controlled phase III clinical trial. Premenopausal patients age &amp;lt;46 with stage I-IIIA, ER/PR-positive BC to be treated with CT were randomized into two arms. Concurrent arm received CT with goserelin (GN) 3.6 mg SQ starting 0-7 days prior to the first CT dose, and after CT, the researchers determined whether continuous GN to 2-5years or cessation. Sequential arm received CT without GN, and after CT, the researchers determined GN 2-5 years immediately or after restoration of ovarian function or bilateral ovariectomy. Neoadjuvant CT was allowed. Five-year tamoxifen after CT was administered to all patients. The primary endpoint is POF, defined as amenorrhea for the prior 12 months and post-menopausal FSH or not assessed after last CT dose or last GN dose. Other endpoints include efficacy of neoadjuvant CT and relapse-free survival (RFS), defined as time to the first of these events: loco-regional recurrence, contralateral breast cancer or distant metastasis. Results: Between 2/09 and 5/13, the trial has finished enrollment, 216 patients were enrolled. The median age were 37.5 in combined arm (n=108) and 39 in sequential arm (n=108), respectively. The median follow-up time was 27.4 months and 25.7 months, respectively. 15 patients and 21 patients received neoadjuvant CT, respectively. There were no significant difference in age, tumor stage and CT regimens (p&amp;gt;.05). The median cycles of GN were 25, respectively. 47% had complete primary endpoint data. POF rate were 5/42 (11.9%) in the combined arm and 16/60 (26.7%) in the sequential arm. POF rate (and post-menopausal FSH) rate were 1/42 (2.4%) in the combined arm and 8/60 (13.3%) in the sequential arm. In neoadjuvant CT subgroup, each has 1 patient achieved pathological complete remission, and there was no significant difference in objective clinical response. There were 9 patients in the combined arm and 3 patients in the sequential arm had occured RFS events (including 2 and 0 deaths, respectively, OR=3.18, 95%CI:0.84-12.09, P=.075). Conclusions:LHRH analog administration with CT might be associated with less POF and did not affect the efficacy of neoadjuvant CT, however, had no RFS benefit, it may need longer follow-up. We will conduct an interim analysis in November 2014. Clinicaltrials.gov Registry Number: NCT01712893. Citation Format: Jian-Wei Li, Guang-yu Liu, Ke-Da Yu, Ya-jie Ji, Miao Mo, Li Lei, Jiong Wu, Gen-hong Di, Yi-feng Hou, Zhen Hu, Can-ming Chen, Zhen-Zhou Shen, Zhi-Ming Shao. Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-02.

Leukocyte mitochondrial DNA content: a novel biomarker associated with prognosis and therapeutic outcome in colorectal cancer.

Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risks of several malignancies in a cancer-specific manner. However, to date, whether leukocyte mtDNA content can predict clinical outcome of cancer patients has never been investigated. In the present study, we measured leukocyte mtDNA content using real-time PCR-based method in a total of 598 colorectal cancer (CRC) patients and explored its prognostic values. To explore potential mechanism, we detected the immunophenotypes of peripheral blood mononuclear cells and plasma concentrations of several cytokines in CRC patients. We found that patients with high mtDNA content showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low mtDNA content in all patient sets. Furthermore, mtDNA content and tumor node metastasis (TNM) stage exhibited a notable joint effect in prognosis prediction. Integration of TNM stage and leukocyte mtDNA content significantly improved the prognosis prediction efficacy for CRC. Importantly, patients with high mtDNA content showed OS and RFS benefits from adjuvant chemotherapy. In addition, we found that patients with high mtDNA content had a higher frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells, higher plasma interleukin-2 and transforming growth factor-β1 and lower tumor necrosis factor-α concentration than those with low mtDNA content, suggesting a stronger immunosuppressive phenotype. In conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with immunosuppression in CRC patients. Additionally, leukocyte mtDNA content might serve as a potential biomarker to select CRC patients who will benefit from adjuvant chemotherapy.

The use of interferon in melanoma patients: A systematic review

Interferon (IFN) and PEG-IFN are the only drugs approved as adjuvant therapy in patients with melanoma at high-risk of recurrence after surgical resection. Several clinical trials of adjuvant IFN, using different doses and durations of therapy, have been conducted in these patients. Results generally suggest relapse-free survival and overall survival benefits; however, questions over the optimal dose and duration of treatment and concerns over toxicity have limited its use. IFN exerts its biological activity in melanoma via multiple mechanisms of action, most of which can be considered as indirect immunomodulatory effects. As such, IFN may also be of benefit in the neoadjuvant setting, where it may have a role in melanoma patients with locally advanced disease for whom immediate surgical excision is not possible. However, this has not been well studied. The use of IFN in patients with metastatic melanoma is controversial, with limited data and no convincing evidence of a survival benefit. However, IFN therapy combined with novel biological and immunotherapies offers the potential for a synergistic effect and improved clinical outcomes. Predictive and prognostic factors to better select melanoma patients for IFN treatment have been identified (e.g. disease stage, ulceration, various cytokines) and may also enhance its therapeutic efficacy, but their incorporation into the clinical decision-making process requires validation in prospective trials. In conclusion, the modest efficacy of IFN shown in clinical trials is largely a reflection of differences in response between patients. Despite advancements in the understanding of its biological mechanisms of action, the huge potential of IFN remains to be fully explored and utilized in patients with melanoma.

New Options for the Adjuvant Treatment of Cutaneous Melanoma?

High-dose interferon is the current standard of care for the adjuvant treatment of high-risk cutaneous melanoma. Despite numerous clinical trials using interferon in a variety of doses and schedules, none have demonstrated a meaningful clinical improvement relative to standard high-dose interferon. Recently however, a phase III trial using biochemotherapy demonstrated a superior relapse-free survival benefit over standard interferon. In addition, several agents approved for use in metastatic melanoma are being investigated in the adjuvant setting.

Cytomegalovirus Reactivation After Allogeneic Stem Cell Transplantation Is Associated With a Reduced Risk Of Relapse In Patients With Acute Myeloid Leukemia: The Japan Society For Hematopoietic Cell Transplantation (JSHCT) Transplantation-Related Complication Working Group

▪ BackgroundCytomegalovirus (CMV) infection is still a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Recently, it is reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study is to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSC in a large cohort of patients. Patients and MethodsThe Transplantation-related Complication Working Group of JSHCT retrospectively surveyed the database of the Transplant Registry Unified Management Program (TRUMP) at the JSHCT. Patients with AML (n=1836), acute lymphoblastic leukemia (ALL) (n=911), chronic myeloid leukemia (CML) (n=223) and myelodysplastic syndrome (MDS) (n=569) who underwent their first allo-HCT from HLA matched related or unrelated donors between 2000 and 2009, and who survived without disease relapse until day 100 after transplantation were analyzed. Patient who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment and the start of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, non-relapse and overall mortality. CMV reactivation and acute/chronic GVHD were evaluated as time-dependent covariates. ResultsCMV reactivation was associated with a decreased cumulative incidence of relapse among patients with AML (20.3% versus 26.4%, p=0.027), but not in patients with ALL, CML or MDS by Gray's test. Among 1836 AML patients, CMV reactivation occurred in 795 patients (43.3%) at median 42 days (-8 - 407 days), and 436 patients (23.7%) relapsed at median 221 days (101-2057 days) after allo-HCT. Grades II to IV acute GVHD developed in 630 patients (34.3%). On multivariate analysis taking competing risk factors into account, three factors significantly associated with a decreased risk of AML relapse: CMV reactivation (HR 0.765, 95%CI 0.59-0.99), unrelated donor compared to related donor (HR 0.593, 95%CI 0.42-0.84) and development of chronic GVHD (HR 0.773, 95% CI 0.60-0.99). However, no benefit in relapse-free survival associated with CMV reactivation was observed (HR 1.025, 95%CI 0.85-1.24). CMV reactivation was associated with increased non-relapse mortality (HR 1.160, 95%CI 1.02-1.32) and overall mortality (HR 1.370, 95%CI 1.11-1.69). Pre-transplant CMV serostatus was not extracted as a risk factor for relapse, non-relapse and overall mortality. ConclusionsA beneficial effect of CMV reactivation on the subsequent relapse risk was observed in patients with AML but no other hematological malignancies in our large cohort study. However, this benefit was canceled out by the increased non-relapse mortality. The underlying mechanism is unclear, but the immunological activation against CMV reactivation plays an essential role in this association. Thus, the immune augmentation treatment options including vaccination and adoptive T-cell transfer might be useful to take advantage of the efficacy of CMV reactivation with minimal increase of non-relapse mortality. Disclosures:Miyamura:Novartis: Speakers Bureau; JRC Nagoya 1st Hospital: Employment. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other. Fukuda:the Japanese Ministry of Health, Labour, and Welfare: Research Funding.

Optimal approach for melanoma

The incidence of cutaneous melanoma is rising faster than that of any other malignancy, and in some parts of Europe it is now the commonest cancer outside of “the big four” common malignancies: i.e. breast, lung, colorectal and prostate cancers. There is little doubt that the major factors in the development of melanoma are skin type, racial origin and sun exposure. Short sharp bursts of sunlight leading to sunburn are dangerous, especially when they occur in children and adolescents. Ten percent of melanomas are familial in origin, and as with other cancers, the biology associated with such tumours has helped us to develop an understanding of the molecular genetics of sporadic melanoma. A number of mutations have been described, including those found in CDKN2A, CDK4, RB1, p14ARF, NRAS and particularly BRAF. BRAF mutations are found in approximately 50% of patients with cutaneous melanoma, and the development of targeted agents against mutations in BRAF has been responsible for one of the most dramatic examples of molecular medicine in oncology. Adjuvant therapy for patients at high risk of relapse following treatment for primary melanoma or locoregional disease remains an area of uncertainty. The use of adjuvant interferon, at various doses and schedules, has been the subject of many randomised trials over 25 years. It is of note that some large trial groups such as those in Europe still feel that there is enough uncertainty as to the efficacy of interferon that randomised trials of adjuvant therapy should still be performed with a no-treatment control arm. The one indisputable fact about adjuvant interferon is that it is associated with a relapse-free survival benefit, but some argue that, unlike treatment in the metastatic setting, the purpose of adjuvant therapy is to improve overall survival. A number of meta-analyses of the randomised trials involving interferon have been published, and it appears that the maximum absolute benefit to overall survival is in the order of 2–3% and again, some argue that this is below the threshold of useful clinical utility. Randomised trials of the newer melanoma therapies are now being brought into the adjuvant arena. Vemurafenib is a BRAF inhibitor, and the results of the first randomised trial of vemurafenib against standard of care – namely, dacarbazine (DTIC) – were dramatic in terms of response rates, progression-free survival and overall survival. The hazard ratio for overall survival at the time of the first analysis was unprecedented in solid tumour oncology. The therapeutic momentum has continued with the development of MEK inhibitors and their combination with BRAF inhibitors. Other targeted therapies are being developed for uveal and acral melanomas, e.g. against c-KIT mutations in the latter. The most important recent development in immunotherapy has been the targeting of inhibitors of the immune system, e.g. CTLA-4, PD-1 and its ligand PD-L1. Ipilimumab targets CTLA-4 and is the first immunotherapy to have shown an overall survival benefit in melanoma within the context of a randomised trial. The magnitude of benefit can be very great in some patients with prolonged complete remissions; however, it is only a minority of patients that benefit. Early results targeting PD-1 and PD-L1 are particularly exciting because they appear to challenge the dogma that immunotherapy only impacts a minority of patients. Early results suggest that the majority of patients show some benefit without necessarily achieving a complete remission. The new immunotherapeutic landscape means that our previous view of follow-up needs to change rapidly. We now know that there is an important immunotherapy that is associated with a survival advantage, but that, as with most immunotherapies, it can take some time before the host response becomes effective. This time-frame may be 2–4 months, and therefore it is completely illogical to wait for a patient to become symptomatic from their metastatic disease before investigating and treating them. Patients must have their metastatic disease diagnosed early, otherwise there is little prospect of a successful outcome to immunotherapy, and therefore patients at high risk of relapse need regular imaging, and treatment should be instituted before high volumes of disease are seen.

Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach

Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. Although early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death, the latter approaching 70% or more at 5 years.In patients at high risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse-free and overall survival. Neoadjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFN-α. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neoadjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neoadjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFN-α, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab, and BRAF inhibitor vemurafenib) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 and anti-PDL-1) as well as other molecularly targeted agents such as the BRAF inhibitor dabrafenib and the MEK inhibitors trametinib, selumetinib, and MEK162 in the near future. Evaluation of the clinical role of these agents as adjuvant therapy will take years to accomplish to ascertain the relapse-free survival benefits and overall survival benefits of these agents, but neoadjuvant exploration may provide early critical evidence of the therapeutic benefits, as well as clarifying the mechanisms of these agents alone and in combination.

Survival Benefit of Adding Chemotherapy to Intensity Modulated Radiation in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma

BackgroundTo evaluate the contribution of chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) and to identify the optimal combination treatment strategy.Patients and MethodsBetween 2006 and 2010, 276 patients with stage II-IVb NPC were treated by IMRT alone or IMRT plus chemotherapy. Cisplatin-based chemotherapy included neoadjuvant or concurrent, or neoadjuvant plus concurrent protocols. The IMRT alone and chemoradiotherapy groups were well-matched for prognostic factors, except N stage, with more advanced NPC in the chemoradiotherapy arm.ResultsWith a mean follow-up of 33.8 months, the 3-year actuarial rates of overall survival (OS), metastasis-free survival (MFS), relapse-free survival (RFS), and disease-free survival (DFS) were 90.3%, 84.2%, 80.3%, and 69.2% for all of the patients, respectively. Compared with the IMRT alone arm, patients treated by concurrent chemoradiotherapy had a significantly better DFS (HR = 2.64; 95% CI, 1.12−6.22; P = 0.03), patients with neoadjuvant-concurrent chemoradiotherapy had a significant improvement in RFS and DFS (HR = 4.03; 95% CI, 1.35−12.05; P = 0.01 and HR = 2.43; 95% CI, 1.09−5.44; P = 0.03), neoadjuvant chemoradiotherapy provided no significant benefit in OS, MFS, RFS, and DFS. Stage group and alcohol consumption were prognostic factors for OS and N stage was a significant predictor for DFS.ConclusionsAddition of concurrent or neoadjuvant-concurrent chemotherapy to IMRT is available to prolong RFS or DFS for locoregionally advanced NPC. Such work could be helpful to guide effective individualized therapy.

Understanding and managing interferon-α-related fatigue in patients with melanoma

Fatigue is the most common toxicity associated with adjuvant interferon-α treatment of melanoma, with an incidence ranging from 80 to 90%. It may be dose-limiting and may lead to treatment discontinuation in a large proportion of patients. Fatigue is commonly diagnosed by self-report, does not have a precise definition, and has a high degree of overlap with symptoms of depression. Specific fatigue scales have been developed over the past few years, assessing fatigue either one-dimensionally or multi-dimensionally. However, the characteristics that define an accurate and efficient fatigue scale have not been established. Despite the debilitating effects of fatigue resulting from interferon treatment, a large proportion of patients place a higher value on the relapse-free survival benefits of treatment compared with quality-of-life deterioration. Pharmacologic interventions to treat and manage fatigue are not well established, although psychostimulants are sometimes used. We recommend incorporating structure and routine into day-to-day activities to cope with fatigue. In our experience, participating in moderate physical activities and drinking sufficient fluids are key factors to ensuring efficient fatigue management. A multidisciplinary team is necessary to translate the fatigue management recommendations into practice. Clinical trials using appropriate fatigue assessment tools to investigate interventional therapies are warranted. We recommend the use of the cross-culturally European Organisation for Research and Treatment of Cancer quality-of-life questionnaire Fatigue Module FA13 for clinical trials as well as in day-to-day clinical trials.

IFN-α in the treatment of melanoma.

Among the IFNs, IFN-α2 has been the most broadly evaluated clinically. At the molecular level, IFN-α has multiple effects in a variety of malignancies that range from antiangiogenic to potent immunoregulatory, differentiation-inducing, antiproliferative, and proapoptotic effects. A multitude of IFN-α2 regimens that may be classified as low dose, intermediate dose, and high dose have been evaluated as adjuvant therapy in melanoma. A durable impact on both relapse-free and overall survival was seen only with the regimen utilizing high-dose IFN-α2b tested in the Eastern Cooperative Oncology Group and intergroup trials E1684, E1690, and E1694 as adjuvant therapy for high-risk surgically resected melanoma (stage IIB or III). Adjuvant pegylated IFN-α2b has also been evaluated at maximally tolerable doses compared with the observation group in the European Organization for Research and Treatment of Cancer trial 18991 and has shown relapse-free survival benefits in patients with microscopic nodal disease.

How Much of a Good Thing? What Duration for Interferon Alfa-2b Adjuvant Therapy?

How Much of a Good Thing? What Duration for Interferon Alfa-2b Adjuvant Therapy?

Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial

The effect of adjuvant chemotherapy on survival for resected soft-tissue sarcoma remains unknown. We investigated the effect of intensive adjuvant chemotherapy on survival in patients after resection of high-risk soft-tissue sarcomas. In this multicentre randomised trial, patients with macroscopically resected, Trojani grade II-III soft-tissue sarcomas at any site, no metastases, performance status lower than 2 and aged between 16 and 70 years were eligible within 4 weeks of definitive surgery. Patients were randomly assigned to receive adjuvant chemotherapy or no chemotherapy (control group). Randomisation was done with a minimisation technique, stratified by hospital, site of primary tumour, tumour size, planned radiotherapy, and isolated limb perfusion therapy. Chemotherapy consisted of five cycles of doxorubicin 75 mg/m(2), ifosfamide 5 g/m(2), and lenograstim every 3 weeks. Patients in both groups received radiotherapy if the resection was marginal or the tumour recurrent. The primary endpoint was overall survival and analyses were done by intention to treat. The final results are presented. This trial is registered with ClinicalTrials.gov, NCT00002641. Between February, 1995, and December, 2003, 351 patients were randomly assigned to the adjuvant chemotherapy group (175 patients) or to the control group (176). 258 (73%) of 351 patients received radiotherapy, 129 in each group. Overall survival did not differ significantly between groups (hazard ratio [HR] 0·94 [95% CI 0·68-1·31], p=0·72) nor did relapse-free survival (HR 0·91 [0·67-1·22], p=0·51). 5-year overall survival rate was 66·5% (58·8-73·0) in the chemotherapy group and 67·8% (60·3-74·2) in the control group. Chemotherapy was well tolerated, with 130 (80%) of 163 patients who started it completing all five cycles. 16 (10%) patients had grade 3 or 4 fever or infection, but no deaths due to toxic effects were recorded. Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft-tissue sarcoma showed no benefit in relapse-free survival or overall survival. Future studies should focus on patients with larger, grade III, and extremity sarcomas.

Adjuvant Treatment of Gastrointestinal Stromal Tumor: The Proof, The Pro, and the Practice

Gastrointestinal stromal tumors (GIST) are rare tumors, but they are the most common mesenchymal tumor of the gastrointestinal tract, driven by mutations in KIT and PDGF. The KIT and PDGF inhibiting agent imatinib has been tested as adjuvant postsurgery in GIST patients with an intermediate or high risk of relapse. Two of three prospective, randomized controlled studies have meanwhile been reported. The American College of Surgical Oncology Group (ACOSOG) in 713 patients reported a relapse-free survival benefit for adjuvant imatinib given for 1 year, but not an overall survival benefit. The Scandinavian Sarcoma Group (SSG) performed a study comparing 1 year of imatinib to 3 years of imatinib. At 3 years the overall survival (OS) in patients with 3 years of imatinib therapy was similar to the OS in those with 1 year of imatinib 96% and 94% respectively, while at 5 years these numbers were 92% and 82% (HR: 0.45; 95% CI [0.22-0.89]; p = 0.019). Data from the largest study, conducted by the European Organisation for Research and Treatment of Cancer (EORTC) in 908 patients randomly assigned to receive either 2 years of adjuvant imatinib or no imatinib, have not yet been reported. Based on the current evidence, 3 years of imatinib at a daily dose of 400 mg should be considered in patients with a 50% or higher risk of relapse within 5 years after surgery. The evidence and the remaining caveats are discussed.

Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non-small cell lung cancer

BackgroundWhile conventionally fractionated radiation therapy alone is an acceptable option for poor prognostic patients with unresectable stage III NSCLC, we hypothesized that accelerated hypofractionated radiotherapy will have similar efficacy without increasing toxicity.MethodsThis is a retrospective analysis of 300 patients diagnosed with stage III NSCLC treated between 1993 and 2009. Patients included in the study were medically or surgically inoperable, were free of metastatic disease at initial workup and did not receive concurrent chemotherapy. Patients were categorized into three groups. Group 1 received 45 Gy in 15 fractions over 3 weeks (Accelerated Radiotherapy (ACRT)) while group 2 received 60-63 Gy (Standard Radiation Therapy 1 (STRT1)) and group 3 received > 63 Gy (Standard Radiation Therapy (STRT2)).ResultsThere were 119 (39.7%) patients in the ACRT group, 90 (30.0%) in STRT1 and 91 (30.3%) in STRT2. More patients in the ACRT group had KPS ≤ 60 (p < 0.001), more commonly presented with weight loss > 5% (p = 0.002), and had stage 3B disease (p < 0.001). After adjusting for clinical variables, there were no differences in the radiation groups in terms of the patterns of local or distant tumor control or overall survival. Some benefit in relapse free survival was seen in the STRT1 group as compared to ACRT (HR = 0.65, p = 0.011). Acute toxicity profiles in the ACRT were significantly lower for grade ≥ 2 radiation dermatitis (p = 0.002), nausea/vomiting (p = 0.022), and weight loss during treatment (p = 0.020).ConclusionsDespite the limitations of a retrospective analysis, our experience of accelerated hypofractionated radiation therapy with 45 Gy in 15 fractions appears to be an acceptable treatment option for poor performance status patients with stage III inoperable tumors. Such a treatment regimen (or higher doses in 15 fractions) should be prospectively evaluated using modern radiation technologies with the addition of sequential high dose chemotherapy in stage III NSCLC.

Adjuvant Therapy Improves Overall Survival in Gastric Cancer

The standard of care for T3 or node-positive gastric cancer combines surgery with adjuvant therapy, including the use of pre- and postoperative chemotherapy with or without postoperative radiotherapy. However, recent studies have revisited the use of adjuvant chemotherapy alone in gastric cancer. A recent pooled analysis showed a survival benefit for adjuvant chemotherapy versus surgery only (JAMA 2010; 303:1729). Also, the prior Adjuvant Chemotherapy Trial for S-1 for Gastric Cancer (ACTS-GC) indicated a relapse-free survival benefit at a median follow-up of 3 years for patients with stage II and III …

Tratamento adjuvante nos GISTs

INTRODUÇÃO: O tumor estromal gastrointestinal (GIST) é o sarcoma mais comum do aparelho digestivo. Essa neoplasia ocorre devido à mutação do gene KIT com consequente ativação constitutiva da proteína KIT. O tratamento primário é cirúrgico e consiste na sua ressecção completa. Entretanto, alguns grupos de pacientes apresentam risco elevado de recorrência mesmo após operação com ressecção completa (R0), indicando diferenças no comportamento biológico. Estudos clínicos comprovaram a atividade clínica do mesilato de imatinibe, fazendo dele a primeira linha de tratamento padrão nos GISTs metastáticos ou irressecáveis, mudando muito o desfecho clínico dessa doença em relação aos benefícios anteriormente obtidos com a quimioterapia antineoplásica. MÉTODO: Foi realizada revisão da literatura com consulta nos periódicos das bases Medline/Pubmed, Scielo e Lilacs cruzando os descritores: tumor estromal gastrointestinal, Gist, tratamento, adjuvância. Além desta revisão foi adicionada a experiência pessoal dos autores. CONCLUSÃO: Melhor refinamento dos critérios de prognóstico tem permitido selecionar de forma mais adequada pacientes para o tratamento adjuvante com imatinibe. Os resultados de maior evidência até o momento respaldam o tratamento adjuvante por um ano, o que produz benefício significativo na sobrevida livre de recidiva, mas não na sobrevida global desses pacientes.

Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer versus curative resection alone: final results of the Japan Clinical Oncology Group trial JCOG9206-2

To evaluate the survival benefit of adjuvant chemotherapy after curative resection in serosa-positive gastric cancer, a multicenter phase III clinical trial was conducted in Japan. From January 1993 to March 1998, 268 patients were randomized to adjuvant chemotherapy (135 patients) or surgery alone (133 patients). All patients underwent gastrectomy with D2 or greater lymph node dissection. The chemotherapy regimen consisted of intraperitoneal cisplatin soon after abdominal closure, postoperative intravenous cisplatin (day 14) and 5-fluorouracil (day 14-16), and daily oral FU (UFT) starting 4 weeks after surgery for 12 months. The primary endpoint was overall survival. Relapse-free survival and site of recurrence were secondary endpoints. Fifty-two patients (38.5%) in the adjuvant chemotherapy arm completed the chemotherapy regimen. There were 4 (1.49%) treatment-related deaths, 1 in the surgery-alone and 3 in the adjuvant chemotherapy arm (2 did not receive chemotherapy). Grade 4 toxicity was observed in 3 patients in the surgery-alone and 2 patients in the adjuvant chemotherapy arm. There was no significant difference in 5-year overall survival (62.0% adjuvant chemotherapy vs. 60.9% surgery-alone, P = 0.482) and 5-year relapse-free survival rates (57.5% adjuvant chemotherapy vs. 55.6% surgery-alone; P = 0.512). There was no benefit in overall and relapse-free survival with this adjuvant chemotherapy regimen for patients with macroscopically serosa-positive gastric cancer after curative resection.

Pegylated interferon alpha-2b as adjuvant treatment of Stage III malignant melanoma: an evidence-based review

Stage III melanoma, also referred to as regional metastatic melanoma, has five-year survival rates ranging between 40% and 78%. In order to reduce the likelihood of recurrence in this high-risk population, patients undergo resection of primary tumors and all involved nodal basins. Systemic therapy is being pursued in an effort to improve outcome data, but the best strategy has yet to be defined. Interferon alpha-2b remains to date the most promising approach available. Toxicities and intensive intravenous administration, unfortunately, are major concerns. An alternative is the use of interferon in its pegylated subcutaneous form. The aim of this research was to review the evidence for the use of pegylated interferon alpha-2b in Stage III malignant melanoma. ECOG 1684 was the pivotal trial that first demonstrated a statistically significant benefit in relapse-free and overall survival for adjuvant interferon alpha-2b in high-risk melanoma. Other larger studies, such as ECOG 1690, confirmed a relapse-free survival benefit but did not achieve statistical significance for overall survival. The first study of the pegylated form of interferon alpha-2b in Stage III melanoma, EORTC 18991, is reviewed here. This trial showed a statistically significant improvement in relapse-free survival but not overall survival. Encouraging data of potential equivalent efficacy, easier administration, and fewer Grade 3 and 4 adverse reactions compared with high-dose intravenous interferon raises the question of its potential role in Stage III melanoma in the adjuvant setting.