National Surgical Adjuvant Breast And Bowel Project Trials Research Articles

Combined Modality Therapy for Rectal Cancer: Too Much Too Often?

The refinement and implementation of multimodal therapy for rectal cancer, including surgery, radiotherapy, and chemotherapy, is certainly one of the most meaningful achievements in the history of clinical cancer research to date. It is thus important to set any harsh critique of current treatment methods and outcomes within this context. Just 30 years ago, the risk of local recurrence after rectal resection ranged from 20 to 40 %. It was often lethal and was associated with significant morbidity, pain, and suffering. This began to change with the report from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Cooperative Group R01 trial in 1985, which demonstrated a reduction in local recurrence from 25 to 16 % with the addition of postoperative long-course chemoradiotherapy. The NSABP trial was followed by serial studies designed to improve results through addition and resequencing. The Gastrointestinal Tumor Study Group (GITSG) reported a 55–33 % reduction in all recurrence with the addition of adjuvant chemotherapy and radiotherapy, leading the National Institutes of Health to generate a consensus statement asserting that chemoradiotherapy should be delivered postoperatively for all stage II and III tumors. The German Rectal Cancer Study later demonstrated improved outcome when long-course chemoradiotherapy was delivered preoperatively rather than postoperatively to clinical stage II and III rectal cancers. Local recurrence at 46 months was reduced from 13 to 6 % without change in distant recurrence. At 10 years, the difference in local recurrence was of a lower magnitude but remained significant (7 vs. 10 %). Disease-free and overall survival did not differ between the groups. This changed the standard of practice to preoperative rather than postoperative long-course chemoradiotherapy for stage II and III rectal cancers. While North America and Central Europe employed a regimen of long-course postoperative chemoradiotherapy administered over 5–6 weeks, Northern Europe was utilizing short-course radiotherapy delivered over 5 days before surgery, and demonstrating similar improvements in outcome. The Swedish Rectal Cancer Trial showed that preoperative short-course radiotherapy reduced local recurrence from 27 to 11 % and increased survival from 65 to 74 % compared with surgery alone. This brings us to 2013, when patients are much less likely to experience local recurrence and more likely to retain sphincter function than decades ago. However, two reports in this issue of Annals of Surgical Oncology remind us that more is not necessarily better, and that one size does not fit all. Lange et al. report on a series of rectal cancer patients treated traditionally under the supervision of Warren Enker, an international leader and pioneer who has spent his career spreading the word about the methodical techniques of anatomic rectal resection and the benefits of total mesorectal excision. In total, 368 patients underwent rectal resection, with a median follow-up of 8 years. Seventy percent underwent sphincter-preserving surgery, with an average anastomotic height of 5.4 cm. Only 5 % of patients undergoing low anterior resection experienced anastomotic leak. The oncologic results are equally impressive. Five-year overall survival was 76 %: 92 % for stage I disease, 78 % for stage II disease, and 69 % for stage III disease. The 5-year local recurrence rate was 5.2 %: 0.8 % for stage I disease, 4.7 % for stage II disease, and 5.4 % for stage III disease. The 5-year rate of distant metastasis was 22 %: 3.9 % for stage I disease, 21 % for stage II disease, and 27 % for stage III disease. Analysis of functional outcome was measured in 50 patients. Irradiated patients had, on average, 3.2 bowel movements per day, compared to 1.2 in nonirradiated Society of Surgical Oncology 2013

Five Year Outcome of 145 Patients With Ductal Carcinoma In Situ (DCIS) After Accelerated Breast Radiotherapy

Accelerated whole-breast radiotherapy (RT) with tumor bed boost in the treatment of early invasive breast cancer has demonstrated equivalent local control and cosmesis when compared with standard RT. Its efficacy in the treatment of ductal carcinoma in situ (DCIS) remains unknown. Patients treated for DCIS with lumpectomy and negative margins were eligible for 2 consecutive hypofractionated whole-breast RT clinical trials. The first trial (New York University [NYU] 01-51) prescribed to the whole breast 42 Gy (2.8 Gy in 15 fractions) and the second trial (NYU 05-181) 40.5 Gy (2.7 Gy in 15 fractions) with an additional daily boost of 0.5 Gy to the surgical cavity. Between 2002 and 2009, 145 DCIS patients accrued, 59 to the first protocol and 86 to the second trial. Median age was 56 years and 65% were postmenopausal at the time of treatment. Based on optimal sparing of normal tissue, 79% of the patients were planned and treated prone and 21% supine. At 5 years' median follow-up (60 months; range 2.6-105.5 months), 6 patients (4.1%) experienced an ipsilateral breast recurrence in all cases of DCIS histology. In 3/6 patients, recurrence occurred at the original site of DCIS and in the remaining 3 cases outside the original tumor bed. New contralateral breast cancers arose in 3 cases (1 DCIS and 2 invasive carcinomas). Cosmetic self-assessment at least 2 years after treatment is available in 125 patients: 91% reported good-to-excellent and 9% reported fair-to-poor outcomes. With a median follow-up of 5 years, the ipsilateral local recurrence rate is 4.1%, comparable to that reported from the NSABP (National Surgical Adjuvant Breast and Bowel Project) trials that employed 50 Gy in 25 fractions of radiotherapy for DCIS. There were no invasive recurrences. These results provide preliminary evidence that accelerated hypofractionated external beam radiotherapy is a viable option for DCIS.

Routine Preventive Care and Cancer Surveillance in Long-Term Survivors of Colorectal Cancer: Results From National Surgical Adjuvant Breast and Bowel Project Protocol LTS-01

National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol LTS-01 examines routine preventive care and cancer surveillance in long-term colorectal cancer (CRC) survivors previously treated in NSABP adjuvant trials. Long-term CRC survivors (≥5 years) from five completed NSABP trials (Protocols C-05, C-06, C-07, R-02, and R-03) at 60 study sites were recruited and surveyed using preventive health care items from the National Health Interview Survey (NHIS). A 3:1 comparison cohort case-matched by age, sex, race, and education was created from the 2005 NHIS. Contingency tables and multivariate models were used to compare cohorts and determine predictors of preventive care and cancer surveillance. A total of 708 patients in protocol LTS-01 (681 patients with colon cancer, 27 patients with rectal cancer) completed the interview: 57.1% male, mean age 66.2 years (standard deviation=10.6), median survival 8 years. Patients in the LTS-01 protocol were more likely to have a usual source of health care (97.7% v 93.8%, P<.0001), have received a flu shot in the past 12 months (67.5% v 44.3%, P<.0001), and have undergone cancer screening by Pap smear (67.3% v 54.8%, P<.0001), mammogram (80.4% v 70.7%, P<.0001), and prostate-specific antigen test (84.5% v 74.5%, P<.0001) than patients in the NHIS cohort. For CRC surveillance, 96.5% of patients in protocol LTS-01 had a colonoscopy, 88.2% had a carcinoembryonic antigen test, and 66.4% had a computed tomography scan in the previous 5 years. Health insurance was the best predictor of cancer screening for all three methods (odds ratio=2.6 to 4.5). No factor was uniformly associated with CRC surveillance. This select population of long-term CRC survivors who participated in clinical trials achieved better routine preventive care and cancer screening than the general population and high rates of cancer surveillance.

Double Helix of Breast Cancer Therapy: Intertwining the Halsted and Fisher Hypotheses

Double Helix of Breast Cancer Therapy: Intertwining the Halsted and Fisher Hypotheses

Magnetic Resonance Imaging in the Breast Cancer Patient: Curb Your Enthusiasm

Magnetic Resonance Imaging in the Breast Cancer Patient: Curb Your Enthusiasm

Chemoprevention Clinical Trials: It Is Time to Turn Success into Progress

We are at the beginning of an important era in the clinical application of cancer prevention research. Research over the last 20 years has successfully shown the feasibility and promise of chemoprevention, and we are now in position to make such preventive therapy common medical practice. However,

Is Sentinel Node Biopsy Necessary in Conservatively Treated DCIS?

We sought to identify the risk of axillary node involvement in patients with ductal carcinoma in situ (DCIS) and to determine whether axillary node assessment is necessary in these patients. Sentinel node biopsy (SNB) is replacing standard axillary lymph node dissection (ALND) for surgical staging of invasive breast cancer. Its use in patients with DCIS versus local excision (LE), observation, and/or breast irradiation remains in question. We examined the records of 813 patients with localized DCIS and disease-negative margins after LE who were randomly assigned to no further therapy or to breast irradiation in National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-17 and 1799 patients randomized to receive placebo or tamoxifen after LE + radiotherapy in NSABP trial B-24. An ALND was performed in 253 patients in NSABP B-17 and in 162 in NSABP B-24. We found that in NSABP trial B-17, seven patients developed ipsilateral nodal recurrence (INR). Overall INR rate was 0.83/1000 patient-years. In NSABP B-24, overall INR rate was 0.36/1000 patient-years. INR can be considered a surrogate for axillary involvement at the time of DCIS diagnosis. INR in patients with DCIS treated conservatively is extremely rare. Our findings do not support the routine use of SNB in patients with conservatively treated, localized DCIS.

Novel Clinical Trial Designs for Treatment of Ductal Carcinoma In Situ of the Breast with Trastuzumab (Herceptin)

Because ductal carcinoma in situ (DCIS) avidly expresses Her2/neu, the target of the monoclonal antibody trastuzumab, and because trastuzumab has been shown to be effective against invasive breast cancer, trastuzumab may be effective for reducing the tumor burden and abrogating or reversing the hypothesized transition from in situ to invasive disease in patients with DCIS. To test this hypothesis, a trial of neoadjuvant trastuzumab for DCIS has been opened at our institution. Because trastuzumab has been shown to act as a radiosensitizing agent for Her2/neu-overexpressing cancer and because there are currently no systemic treatments for estrogen-receptor-negative DCIS, it makes sense to investigate whether use of trastuzumab concurrently with postoperative radiation therapy improves local control of DCIS. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is planning a trial to test this hypothesis. The risk of cardiac toxicity associated with the doses of trastuzumab planned for these trials (cumulative doses of 8 mg/kg for our trial and 14 mg/kg in the NSABP trial) is believed to be minimal, but the safety profile of these approaches will need to be closely monitored.

Conditional survival for patients with colon cancer: An analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) trials C-03 through C-06

6005 Background: Survival for cancer patients is usually only reported as survival from time of diagnosis to some time landmark (e.g., 5 yrs). For pts surviving one or more years after diagnosis, however, their survival probability changes, and is more accurately depicted by conditional survival (CS), defined as the probability of surviving for an additional fixed time interval given that the pt has already survived a period of time. The purpose of this study was to determine the 5-yr CS of colon cancer pts in 4 NSABP trials. Methods: We analyzed long-term overall survival data from the 5587 colon cancer pts who were enrolled in fluorouracil (or equivalent) arms of NSABP trials C-03 through C-06. We computed observed 5-yr overall CS for pts who had already survived without disease from 0 to 5 yrs after diagnosis, and stratified the results by age, sex, race, stage, number of positive nodes, number of nodes resected, tumor location, and performance status. Results: The Table below shows the 5-yr overall CS for all pts and for selected subgroups for different survival times since diagnosis. As disease-free survival time since diagnosis increased, 5-yr observed overall CS increased from 76% to 90% at 5 yrs. For pts under age 50, CS increased from 78% to 95% at 5 yrs, but for pts &gt; 70 yrs, CS remained fairly constant (71–82%). For pts with &gt; 10 positive nodes, CS increased from 37% to 81% at 5 yrs, but did not change appreciably for node-negative pts (87–92%). Dukes’ C pts saw an increase in CS from 68% to 88% at 5 yrs, while CS for Dukes’ B pts did not change appreciably. Conclusion: Projected survival probability generally increases with time for colon cancer pts who remain disease-free for a period of time after diagnosis, and conditional survival can provide more informative prognostic information for these pts. An additional effect is that prognostic factors that are important at baseline become less important for conditional survival as the disease-free period increases. [Table: see text] No significant financial relationships to disclose.

Show me the genes – I will tell you who/how to treat!

Show me the genes – I will tell you who/how to treat!

Tamoxifen--an update on current data and where it can now be used.

Over the past 30 years, data from a large number of clinical trials have confirmed the efficacy of tamoxifen in estrogen receptor (ER)-positive breast cancer, both as adjuvant therapy and for advanced disease. The 1995 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of randomized trials of adjuvant tamoxifen versus no tamoxifen showed that during approximately 10 years of follow-up, the proportional reductions in mortality for 1, 2 and approximately 5 years of adjuvant tamoxifen were 12, 17 and 26%, respectively. Tamoxifen is also effective for the prevention of breast cancer. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer prevention study (P-1), 5 years of tamoxifen therapy reduced the incidence of invasive and non-invasive breast cancers by 49 and 50%, respectively. In a randomized NSABP trial in women with ductal carcinoma in situ (DCIS), tamoxifen brought about a significant 47% reduction in ipsilateral invasive breast cancers and a 15% reduction in non-invasive breast cancers, compared with placebo. In trials performed by the Swedish Breast Cancer Co-operative Group and the NSABP, the optimal duration of adjuvant tamoxifen therapy appears to be 5 years, although this is equivocal and not yet conclusively defined.

Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer.

Before 1989, credible information about the treatment of breast cancer was derived mainly from randomized clinical trials that enrolled women with either metastatic (stage IV); locally advanced (stage III); or primary, operable, axillary lymph node-positive (stage II) disease. This report provides information from six recent National Surgical Adjuvant Breast and Bowel Project (NSABP) trials involving lymph node-negative (stage I) patients. Findings from NSABP B-13 demonstrated, through 14 years of follow-up, improvements in disease-free survival (DFS) and overall survival from methotrexate and fluorouracil (MF), regardless of age, in women with estrogen receptor (ER)-negative tumors. Results from NSABP B-19, which was conducted with similar patients, demonstrated, through 8 years, a greater overall DFS and survival advantage with cyclophosphamide and MF (CMF) than that observed with MF. Findings from NSABP B-23, in which patients similar to those in B-13 and B-19 were randomly assigned to receive CMF plus placebo, CMF plus tamoxifen (TAM), doxorubicin (Adriamycin) and cyclophosphamide (AC) plus placebo, or AC plus TAM, demonstrated no difference in relapse-free survival (RFS) or overall survival among the four groups through 5 years, either for all patients or relative to age. NSABP B-14, which was carried out in women with ER-positive tumors, compared the outcomes of those who received either placebo or TAM. Through 14 years, superior DFS and overall survival advantages, as well as a reduction in contralateral breast cancer, were observed with TAM. No additional benefit resulted from TAM administration beyond 5 years. Findings from NSABP B-20, a second study conducted in patients with ER-positive tumors, showed, after 8 years, both a DFS and an overall survival advantage from TAM plus either MF or CMF over that achieved with TAM alone. A recent meta-analysis in women with negative lymph nodes and either ER-negative or ER-positive tumors of less than or equal to 1 cm in size was conducted using patients from five NSABP trials. After 8 years, the RFS in women with ER-negative tumors was greater in the group treated with surgery and chemotherapy than in those who underwent surgery alone. In women with ER-positive tumors, RFS and overall survival advantages were observed from the addition of chemotherapy to TAM when that treatment regimen was compared with TAM alone. In addition, evidence has been presented from NSABP B-21, a trial evaluating radiation therapy (XRT) and/or TAM for the prevention of ipsilateral breast tumor recurrence (IBTR) after lumpectomy in women with tumors less than or equal to 1 cm. Findings have shown that XRT is superior to TAM and that XRT + TAM is superior to XRT alone for preventing IBTR. The findings demonstrate that chemotherapy and/or hormonal therapy is effective for the management of women with negative axillary lymph nodes and either ER-negative or ER-positive tumors. Because it also has been proven effective in women with tumors less than or equal to 1 cm, such therapy might also be considered in the treatment of that patient population.

Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women.

Observed variations in breast cancer survival by racial/ethnic background have been attributed to many factors, including differences in clinical and pathologic disease features at diagnosis and economic resource inequities that may affect treatment access and quality. In this report, we examine outcomes for African-American and Caucasian breast cancer patients participating in selected randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine whether prognosis or efficacy of systemic adjuvant therapy differed between these groups. Randomized clinical trials offer the advantages of a similar disease stage and a uniform treatment plan for all participants. Patients from four NSABP trials enrolling patients from 1982 through 1994 with axillary lymph node-negative disease (543 African-American and 7582 Caucasian) and three trials enrolling patients from 1984 through 1991 with axillary lymph node-positive disease (548 African-American and 4986 Caucasian) were included. Disease-free survival (DFS), which was defined as time on study free of breast cancer recurrence, second primary cancer, or death preceding these events, and survival risk ratios (RRs) with two-sided 95% confidence intervals (CIs) for African-Americans versus Caucasians were computed from Cox proportional hazards models that included relevant prognostic covariates. Treatment benefits for the therapies evaluated in these trials were estimated separately for African-Americans and for Caucasians. Among patients with lymph node-negative disease, African-Americans had similar DFS rates to Caucasians (African-American/Caucasian RR = 1.06, 95% CI = 0.92 to 1.23) but had modestly greater mortality rates (RR = 1.21, 95% CI = 1.01 to 1.46). Among lymph node-positive patients, DFS was similar (RR = 1.04, 95% CI = 0.93 to 1.17) and survival was again less favorable for African-Americans (RR = 1.18 95% CI = 1.03 to 1.34). Survival excluding deaths most likely attributable to causes other than cancer was similar between African-Americans and Caucasians (RR = 1.08 [95% CI = 0.88 to 1.33] for lymph node-negative patients and RR = 1.09 [95% CI = 0.96 to 1.25] for lymph node-positive patients). Among lymph node-negative and lymph node-positive patients, African-Americans and Caucasians realized comparable benefit from either the addition of chemotherapy or tamoxifen to surgery alone or the addition of chemotherapy to tamoxifen. In summary, African-American women and Caucasian women who were diagnosed at a comparable disease stage and were similarly treated tended to experience similar breast cancer prognosis. However, a mortality deficit persisted for African-American women relative to Caucasian women, which may be in part due to greater mortality from noncancer causes among African-Americans. Benefit from systemic adjuvant therapy for recurrence and mortality reduction was comparable between African-Americans and Caucasians. This study and investigations in other health-care settings suggest that African-American women and Caucasian women with breast cancer derive a similar benefit from systemic adjuvant therapy when it is administered in accordance with their clinical and pathologic disease presentation.

National Surgical Adjuvant Breast and Bowel Project trials in colon cancer

During the last decade, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has completed six adjuvant chemotherapy trials comparing different adjuvant therapy regimens or adjuvant therapy versus surgery alone. A seventh trial is ongoing. These trials have contributed to defining the role of adjuvant therapy in colon cancer. Patients eligible for inclusion in NSABP trials had been diagnosed as having stage II or III colon cancer with no evidence of gross residual or metastatic disease. The follow-up strategies were similar in the reported trials with follow-up every 3 months for the first 2 years, then every 6 months for the next 3 to 5 years, and annually thereafter. The NSABP C-01 protocol was a three-arm trial comparing an adjuvant semustine/vincristine/5-fluorouracil (5-FU) regimen (MOF) to a Bacille Calmette-Guérin treatment, and to surgery alone. The C-02 protocol investigated whether portal vein infusion of 5-FU improved survival outcome compared with surgery alone. Protocol C-03 compared a semustine/vincristine/5-FU regimen to a 5-FU plus leucovorin (LV) (5-FU/LV) regimen. The NSABP C-04 protocol was a three-arm trial comparing 5-FU/LV, 5-FU plus levamisole, and 5-FU/LV plus levamisole. The NSABP C-05 trial compared 5-FU/LV to 5-FU/LV plus alpha-interferon. Results of NSABP C-01, C-02, C-03, C-04, and C-05 trials are summarized in this report. Patient accrual has completed in the NSABP C-06 trial comparing 5-FU/LV with oral tegafur and plus uracil leucovorin. The NSABP is currently conducting another trial (C-07) comparing 5-FU/LV with 5-FU/LV plus oxaliplatin. The role of adjuvant chemotherapy in stage II colon cancer is also discussed in this report. A recent pooled analysis of studies C-01, C-02, C-03, and C-04 has indicated that the relative treatment benefit in stage II disease is at least equal to the benefit in stage III colon cancers, and concluded that adjuvant chemotherapy also should be considered as the standard of care for stage II colon cancer patients.

Endometrial Cancer in Tamoxifen-Treated Breast Cancer Patients: Findings From the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 *

Tamoxifen is advantageous in treating all stages of breast cancer. However, studies have suggested that incidence and severity of endometrial cancer increase in women treated with tamoxifen. We compared rates of endometrial and other cancers in tamoxifen- and non-tamoxifen-treated patients and described the pathologic characteristics of the endometrial cancers. Data were analyzed on 2843 patients with node-negative, estrogen receptor-positive, invasive breast cancer randomly assigned to placebo or tamoxifen (20 mg/d) and on 1220 tamoxifen-treated patients registered in NSABP B-14 subsequent to randomization. Average time on study is 8 years for randomly assigned patients and 5 years for registered patients. The incidence rates of liver, gastrointestinal, urinary tract, and nonuterine genital tumors were not increased by tamoxifen treatment. Twenty-five endometrial cancers were originally reported, one of which was reclassified after subsequent review. Two cases occurred in the placebo group in patients whose medical status subsequent to random assignment had required tamoxifen treatment. Twenty-three occurred in the tamoxifen groups. Twenty-one of the 24 originally reported endometrial cancers were FIGO stage 1; 18 of 23 gradable cases were of good to moderate histologic grade. Four tamoxifen-treated women died of uterine cancer. The average annual hazard rate of endometrial cancer as a first event within the first 5 years of follow-up in the randomized, tamoxifen-treated group was 1.2/1000 patient-years; the cumulative hazard rate was 6.3/1000. Findings for the registered, tamoxifen-treated group were similar. Including all originally reported endometrial cancers, the annual hazard rate through all follow-up was 0.2/1000 in the placebo group and 1.6/1000 in the randomized, tamoxifen-treated group; the relative risk of endometrial cancer for the latter versus the former group was 7.5. Again for the latter group, using population-based rates of endometrial cancer from SEER data and information from another NSABP (B-06) trial, relative risks were 2.2 and 2.3, respectively. The 5-year cumulative hazard rate for disease-free survival in the randomized tamoxifen group was 38% less than that in the placebo group. Some data in this paper were provided by an investigator who submitted fraudulent data to the NSABP [see the "News" section]; therefore, the reader must read the entire text including Table 10 and the Editor's notes. In brief, data on 182 of the 2843 randomly assigned patients and 37 of the 1220 registered patients were provided by the investigator in question. After review, 24 of the 182 records showed falsification, all involving characteristics of patients prior to random assignment. Of the 37 registered-patient records, 8 showed falsification. Risk of endometrial cancer increases following tamoxifen therapy for invasive breast cancer; however, net benefit greatly outweighs risk. Endometrial cancers occurring after tamoxifen therapy do not appear to be of a different type with a worse prognosis than are such tumors in non-tamoxifen-treated patients. Tamoxifen treatment for breast cancer should continue. In addition, the relative risk of endometrial cancer observed in B-14 tamoxifen-treated patients is consistent with the twofold relative risk used in the initial risk-benefit computation for the NSABP breast cancer prevention trial.