William M. Sikov

Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

PURPOSE One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. PATIENTS AND METHODS Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. RESULTS Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. CONCLUSION In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.

Frequent Pathologic Complete Responses in Aggressive Stages II to III Breast Cancers With Every-4-Week Carboplatin and Weekly Paclitaxel With or Without Trastuzumab: A Brown University Oncology Group Study

PURPOSE To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel +/- weekly trastuzumab in resectable and locally advanced breast cancer. PATIENTS AND METHODS Women with stages IIA to IIIB disease received carboplatin dosed by six times the area under the curve every 4 weeks and paclitaxel 80 mg/m(2) weekly for 16 weeks, and weekly trastuzumab was added for human epidermal growth factor receptor 2 (HER2) -positive status. The primary end point was the pathologic complete response (pCR) rate, defined as the absence of invasive disease in the breast and axillary nodes. Postoperative therapies were at the discretion of the treating physicians. RESULTS Fifty-five patients were enrolled, and of these 43 had resectable disease. The median age was 54 years (range, 31 to 74 years). Treatment was well tolerated; there were no episodes of febrile neutropenia or grade 4 thrombocytopenia, and there were only two instances of grade 3 peripheral neuropathy. Overall, the pCR rate was 45%. The pCR rate was 43% (95% CI, 28% to 58%) in patients with resectable disease. Higher pCR rates occurred in patients with HER2-positive tumors (76% v 31% for HER2-negative tumors; P = .003), with estrogen receptor (ER) -negative tumors (75% v 27% for ER-positive tumors; P = .001), or with triple-negative tumors (67% v 12% ER-positive and HER2-negative tumors; P = .002). At a median of 28 months postoperation, recurrence-free survival (RFS) was 88.7%. If patients with ER-positive and HER2-negative tumors are excluded from analysis, patients who achieved a pCR were less likely to experience disease recurrence (RFS, 86%) than those who did not achieve a pCR (RFS, 75%). CONCLUSION Neoadjuvant carboplatin and weekly paclitaxel +/- trastuzumab achieve high pCR rates in patients with HER2-positive and triple-negative disease without exposure to an anthracycline. Preliminary RFS results are encouraging but are likely influenced by adjuvant therapy received. Additional study of this regimen in high-risk patients is warranted.

Multicentric warfarin‐induced skin necrosis complicating heparin‐induced thrombocytopenia

Two patients developed catastrophic multicentric skin necrosis while receiving warfarin to treat venous thromboembolism complicated by immune‐mediated heparin‐induced thrombocytopenia (HIT). Patient 1 developed skin necrosis involving the breasts, thighs, and face, as well as venous limb gangrene and bilateral hemorrhagic necrosis of the adrenal glands, resulting in death. The second patient developed bilateral mammary necrosis necessitating mastectomies, as well as skin necrosis involving the thigh. Neither patient had an identifiable hypercoagulable syndrome, other than HIT. HIT may represent a risk factor for the development of multicentric warfarin‐induced skin necrosis (WISN). Am. J. Hematol. 62:44–48, 1999.

Neoadjuvant Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Radiation for Rectal Cancer

PURPOSE To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. METHODS AND MATERIALS Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m(2)/week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m(2)/week. Resection was performed 4-8 weeks after the completion of chemoradiation. RESULTS The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). CONCLUSIONS Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.

Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study.

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for locally advanced pancreatic and gastric cancer. PATIENTS AND METHODS Thirty-four patients with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.) infusion repeated every week for 6 weeks with 50 Gy RT. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients until dose-limiting toxicity was observed. RESULTS The dose-limiting toxicities at 60 mg/m2/wk were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective responses for an overall response rate of 48%. CONCLUSION Concurrent paclitaxel with upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.

Impact of Neoadjuvant Chemotherapy in Stage II–III Triple Negative Breast Cancer on Eligibility for Breast-conserving Surgery and Breast Conservation Rates: Surgical Results From CALGB 40603 (Alliance)

OBJECTIVE To assess the efficacy of neoadjuvant systemic therapy (NST) at increasing the rate of successful breast-conserving therapy (BCT) in triple negative breast cancer. BACKGROUND Inducing tumor regression to permit BCT is often cited to support administration of NST. To quantify this benefit, we conducted a surgical companion study to CALGB40603, a randomized phase II, 2×2 factorial trial of neoadjuvant paclitaxel ± carboplatin ± bevacizumab (B) followed by doxorubicin plus cyclophosphamide ± B in stage II-III triple negative breast cancer. METHODS Before and after NST, treating surgeons evaluated BCT candidacy by clinico-radiographic criteria; surgery performed was at surgeon and patient discretion. We measured (1) conversion rates from BCT-ineligible to BCT-eligible, (2) surgical choices in BCT candidates, and (3) rates of successful BCT with tumor-free margins. RESULTS Four hundred four patients were assessable for surgical outcomes. Two hundred nineteen (54%) were BCT candidates before NST. One hundred ninety-seven (90%) remained BCT candidates after NST, of whom 138 (70%) chose BCT, which was successful in 130 (94%). Of 185 (46%) who were not BCT candidates before NST, 78 (42%) converted to candidates with NST. Of these, 53 (68%) chose BCT with a 91% (48/53) success rate. The overall BCT-eligibility rate rose from 54% to 68% (275/404) with NST. Addition of carboplatin, B, or both increased conversion rates. CONCLUSIONS This is the first study to document prospectively a 42% conversion rate from BCT-ineligible to BCT-eligible, resulting in a 14% absolute increase in BCT eligibility. BCT was successful in 93% of patients who opted for it, but 31% of BCT-eligible patients still chose mastectomy.

Abstract S5-01: Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance)

Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAC) results in a pCR in 30-35% of TNBC patients (pts), which is associated with improved recurrence-free and overall survival (RFS/OS). Thus, pCR rates may be useful in evaluating novel regimens in TNBC. In advanced TNBC, platinum analogues like Cb are active and addition of B to chemotherapy increases response rates and time to progression. CALGB 40603 is a 2×2 randomized phase II study designed to determine if the addition of either Cb or B to standard NAC significantly increases pCR rates in TNBC. Methods: Pts had operable clinical stage II-III TNBC, defined as hormone receptors Results: 454 pts enrolled, median age 48, stage II 68%/stage III 32%. Of 354 pts with treatment data, 59 did not complete NAC, 30 withdrew due to AEs, more often with B vs. not (11.5% vs. 3.5%). B was discontinued in 23% of assigned pts vs. 6-13% for other agents. Grade 3-4 neutropenia (56% vs. 20%) and thrombocytopenia (22% vs. 4%) were more common with Cb vs. not, while grade 3 hypertension was more common with B vs. not (11% vs. There is no evidence of an interaction between the effects of Cb and B (p = 0.64 and 0.44, for breast and breast/axilla, respectively). Conclusions: Preliminary results suggest that adding Cb or B to standard NAC significantly increases pCR rates in stage II-III TNBC. These increases are additive, with pCR (breast) in 60.6% and pCR (breast/axilla) in 50% of pts who received both. Complete and confirmed results will be reported, including pCR rates for basal-like tumors vs. not. Pts will be followed for RFS/OS to assess the impact of pCR on these endpoints. Conduct of the trial was supported by grants from the NIH (ACTNOW and CA31946/CA33601), Genentech and the BCRF. Clinical trial information: NCT00861705. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-01.

Splenosis presenting as occult gastrointestinal bleeding

A 48‐year‐old man presented with recurrent gastrointestinal bleeding and anemia. Routine endoscopic evaluation was nondiagnostic. Angiography demonstrated multiple apparent arteriovenous malformations. Exploratory laparotomy revealed numerous splenic implants along the small and large bowels, some of which had apparently eroded through the bowel mucosa and bled. Excision of these penetrating lesions prevented further bleeding. An incidentally noted renal cell cancer was also resected. The patients splenosis was the result of childhood trauma that caused splenic rupture and precipitated splenectomy. Splenosis develops frequently following traumatic splenic rupture. Experimental evidence suggests that the presence of an intact spleen suppresses the growth and development of splenic implants. Following splenectomy, splenules may replace some of the “housekeeping” and immunologic functions of the spleen, but even patients with documented splenosis should be considered functionally hyposplenic. While in most cases splenules cause no symptoms, splenosis must be considered in the differential diagnosis of previously splenectomized patients who present with unexplained masses or occult bleeding. Am. J. Hematol. 65:56–61, 2000.

Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a rare and aggressive CD20‐negative lymphoma. Despite improvements of the biology behind PBL, it still represents a challenge from the diagnostic and therapeutic perspectives for pathologists and clinicians. PBL is characterized by high rates of relapse and short median survival with standard approaches. Here, we report the use of the combination of bortezomib and infusional etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V‐EPOCH) in three patients with PBL; two were HIV‐positive and one was HIV‐negative. All three patients obtained a durable complete response to V‐EPOCH with survival times of 24, 18 and 12 months respectively.

Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance)

Background: CALGB (Alliance) 40603 measured the effects of adding carboplatin (Cb) and/or bevacizumab (Bev) to standard neoadjuvant chemotherapy (weekly paclitaxel x 12 then doxorubicin/cyclophosphamide every 2 weeks x 4) on pathologic complete response (pCR) rates in stage II-III triple-negative breast cancer (TNBC). As previously reported (Sikov et al, JCO 2015), pCR breast (ypT0/is) and pCR breast/axilla (pCR Br/Ax) (ypT0/isN0) rates increased from 46% to 60% and 41% to 54%, respectively, with Cb and from 48% to 59% and 44% to 52%, respectively, with Bev. Secondary endpoints included event-free survival (EFS) and overall survival (OS). Methods: EFS is measured from study entry to ipsilateral invasive breast or locoregional recurrence, distant recurrence or death from any cause and OS from study entry to death from any cause in all patients (pts) who started study treatment. Pts without an event were censored as of their last clinical assessment. Hazard ratios (HR) were calculated for pts who achieved pCR vs. not and for pts assigned to receive drug (Cb or Bev) vs. not. All p-values are 2-sided. Results: 443 pts started study treatment. Median follow-up was 39 months (range 28-66). 110 EFS events and 77 deaths have been reported. At 3 yrs, overall EFS was 74.1% and OS 83.2%. Pts who achieved pCR breast had 3-yr EFS of 84.8% vs. 61.8% for those who did not. Table 1 shows the association between pCR and pCR or minimal residual invasive disease (Residual Cancer Burden Class I (RCB I), Symmans et al, JCO 2007) and outcomes; p-values for all comparisons Pts assigned to Cb vs. not had 3-yr EFS 76.5% vs. 71.6% and OS 81.9% vs. 84.6%. Pts assigned to Bev vs. not had 3-yr EFS 75.5% vs. 72.9% and OS 85.5% vs. 80.9%. Table 2 shows HRs by assigned treatment: Conclusions: Pts with TNBC who achieved pCR with study treatment had significantly better EFS and OS than pts who did not, consistent with findings from a published meta-analysis (Cortazar et al, Lancet 2014); the addition of RCB I did not weaken this association. Our study was not powered to assess the impact of Cb or Bev on these endpoints. While our findings are consistent with predictions from the meta-analysis as to the impact of raising the pCR rate on EFS (Berry-Hudis, JAMA Oncology 2015), the wide confidence intervals illustrate the challenge of conclusively demonstrating a correlation between pCR increment and EFS benefit, especially as the control pCR rate rises. While the addition of Bev has failed to improve long-term outcomes in TNBC in large randomized adjuvant trials, our results support ongoing and planned neoadjuvant and adjuvant studies designed to further assess the value of Cb-containing regimens in stage II-III TNBC. Support: U10s - CA180821, CA180882, CA180820, CA076001, CA025224, CA180868, CA180888. Citation Format: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Somlo G, Port ER, Qamar R, Sturtz K, Mamounas E, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-05.