Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Centralized medical monitoring in phase III clinical trials: the National Surgical Adjuvant Breast and Bowel Project (NSABP) experience.

BACKGROUND: There is a need for data quality assurance procedures in phase III cancer trials. At the National Surgical Adjuvant Breast and Bowel Project (NSABP) 'real-time' systems have been developed for quality assurance and study monitoring: (1) manual review and triage of data forms by data managers at the time of submission; (2) computerized edit checking of all submitted data forms; (3) systematic review of eligibility, treatment compliance and toxicity in the first 100 patients of a new protocol; (4) prospective centralized medical review of all reported serious adverse events, treatment failures, second primary cancers and deaths; (5) quarterly review and approval of study summary data files by project statistician; and (6) on-site auditing. PURPOSE: To assess the utility of an additional final comprehensive review of all patient records to confirm eligibility, disease status and vital status prior to manuscript submission. METHODS: Four phase III NSABP studies, which had been monitored using the triage-based quality assurance program described above, were selected for analysis (n = 7972). Charts for 5965 patients were identified that had not been previously medically reviewed for protocol events of recurrence, second primary cancer or death. Submitted source documents and data forms of these 5965 NSABP patient records underwent medical review to verify patient eligibility, disease status and vital status. RESULTS: This final comprehensive review found no additional treatment failures or deaths, identified seven additional cases of ineligibility, was time-intensive requiring enormous use of expensive resources, and was therefore judged not to add significantly to the integrity of the database. LIMITATIONS: Our findings are influenced by the procedures the NSABP employs for quality assurance and study monitoring for Phase III clinical trials and may have limited generalizability to other settings. CONCLUSION: In the presence of multiple quality assurance and data monitoring systems, the rare discrepancies found between the data forms and source documentation does not support the routine use of a final comprehensive chart review for phase III trials at the NSABP Biostatistical Center.

Combined anthracycline-taxane regimens in the adjuvant setting.

Within the past decade there has been enormous interest in integrating the taxanes into the adjuvant breast cancer setting. Adjuvant trial designs in the early 1990s were absent of taxanes. By the mid 1990s, the taxanes were included in adjuvant trials, but were mainly limited to trials conducted in node-positive patients. Currently, taxanes are a chemotherapeutic modality in the majority of ongoing adjuvant trials in both node-negative and node-positive patients. These trials are being conducted in thousands of patients worldwide by several of the cooperative research organizations. Most of the adjuvant trials have focused on defining the clinical efficacy and toxicity of the concurrent or sequential use of taxanes with anthracyclines. The collective experience with taxanes over the next 3 to 5 years will make them one of the most intensely studied treatments in the history of patients with breast cancer. The outcome of these trials is greatly anticipated because they have the potential of changing the current standards of care in the adjuvant treatment of patients with breast cancer.

Preoperative (neoadjuvant) chemotherapy in patients with breast cancer.

The concept of using preoperative chemotherapy in patients with operable breast cancer originated from experimental and clinical observations, as well as from theoretical hypotheses on tumor cell growth and dissemination. Results from nonrandomized studies with different chemotherapeutic agents or combination regimens given preoperatively demonstrated substantial clinical response rates but low pathologic tumor response rates. In addition, several such studies were able to show that-by reducing primary breast tumor size-preoperative chemotherapy can lead to an increase in the rate of breast-preserving procedures. Although nonrandomized studies provided useful clinical information about the effect of preoperative chemotherapy on primary breast tumors and on axillary nodes involved with tumor, they could not address the relative efficacy of preoperative versus postoperative (adjuvant) chemotherapy on disease-free survival (DFS) and overall survival (OS). As a result, several randomized trials were implemented to address the above questions. Some of the earlier trials, however, were not designed as straightforward comparisons of preoperative versus postoperative chemotherapy and, thus, did not provide meaningful answers to the fundamental question of whether DFS and OS can be prolonged by the administration of chemotherapy before surgery rather than after. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial was the largest randomized trial that aimed to compare preoperative to postoperative chemotherapy in operable breast cancer. Results from this trial on the effect of preoperative chemotherapy on local-regional disease and outcome are presented. The potential advantages and disadvantages of each approach, as well as surgical considerations and current and future directions in the use of preoperative chemotherapy, are also discussed.

Adjuvant exemestane therapy after 5 years of tamoxifen: rationale for the NSABP B-33 trial.

Tamoxifen (Nolvadex) has long been established as "standard" adjuvant therapy for receptor-positive, early-stage breast cancer. Results from clinical trials suggest that after approximately 5 years, tamoxifen may lose its effectiveness and may even become harmful if not stopped. At the time of tamoxifen discontinuation, "seemingly" disease-free patients may still have residual micrometastatic tumor cells. In a proportion of such patients, these cells may still be responsive to tamoxifen and thus could grow as a result of stopping the drug. The majority of clinical information, however, suggests that by 5 years of therapy, a greater proportion of patients will have micrometastatic tumor cells that have become resistant to tamoxifen and will be stimulated by continuation of the drug for a longer time. Because in both such cases the micrometastases are hormonally sensitive, a reasonable approach--in addition to stopping tamoxifen--is to decrease the level of estrogenic stimulation by introducing an aromatase inhibitor. The National Surgical Adjuvant Breast and Bowel Project is launching a clinical trial (NSABP B-33) to evaluate the sequential administration of 2 years of exemestane (Aromasin), a steroidal aromatase inactivator, after 5 years of tamoxifen in postmenopausal, receptor-positive patients who are disease-free at the time of tamoxifen discontinuation.

Present state and future prospects: a review of cooperative groups' adjuvant and neoadjuvant trials in breast cancer.

In patients with operable breast cancer, adjuvant hormonal therapy and adjuvant chemotherapy result in significant and long-term reductions in the rates of disease recurrence and death. These reductions are evident in both patients with node-negative as well as in those with node-positive disease. However, several issues in the adjuvant treatment of breast cancer still remain unresolved. These issues were recently considered at the 2000 National Institutes of Health (NIH) Consensus Development Conference, which reviewed the current state of knowledge on adjuvant therapy and outlined strategies for future research. In the area of adjuvant hormonal therapy, tamoxifen is still the gold standard, and present evidence supports the use of tamoxifen for patients with estrogen receptor (ER)-positive tumors irrespective of age, menopausal status, nodal status, or tumor size. Optimal duration of tamoxifen therapy is about 5 years. Future research directions include evaluating the benefit of extending tamoxifen beyond 5 years, the contribution of ovarian ablation, and the role of hormonal manipulations involving selective ER modulators and aromatase inhibitors instead of or in addition to tamoxifen. In the area of adjuvant chemotherapy, polychemotherapy regimens have been consistently found to be superior to single agents, and anthracycline-containing regimens produce a small but statistically significant improvement in survival when compared with regimens not containing an anthracycline. High-dose adjuvant chemotherapy with stem cell support has not been proven superior to standard regimens. Neoadjuvant therapy offers the possibility of testing in vivo the sensitivity of individual tumors to particular cytotoxic regimens and, hence, of improving ultimate disease control, as well as reducing the extent of local therapy. The contribution and optimal integration of taxanes in the adjuvant setting are yet to be established but are the subject of intense research effort. Similarly, novel targeted therapies such as trastuzumab and bisphosphonates are currently being evaluated in adjuvant studies

UFT/leucovorin vs 5-FU/leucovorin in colon cancer.

Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (fluorouracil [5-FU] plus leucovorin and 5-FU plus levamisole) have been found to prolong disease-free survival and overall survival in affected patients. Previous comparisons of these two regimens indicate that 5-FU plus leucovorin may offer a small disease-free survival and overall survival advantage. Evidence that UFT (uracil and tegafur) plus oral leucovorin is associated with significant antitumor activity and has an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer. The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU plus leucovorin vs UFT plus leucovorin. Preliminary analysis of the toxicity findings among 1,530 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles.

Preoperative chemotherapy for operable breast cancer.

In the NSABP B-18 study, it was demonstrated that, in patients with operable breast cancer, the administration of preoperative and postoperative chemotherapy resulted in similar DFS and overall survival outcomes. In addition, preoperative chemotherapy resulted in high clinical response rates but in low rates of pathologic response in the breast. Axillary nodal downstaging was convincingly demonstrated. In addition, it was also demonstrated in B-18, as well as in other studies, that there was an increase in breast conservation rates after the administration of preoperative chemotherapy. The role of preoperative chemotherapy for operable breast cancer continues to be evaluated in randomized trials, which have the potential of providing further insight into the biologic and clinical questions relative to the timing of adjuvant therapy for the disease.

Antiaromatase agents after adjuvant tamoxifen: rationale and clinical implications.

Although tamoxifen is considered standard adjuvant hormonal therapy in receptor-positive, stage I and II breast cancer, information on its optimal duration of administration has only been reported recently and, for many, the subject is still a matter of scientific debate. Data suggest that there is a time period beyond which, if tamoxifen is continued, it may become ineffective or even detrimental to the patient. Tamoxifen is usually discontinued after approximately 5 years of therapy, at which time most patients are thought to be disease free; however, some patients may harbor residual micrometastases. A fraction of these patients will have micrometastatic tumor cells that are still responsive to tamoxifen, and tamoxifen discontinuation could result in cancer cell growth. The preponderance of clinical data, however, indicate that a greater fraction of patients will have micrometastatic tumor cells that have become progressively resistant to tamoxifen. In fact, tumor cell growth could be stimulated by continued therapy with the drug. Although in some patients the micrometastatic tumor cells may have become hormonally unresponsive, in most cases (tamoxifen-responsive or tamoxifen-stimulated micrometastases), the tumor remains hormonally responsive. Therefore, the use of anti-aromatase agents to reduce the level of estrogenic stimulation and, as a result, the risk of recurrence may prove to be a valuable approach at the time of tamoxifen discontinuation. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is in the final stages of developing a clinical trial (NSABP B-33) to evaluate the effect of administering 2 years of therapy with the aromatase inactivator exemestane to postmenopausal, receptor-positive patients who have completed 5 years of tamoxifen therapy and are disease free at the time of tamoxifen discontinuation.

Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26.

PURPOSE: Paclitaxel is an active drug for the treatment of breast cancer; however, the appropriate duration of administration is unknown. We assessed and compared the response rate, event-free survival, survival, and toxicity of paclitaxel 250 mg/m(2) delivered every 3 weeks as a 3-hour or 24-hour infusion. PATIENTS AND METHODS: A total of 563 women with stage IV or IIIB breast cancer were randomized into one of two groups: 279 received 3-hour paclitaxel and 284 received 24-hour paclitaxel. Patients were stratified by age, stage of disease, and prior therapy. RESULTS: A significantly higher rate of tumor response occurred in the first four cycles of therapy in patients who received the 24-hour infusion of paclitaxel (51% v 41%, respectively; P =.025). Tumor response over all cycles was also significantly higher in the group that received 24-hour infusion (54% v 44%, respectively; P =.023). There were no significant differences in event-free survival or survival between the two arms of the study (P =.9 and.8, respectively). No treatment by stage or by age interactions were observed. During the first four cycles of therapy, at least one episode of >/= grade 3 toxicity (excluding nadir hematologic values, alopecia, and weight change) occurred in 45% of patients who received the 3-hour paclitaxel infusion and in 50% of those who received the 24-hour paclitaxel infusion. Febrile neutropenia, >/= grade 3 infection, and >/= grade 3 stomatitis were less frequent, and severe neurosensory toxicity was more frequent in those who received the 3-hour paclitaxel infusion. Ten treatment-related deaths occurred in the first four cycles. Age, stage, and prior chemotherapy did not influence the effect of treatment. CONCLUSION: When administered as a continuous 24-hour infusion, high-dose paclitaxel results in a higher tumor response rate than when administered as a 3-hour infusion but does not significantly improve event-free survival or survival. Paclitaxel as a 24-hour infusion results in increased hematologic toxicity and decreased neurosensory toxicity.

UFT plus calcium folinate vs 5-FU plus calcium folinate in colon cancer.

Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (5-fluorouracil [5-FU] plus calcium folinate and 5-FU plus levamisole [Ergamisol]) have been found to prolong disease-free survival and overall survival in affected patients. Previous comparisons of these two regimens indicate that 5-FU plus calcium folinate may offer a small disease-free survival and overall survival advantage. The demonstration that UFT (uracil and tegafur) plus oral calcium folinate (Orzel) offers significant antitumor activity and an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer. The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU/calcium folinate vs UFT plus oral calcium folinate. Preliminary analysis of toxicity findings among 473 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles. If, in the final survival analysis, UFT plus oral calcium folinate treatment yields the same or better disease-free survival and/or overall survival as the 5-FU/calcium folinate treatment and the toxicity profiles remain similar, it is likely that UFT plus oral calcium folinate will be accepted as a new standard for adjuvant treatment of colon cancer.

NSABP Protocol B-27. Preoperative doxorubicin plus cyclophosphamide followed by preoperative or postoperative docetaxel.

Protocol B-27, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), is a phase III, randomized trial designed to evaluate whether sequencing docetaxel (Taxotere) to neoadjuvant doxorubicin/cyclophosphamide (Cytoxan, Neosar) prolongs disease-free and overall survival in patients with operable breast cancer. Patients are being randomized into three groups. The control group receives four 21-day courses of doxorubicin/cyclophosphamide chemotherapy with tamoxifen (Nolvadex), followed by breast surgery (and postoperative radiation for patients receiving breast-conserving surgery). Two experimental groups receive the same doxorubicin/cyclophosphamide chemotherapy and tamoxifen, followed by docetaxel--either before (preoperative group) or after (postoperative group) surgery. In the first 11 months of the study, 283 patients--of a projected 1,606 patients over a 5-year period--have been entered. Slightly more than half of the patients are younger than 50 years of age. Nearly half of the patients presented with tumors that were more than 4.0 cm in greatest diameter. Biopsy was performed by fine-needle aspiration slightly more than half of the time. Slightly more than two-thirds of the patients had clinically negative nodes. Lumpectomy was the proposed surgery at entry in 40% to 43% of the patients. As of November 1996, toxicity information is available on 29 patients in the preoperative docetaxel group and 23 patients in the postoperative docetaxel group. So far, there have been no unexpected toxicities, but the data are too preliminary to report in detail.

A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03.

PURPOSE: National Surgical Adjuvant Breast and Bowel Project Protocol R-03 was designed to determine the worth of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. METHODS: Thus far, 116 patients of an eventual 900 with primary operable rectal cancer have been randomized to receive multimodality therapy to begin preoperatively (59 patients) or identical therapy beginning after curative surgery (57). All patients received seven cycles of 5-fluorouracil (FU)/leucovorin (LV) chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In Cycles 2 and 3, FU and low-dose LV chemotherapy was given during the first and fifth week of radiation therapy (5,040 cGy). The preoperative arm (Group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (Group 2) received all radiation and chemotherapy after surgery. Primary study end points included disease-free survival and survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. RESULTS: Overall treatment-related toxicity was similar in both groups. Although seven preoperative patients had events after randomization that precluded surgery, eight events occurred during an equivalent follow-up period in the postoperative group. No patient was deemed inoperable because of progressive local disease. Sphincter-saving surgery was intended in 31 percent of Group 1 patients and 33 percent of Group 2 patients at the time of randomization. Such surgery was actually performed in 50 percent of the preoperatively treated patients and 33 percent of the postoperatively treated patients. The use of protective colostomy in patients undergoing sphincter-sparing surgery and the development of perioperative complications in all surgical patients were similar in both groups. There was evidence of tumor downstaging in evaluable patients undergoing preoperative therapy, with 8 percent of Group 1 patients having had a pathologic complete response. CONCLUSION: These data do suggest that the preoperative chemotherapy and radiation therapy regimen used are, at least, as safe and tolerable as standard postoperative treatment. There is presently a trend to tumor downstaging and sphincter preservation in the preoperative arm. Whether this arm will have greater or lesser survival and long-term toxicity awaits the completion of this relevant study.