Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. RESULTS: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. CONCLUSIONS: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. GOV REGISTRATION NUMBER: NCT02400476.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019 was held in Morell, Prince Edward Island, 19-21 September 2019. Experts in medical oncology, radiation oncology, and surgical oncology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of anal, colorectal, biliary tract, and gastric cancers, including: radiotherapy and systemic therapy for localized and advanced anal cancer; watch and wait strategy for the management of rectal cancer; role of testing for dihydropyrimidine dehydrogenase (DPD) deficiency prior to commencement of fluoropyrimidine therapy; radiotherapy and systemic therapy in the adjuvant and unresectable settings for biliary tract cancer; and radiotherapy and systemic therapy in the perioperative setting for early-stage gastric cancer.

NRG Oncology/NSABP B-47 menstrual history study: impact of adjuvant chemotherapy with and without trastuzumab.

The NRG Oncology/NSABP B-47 menstrual history (MH) study examined trastuzumab effects on menstrual status and associated circulating reproductive hormones. MH was evaluated by questions related to hysterectomy, oophorectomy, and reported menstrual changes. Pre/perimenopausal women were assessed at entry, 3, 6, 12, 18, 24, 30, and 36 months. Consenting women had estradiol and FSH measurement at entry, 3, 6, 12, 18, and 24 months. Logistic regression determined predictors of amenorrhea and hormone levels at 12, 24, and 36 months. Between 2/8/2011 and 2/10/2015, 3270 women with node-positive/high-risk node-negative HER2-low breast cancer were enrolled. There were 1,458 women enrolled in the MH study; 1231 consented to baseline blood samples. Trastuzumab did not contribute to a higher amenorrhea rate. Amenorrhea predictors were consistent with earlier studies; however, to our knowledge, this is the largest prospective study to include serial reproductive hormone measurements to 24 months and clinical amenorrhea reports to 36 months. These data can help to counsel patients regarding premature menopause risk.

Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial.

PURPOSE: CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy. PATIENTS AND METHODS: Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the  MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase. RESULTS: Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (-4.1 v -2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of -97.4% versus -88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (-0.80 v -0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia. CONCLUSION: Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.

Survival and recurrence patterns after neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) for locally advanced esophagogastric adenocarcinoma.

INTRODUCTION: We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a safe, tolerable, and effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophagogastric junction (EGJ). We hypothesized that DCF combined with enhanced surgical control would result in a low rate of local or regional recurrence, and thus reviewed our outcomes with this treatment regimen. METHODS: A prospectively entered database of all esophageal and EGJ ADC patients resected at a high-volume referral center over 6 years (9/07-9/13) was reviewed for cases treated with curative intent neoadjuvant DCF followed by en bloc resection with extended lymphadenectomy (D2/D3). Recurrences was defined as locoregional (biopsy on endoscopy/regional lymph nodes (LNs)) and distant. Standard statistical techniques were used. RESULTS: Of 279 patients with ADC, 86 (85% male, mean age 63 years (interquartile range 56-70)) underwent preoperative DCF and curative intent resection for locally advanced ADC (cT3 93%; cN+ 69%) of the EGJ (54%) or distal esophagus (46%). After median follow-up of 40 months, the overall 5-year survival was 54% and 43 (52%) had recurred at a median time of 14 months. Sites of recurrence included locoregional only in 2 of 45 (4%), distant only in 40 of 45 (89%), and locoregional and distant in 3 of 45 (7%). DISCUSSION: The present study demonstrates favourable oncologic outcomes with low local/regional recurrence and an excellent overall 5-year survival after neoadjuvant DCF for esophageal and EGJ ADCs. Because the majority of recurrences were distant, our data support the notion that efforts to improve outcomes in these patients should concentrate on enhancing systemic, rather than local, therapy.

Response to chemotherapy in metastatic colorectal cancer after exposure to oxaliplatin in the adjuvant setting.

AIM: Oxaliplatin with 5-fluorouracil (5-FU) and leucovorin (FOLFOX and FLOX) or capecitabine (XELOX) is the standard adjuvant treatment for colonic cancer. In metastatic disease, 5-FU/leucovorin/irinotecan (FOLFIRI) and FOLFOX are equivalent in respect to response rates, progression-free and overall survival. Little data are available to compare their efficacy after exposure to oxaliplatin-containing adjuvant chemotherapy. PATIENTS AND METHODS: We carried out a retrospective study of patients who underwent surgery and FOLFOX adjuvant chemotherapy, followed by FOLFIRI or FOLFOX for metastatic disease. Exclusion criteria were: metastatic disease at presentation and no oxaliplatin in adjuvant chemotherapy. The end-point was the overall response rate (ORR) to first-line chemotherapy for metastatic disease after three months, as assessed by computed tomography (CT). RESULTS: A total of 205 patients received FOLFOX as adjuvant treatment for colorectal adenocarcinoma between 2006 and 2010. Metastatic disease was diagnosed later in 32 cases after a median follow-up of three years (range=1-5.5 years). The median time between the beginning of adjuvant chemotherapy and onset of metastatic disease was 1.7 years (range=0.5-5.5 years). Twenty-eight patients were evaluable for effects of treatment: six patients received FOLFOX plus bevacizumab and 22 FOLFIRI plus bevacizumab. The ORR was 17% in the FOLFOX group versus 36% in the FOLFIRI group (p=0.22). This difference was not statistically significant, despite a trend in favor of FOLFIRI. CONCLUSION: Metastatic disease after exposure to oxaliplatin in the adjuvant setting tends to occur early and can be characterized by partial resistance to this agent. Despite insufficient statistical power, our results suggest that FOLFIRI may result in higher response rates than FOLFOX in this situation. However, oxaliplatin re-challenge can also lead to radiological responses and disease stabilization.

Efficacy, safety, and steady-state pharmacokinetics of once-a-day controlled-release morphine (MS Contin XL) in cancer pain.

The efficacy, safety, and pharmacokinetics of a novel once-daily morphine formulation (OAD morphine) and a 12-hourly formulation (twice-daily CR morphine) were compared in a double-blind, multi-centered crossover study. Chronic cancer pain patients (n=25) were randomized to OAD morphine (mean 238 +/- 319 mg q24h) or twice-daily CR morphine (mean 119 +/- 159 mg q12h) for one week. They then crossed over to the alternate drug, which also was taken for one week. There was no difference between treatments for evaluations of overall pain intensity, analgesic efficacy, or adverse events. However, whereas pain scores increased during the day on twice-daily CR morphine (P=0.0108), they remained stable on OAD morphine. Most patients (68%) chose once-daily dosing for continuing pain management (P=0.015). The AUC ratio was 100.3%, indicating equivalent absorption. Fluctuation indices were 93.5 +/- 28.8% and 179.3 +/- 41.3% (P=0.0001) for OAD morphine and twice-daily CR morphine, respectively. OAD morphine provides analgesia similar to twice-daily CR morphine with reduced fluctuation in plasma morphine concentration and more stable pain control.

Radioembolization for hepatic metastases.

In a phase I/II study, 37 patients with metastatic liver disease, predominantly from colorectal cancer (n = 33) were treated between 1986 and 1994 by intrahepatic arterial embolization of radioactive yttrium 90 (Y 90) glass microspheres. The calculated total liver dose increased in stages from 5,000 cGy to 15,000 cGy. Mean follow-up was 8 months (range, 1 to 49). No major procedural, hematologic, or pulmonary complications occurred. Late gastroduodenal ulceration occurred early in the study at 6 to 8 weeks in three patients with a history of chronic alcohol abuse and was treated successfully medically. Of 30 patients with either computed tomography (CT) or sonography follow-up for 4 months or longer, 15 had tumor involvement in the liver that was diffuse, irregular, or infiltrating with mixed or poor vascularity and thus definitive imaging changes could not be appreciated on follow-up. In 15 patients with identifiable marker lesions with developed hypervascularity, post-treatment beneficial effects were noted. In seven of these patients followed by CT, decreased tumor attenuation and sharper definition of tumor-liver interface were noted. Findings on sonography in eight patients were increased tumor sonolucency centrally, consistent with liquefaction necrosis, and rim hyperechogenicity, consistent with calcification. A 25% to 40% decrease in area of marker lesions occurred in five patients and one other patient had small 1.0- to 1.5-cm lesions disappear temporarily on sonography. In conclusion, this method provides a feasible single-session technique for treatment of hepatic metastases. Complications are low and if the tumor pattern is nodular with some hypervascularity, beneficial effects are observed clinically and on imaging studies.

Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer.

PURPOSE: To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m(2)/1.15 mg/m(2) twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m(2)/20 mg/m(2) once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point. RESULTS: A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P =.01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P =.354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients. CONCLUSION: Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.