The best use of adjuvant chemotherapy: New drugs and new use of “old” drugs

Modern chemotherapy has diminished the risks of distant relapse and death in many subgroups of patients with early stage breast cancer. Although the initial trials relied on empirically designed regimens, studies are increasingly based on preclinical science and reflect the growing understanding of the molecular basis of cancer. Empiric clinical trials proved the worth of combination chemotherapy, the limited value of very long courses of treatment, and the benefits of adding first anthracyclines and then later taxanes. More recent trials have demonstrated the limits on empiric dose escalation and the benefits of optimized scheduling. Many trials are currently focused on novel targeted agents. Based on several decades of studies in thousands of women it is reasonable to consider a combination of chemotherapy agents for patients with hormone unresponsive or otherwise high-risk tumors. Anthracyclines and taxanes should be incorporated into the treatment plans of patients in the higher risk subsets and the specific regimens should be taken from the several randomized studies. When available, eligible patients should be enrolled on prospective clinical trials.     

Short term quality of life with epirubicin-fluorouracil-cyclophosphamid (FEC) and sequential epirubicin/cyclophosphamid-docetaxel (EC-DOC) chemotherapy in patients with primary breast cancer – Results from the prospective multi-center randomized ADEBAR trial

BackgroundThe recommendation for adjuvant dose-dense chemotherapy in high risk primary breast cancer is heterogeneous among guidelines. Understanding the impact on QoL is thereby a crucial factor, especially if the benefit is potentially low. This study aims to assess QoL as a secondary outcome in the prospective randomized multi-center ADEBAR trial.MethodsQoL was assessed at baseline (t1), before cycle 4 FEC and cycle 5 EC-DOC (t2), 4 weeks after chemotherapy (t3) and 6 weeks after radiation (t4) using the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Breast Cancer-Specific Module (QLQ-BR23).Results1306 patients were enrolled into the ADEBAR trial. 675 were assigned to the FEC and 688 to the EC-DOC arm. After the beginning of treatment, global QoL dropped in both arm by 3–4 points. In the EC-DOC arm, QoL dropped further at t3 by 7 points and stayed stable in the FEC arm. 6 weeks after radiation, QoL exceeded baseline in both arms by 6–8 points. The differences between treatment arms were strongest at t3 (53.0 vs. 49.5) but did not reach clinical relevance at any point in time. Physical functioning, nausea and vomiting, fatigue and systemic therapy side effects followed with some minor exceptions similar patterns but showed higher amplitudes.ConclusionIn conclusion, we could not detect a clinically relevant difference between the two treatment arms in global QoL, although the results consistently show that patients on EC-DOC report worse scores during the treatment.     

Achieving optimal dose intensity with adjuvant chemotherapy in elderly breast cancer patients: a 10-year retrospective study in a UK institution

The study was to determine if breast cancer patients aged 65 and above could be given adjuvant chemotherapy safely while achieving an acceptable relative dose intensity of at least 85%. We identified all patients aged 65 and over who received adjuvant chemotherapy over the 10 year period, November 1999 to October 2009, and determined the proportion that achieved a relative dose intensity of at least 85% as well as the tolerability of their treatment. A total of 101 patients were identified, with a median age of 69 years (range 65-78).Of these, 25.7% of patients had at least one major comorbidity, 84.2% had a tumor size of 5 cm or less, 73.3% were node positive and 58.4% were hormone receptor positive. The chemotherapy regimens used were AC (Doxorubicin and Cyclophosphamide), FEC (Fluorouracil, Epirubicin, and Cyclophosphamide), CMF (Cyclophosphamide, Methotrexate, and Fluorouracil) and ECMF (Epirubicin followed by CMF). Seventy-nine patients (78.2%) achieved the relative dose intensity of at least 85%. With respect to toxicity, 11.9% of patients developed febrile neutropenia and 23.8% of patients required hospital admission during the treatment period, but there were no treatment-related deaths in the group. A significant proportion of patients aged 65 and above achieved the intended dose intensity of at least 85% over this 10-year period, with manageable toxicity levels. This supports the use of these regimens as adjuvant chemotherapy for breast cancer in this age group.     

Adjuvant chemotherapy with 5-FU,adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A southwest oncology group study

Purpose: To evaluate FAM [5-FU (5-fluorouracil), doxorubicin, mitomycin C] chemotherapy as adjuvant therapy for patients with resected TNM stage I, II, or III gastric carcinoma. Patients and Methods: One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles (1 year) of postoperative FAM chemotherapy with observation only. Results: The median follow-up on this study was 9.5 years. For all patients, no differences (log-rank analysis) in disease-free survival (p=0.45) and overall survival (p=0.57) between FAM therapy (93 cases) and surgery (100 cases) were observed. Quality of surgical resection affected survival irrespective of FAM use. Cases with curative resection, defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins >1 cm, had superior survival compared to cases not meeting these requirements (p<0.001). FAM was well tolerated with 6% (five of 90) of cases demonstrating grade IV hematologic toxicity. There were two drug-related fatalities (one cardiomyopathy, one hematolytic uremic syndrome). Conclusion: FAM is not effective adjuvant therapy for TNM stage I, II, and III patients with resected gastric cancer. Future adjuvant studies must emphasize prospective surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period. Address reprint requests to Southwest Oncology Group (SWOG-7804), Operations Office, 14980 Omicron Drive, San Antonio TX 78245-3217, USA.     

Axillary lymph node dissection for breast cancer: A decision analysis of T1 lesions

Background: The value of routine axillary dissection for patients with breast cancer is still being debated. The argument centers around whether the information gained by knowing the lymph node status, which aids in making the decision about adjuvant chemotherapy, justifies the morbidity. This study quantitatively analyzes the potential outcomes of routine, selective, and no axillary dissection. Methods: A decision analysis was performed of the strategies of lumpectomy and radiation versus simple mastectomy followed by no dissection, selective dissection, or routine dissection. Factors included biologic markers to identify high-risk lesions, the morbidity of axillary dissection, the effects of adjuvant chemotherapy on lymph node-negative and lymph node-positive disease, and the life expectancy of patients with high-risk and low-risk node-negative and node-positive lesions. Sensitivity analysis was done to determine threshold levels of these factors in choosing an option. Results: We discovered an advantage in quality-adjusted life expectancy (QALE) for no axillary dissection until the probability of positive lymph nodes reaches >15%; after that, selective node dissection is superior. Selective dissection is superior for lower morbidity rates of axillary dissection. Routine dissection is never a superior strategy. The difference among these strategies is small, however, with no one strategy providing a QALE greater than 1 year longer than any other. Conclusions: Axillary dissection can be avoided in patients with high-risk lesions who would be candidates for adjuvant chemotherapy regardless of lymph node status, and possibly in patients with low-risk T1a lesions, but it should be recommended for low-risk T1b and T1c lesions for which lymph node status may determine the need for adjuvant chemotherapy.     

When to recommend and to pay for first-line adjuvant breast cancer treatment? A structured review of the literature

A structured review of studies on the health-economic evaluation of systemic adjuvant therapy for early-stage breast cancer was carried out. Of the eight articles that have been identified four were related to the cost-effectiveness of chemotherapy, three compared chemotherapy with combined chemotherapy and hormonal therapy and one compared tamoxifen (TAM) with third-generation aromatase inhibitors (ATIs). Results of the review indicate that the cost-utility of adjuvant breast cancer therapy is within the range of other oncological interventions. Adjuvant chemotherapy is most cost-effective in pre-menopausal women with node-positive breast cancer while cost-effectiveness decreases considerably with increasing age. Endocrine therapy with TAM is most cost-effective in ER-positive tumours with no significant age effect. The cost-utility of using the ATI anastrozole instead of TAM in adjuvant therapy cannot be conclusively assessed on the basis of the existing evidence.     

Postoperative adjuvant treatments for biliary tract cancer

Surgery currently remains the only potentially curative treatment for biliary tract cancer, and most patients develop recurrence. Thus, effective adjuvant therapy is required to increase the curability of surgery and to prolong the survival in these patients. However, to date, no standard postoperative adjuvant therapy regimen has been established for patients with biliary tract cancer. Based on favorable results reported from phase II trials, gemcitabine and S-1 are currently available as promising agents for the treatment of unresectable biliary tract cancer in Japan. Both agents are also expected to be effective in the postoperative adjuvant therapy setting for biliary tract cancer, and well-designed randomized controlled trials (phase III trials) to determine the efficacy of these agents in the postoperative adjuvant setting should be pursued vigorously. In phase III trials, appropriate stratification of patients is important, and the primary disease (gallbladder cancer versus nongallbladder cancers), curability (R0 or R1), and presence/absence of lymph node metastasis should be taken into account.     

Commentary on “A novel treatment strategy for newly diagnosed high-grade T1 bladder cancer: Gemcitabine and cisplatin adjuvant chemotherapy—A single-institution experience.”

Background

Management of high-grade T1 (formerly T1G3) bladder cancer continues to be controversial. Should patients with T1G3 bladder cancer have an immediate radical cystectomy or should they receive intravesical bacillus Calmette-Guérin preserving bladder? Gemcitabine and cisplatin (GC) adjuvant chemotherapy may help to strike a balance between intravesical and early cystectomy. For purposes of this study, we continue to refer high-grade T1 lesion as “T1G3.”

A novel treatment strategy for newly diagnosed high-grade T1 bladder cancer: Gemcitabine and cisplatin adjuvant chemotherapy—A single-institution experience

Background

Management of high-grade T1 (formerly T1G3) bladder cancer continues to be controversial. Should patients with T1G3 bladder cancer have an immediate radical cystectomy or should they receive intravesical bacillus Calmette-Guérin–preserving bladder? Gemcitabine and cisplatin (GC) adjuvant chemotherapy may help to strike a balance between intravesical and early cystectomy. For purposes of this study, we continue to refer high-grade T1 lesion as “T1G3.”

European inter-institutional impact study of MammaPrint

AimTo measure the impact of MammaPrint on adjuvant treatment decisions and to analyze the agreement in treatment decisions between hospitals from 4 European countries for the same patient cohort.MethodsBreast cancer patients were prospectively enrolled and MammaPrint was assessed. Patients' clinical data without and then with MammaPrint results were sent to the different multidisciplinary teams and treatment advice was provided for each patient.ResultsUsing MammaPrint, chemotherapy treatment advice for ER+/HER2- breast cancer patients was changed in 37% of patients by the Dutch, 24% by the Belgian, 28% by the Italian and 35% by the Spanish teams. MammaPrint increased the inter-institutional agreement in treatment advice (chemotherapy or no chemotherapy) from 51% to 75%.ConclusionThe results of this study indicate that MammaPrint impacts adjuvant chemotherapy recommendation. MammaPrint can decrease inter-institutional and inter-country variability in adjuvant treatment advice for breast cancer patients.     

Adjuvant Chemotherapy for Invasive Bladder Cancer: A 2013 Updated Systematic Review and Meta-Analysis of Randomized Trials

Context

The role of adjuvant chemotherapy remains poorly defined for the management of muscle-invasive bladder cancer (MIBC). The last meta-analysis evaluating adjuvant chemotherapy, conducted in 2005, had limited power to fully support its use.

Objective

To update the current evidence of the benefit of postoperative adjuvant cisplatin-based chemotherapy compared with control (ie, surgery alone) in patients with MIBC.

Evidence acquisition

A comprehensive literature review was performed to identify all randomized controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy with control for patients with MIBC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to May 2013. An updated systematic review and meta-analysis was performed.

Evidence synthesis

A total of 945 patients included in nine RCTs (five previously analyzed, one updated, and three new) were examined. For overall survival, the pooled hazard ratio (HR) across all nine trials was 0.77 (95% confidence interval [CI], 0.59–0.99; p = 0.049). For disease-free survival, the pooled HR across seven trials reporting this outcome was 0.66 (95% CI, 0.45–0.91; p = 0.014). This disease-free survival benefit was more apparent among those with positive nodal involvement (p = 0.010).

Conclusions

This updated and improved meta-analysis of randomized trials provides further evidence of an overall survival and disease-free survival benefit in patients with MIBC receiving adjuvant cisplatin-based chemotherapy after radical cystectomy.     

Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment.