Jane E. Rogers

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study

BACKGROUND Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. METHODS We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. RESULTS We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. INTERPRETATION To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. FUNDING National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Differentiation syndrome in patients with acute promyelocytic leukemia

Objective. To review the pathophysiology, risk factors, and management of differentiation syndrome (DS) associated with acute promyelocytic leukemia (APL). Data source. A MEDLINE search was conducted (1977–November 2010) using the terms APL, DS, all-trans retinoic acid (ATRA), retinoic acid syndrome, and arsenic trioxide (ATO). Methods of study selection. English articles identified from the MEDLINE search were evaluated. Data extraction and synthesis. With ATRA, ATO, and chemotherapy, a complete remission is achievable for most newly diagnosed APL patients. However, treatment with the differentiating agents, ATRA and ATO, can lead to the development of DS. Signs and symptoms of this syndrome include hyperleukocytosis and cardiorespiratory compromise. Severe complications can develop, if DS is not recognized early and treated promptly with corticosteroids. In addition, patients with a high white blood cell count at diagnosis may benefit from prophylactic steroids. Conclusions. Early recognition and prompt initiation of corticosteroids are key factors in the management of DS. Healthcare professionals need to be familiar with this complication which can arise from differentiation agents.

Clinicopathologic Features Associated With Human Papillomavirus/p16 in Patients With Metastatic Squamous Cell Carcinoma of the Anal Canal

BACKGROUND The incidence of anal carcinoma in the U.S. continues to increase steadily, and infection with the human papillomavirus (HPV) is an established risk factor for the development of anal carcinoma. However, the clinicopathologic characteristics of patients with metastatic squamous cell carcinoma of the anal canal according to HPV status have not yet been defined. MATERIALS AND METHODS The records of patients treated for metastatic squamous cell carcinoma of the anal canal at the MD Anderson Cancer Center from June 2005 to August 2013 were reviewed. The patients were tested for the presence of HPV DNA by in situ hybridization and/or the p16 oncoprotein by immunohistochemistry. Associations between the presence of HPV and clinicopathologic attributes were measured. RESULTS Of the 72 patients reviewed, 68 tumors (94%) had detectable HPV. Patients with HPV-negative tumors were more likely to be of nonwhite ethnicity (odds ratio, 8.7) and have a strong (>30 pack-year) tobacco history (odds ratio, 8.7). A trend toward improved survival from the time of diagnosis of metastatic disease was noted among patients with HPV-positive tumors. CONCLUSION Most patients with metastatic anal cancer had detectable HPV, with differences in tobacco history and ethnicity detected according to HPV status. The high frequency of HPV positivity for patients with metastatic anal cancer has important implications for novel immunotherapy treatment approaches, including ongoing clinical trials with immune checkpoint blockade agents using antibodies targeting the programmed death-1 receptor. IMPLICATIONS FOR PRACTICE Previous studies investigating the clinical features of patients with anal cancer focused on those with early-stage disease. The present study characterizes, for the first time, clinical and pathological features according to human papillomavirus (HPV) status for patients with metastatic anal cancer. A high frequency of HPV-positive tumors and correlations between HPV status and both ethnicity and tobacco history was found. No standard-of-care therapy is available for patients with metastatic anal cancer, and most receive cytotoxic chemotherapy. The high prevalence of HPV in the current population generates optimism for ongoing clinical trials investigating the role of immune checkpoint blockade agents as a novel treatment approach for this disease.

Epidermal growth factor receptor inhibition in metastatic anal cancer.

Metastatic squamous cell carcinoma (SCCA) anal cancer is relatively rare. With limited data, cisplatin plus 5-fluorouracil has traditionally been utilized in the first-line setting. Treatment beyond front-line cisplatin progression is not well defined. Epidermal growth factor receptor (EGFR) is highly overexpressed in SCCA anal cancer and EGFR inhibition may represent a potential treatment target for this population in need. Our case series evaluated metastatic SCCA anal cancer patients who received an EGFR monoclonal antibody as second-line or third-line therapy. Data collected consisted of demographics, previous treatment, metastatic disease sites, localized therapy received, regimen received, first radiographic result, progression-free survival, and overall survival. A total of 17 patients were included, with most (76%) patients receiving an EGFR monoclonal antibody in the second-line setting. Common regimens identified combined cetuximab or panitumumab with a fluoropyrimidine plus platinum (35%), carboplatin plus paclitaxel (29%), or cisplatin plus vinorelbine (18%). Thirty-five percent of patients achieved a response and 24% had stable disease. The overall median progression-free survival and overall survival were 7.3 and 24.7 months, respectively. Compared with our large retrospective study in the front-line metastatic anal cancer setting, our study suggests that anti-EGFR therapy in combination with certain chemotherapy derived additional benefit in the refractory setting. In the metastatic setting, there is a need to discover effective therapies. We present a diverse metastatic SCCA anal cancer patient population who received cetuximab or panitumumab with chemotherapy in the second-line or third-line setting. Our case series strengthens the concept of EGFR inhibition in metastatic SCCA anal cancer.

18-fluorodeoxy-glucose positron emission computed tomography as predictive of response after chemoradiation in oesophageal cancer patients.

INTRODUCTION The purpose of this study was to evaluate if a baseline, an interim or a post-chemoradiation (CTRT) 18-fluorodeoxy-glucose positron emission computed tomography (18F-FDG PET/CT) studies could provide information on pathologic response to CTRT and overall survival (OS). MATERIALS AND METHODS Thirty-one patients with histologically proven adenocarcinoma or squamous cell carcinoma of the oesophagus, fit for trimodality therapy were prospectively enrolled. Most were men (93.5%), and had a stage III cancer (74.2%). Chemotherapy consisted of oxaliplatin/5-fluorouracil (45.2%) and taxane/5-fluorouracil (54.8%). All patients underwent a baseline, an interim (performed 12 ± 2 days after the onset of CTRT) and a post-CTRT 18F-FDG PET/CT study. The 18F-FDG PET/CT variables evaluated were at baseline, interim and post-CTRT studies maximum standardised uptake value (SUV max) and total lesion glycolysis (TLG). Clinical and 18F-FDG PET/CT parameters were correlated with pathologic complete response (pathCR) and OS. RESULTS Among the 31 patients studied, 61.3% achieved a clinical complete response (cCR) and 87.1% had surgery. The median OS was 35.1 months (95% confidence interval (CI): 19.9-NA). PathCR rate was 22.2%. There was only a marginal association between cCR and pathCR (p = 0.06). None of the other variables was predictive of pathCR. There was association between OS and baseline TLG (p = 0.03) at the optimal cutoff TLG value of 75.15. Additionally, TLG and ΔTLG post-CTRT were also associated with OS (p = 0.01 and 0.03, respectively). CONCLUSION None of the PET parameters is predictive of pathCR but TLG at baseline and post-CTRT are prognostic of OS.

Second-line systemic treatment for advanced cholangiocarcinoma

BACKGROUND Gemcitabine plus platinum (GEM-P) combination chemotherapy is standard treatment for first-line advanced cholangiocarcinoma (aCC). GEM-P first-line therapy reports a progression-free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Treatment in the second-line setting is less clear. Five-year survival for aCC remains dismal at 5-10%. The purpose of this study was to describe the outcomes with second-line systemic treatment at our institution. METHODS This study was a single institution retrospective chart review of aCC patients who initiated second-line systemic treatment during 1/1/2009 to 12/31/2012. The primary objective was to evaluate PFS with second-line systemic treatment. Secondary objectives were OS and disease control rate. Second-line systemic regimens were classified into four treatment groups: GEM-P, gemcitabine + fluoropyrimidine (GEM-FU), other FU combination (FU-combo), and others. RESULTS Fifty-six patients were included and the majority had intrahepatic aCC. A total of 80% received first-line gemcitabine-based therapy. Second-line therapy consisted of GEM-P (19.6%), GEM-FU (28.6%), FU-combo (37.5%), and others (14.3%). Median PFS was 2.7-month (95% CI, 2.3-3.8 months) with a median OS of 13.8 months (95% CI, 12-19.3 months) and a disease control rate of 50%. No significant difference in survival was identified between the four treatment groups. CONCLUSIONS This study revealed a 2.7-month PFS, 50% disease control rate, and potential survival benefit with second-line treatment. Options for second-line systemic therapy include GEM-FU, FU-combo, GEM-P if not given in the first-line setting. Targeted therapy with erlotinib or bevacizumab could be considered in addition to chemotherapy.

The Treatment of Colorectal Cancer During Pregnancy: Cytotoxic Chemotherapy and Targeted Therapy Challenges

UNLABELLED : Cancer diagnosed during pregnancy has increased because of delayed child-bearing and the known occurrence of age-dependent malignancies. Cases of colorectal cancer (CRC) in pregnancy have recently been reported. With the expected rise in CRC diagnosed in young adults coupled with the current trend of delayed child-bearing, CRC during pregnancy is likely to increase. Treating pregnant women with CRC by using antineoplastics presents a dilemma because there are many unknowns to guide treatment decisions. We review the issues regarding the use of 10 CRC-approved agents in pregnancy. IMPLICATIONS FOR PRACTICE Colorectal cancer (CRC) in pregnancy is likely to become more common because of the current population trend in delayed child-bearing and the increase in CRC incidence expected among young adults. Practitioners should become familiar with the challenges associated with systemic treatment of a pregnant patient with CRC. This review addresses concerns surrounding the 10 systemic agents approved for CRC to help provide treatment guidance when such a case arises.

Metastatic Gastroesophageal Adenocarcinoma Patients Treated with Systemic Therapy Followed by Consolidative Local Therapy: A Nomogram Associated with Long-Term Survivors

Objective: Patients with metastatic gastroesophageal adenocarcinoma (MGEAC) have a poor but heterogeneous clinical course. Some patients have an unusually favorable outcome. We sought to identify clinical variables associated with more favorable outcomes. Methods: Of 246 patients with MGEAC, we identified 64 who received systemic therapy and eventually received local consolidation therapy. Univariate and multivariate Cox regression models were used, and a nomogram was developed. Results: Of these 64 patients, 61% had received consolidation chemoradiation (CRT) with doses of 50-55 Gy and 78% did not undergo surgery. The median follow-up time of survivors was 3.9 years, and the median overall survival (OS) from CRT start was 1.5 years (95% CI, 1.2-2.2). Surgery (as local consolidation) was an independent prognosticator for longer OS in the multivariate analysis (p = 0.02). The 5-year OS rate was 25% (SE = 6%). The contributors to the nomogram were longer duration of systemic therapy before CRT and the type of local therapy. Conclusions: Our data suggest that a subset of patients with MGEAC have an excellent prognosis (OS >5 years). However, these patients need to be identified during their clinical course so that local consolidation (CRT, surgery, or both) may be offered.

Continuation of trastuzumab beyond disease progression in HER2-positive metastatic gastric cancer: the MD Anderson experience

BACKGROUND Despite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity. METHODS HER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression. RESULTS Forty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01-5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5-53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population. CONCLUSIONS In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic gastric cancer is feasible and safe. Randomized studies are warranted.

The Proportion of Signet Ring Cell Component in Patients with Localized Gastric Adenocarcinoma Correlates with the Degree of Response to Pre-Operative Chemoradiation

Background: Patients with localized gastric adenocarcinoma (LGAC), who get pre-operative therapy, have heterogeneous/unpredictable outcomes. Predictive clinical variables/biomarkers are not established. Methods: We analyzed 107 LGAC patients who had chemoradiation and surgery. LGACs were grouped for (1) presence/absence of signet ring cell histology (SRC) and (2) histologic grade: G2 or G3. %SRC was assessed (0, 1-10, 11-49, and 50-100%) and correlated with pathologic complete response (pathCR) or <pathCR in the resected specimens. Results: Most patients were men (60%), had stage cIII LGAC (50%), and received chemotherapy before chemoradiation (93%). Most had G3 tumors (78%) and SRC (58%). Presence of SRC was associated with a lower rate of pathCR (11 vs. 36%, p = 0.004), and the association remained significant even with a low percentage of SRC (1-10%; p = 0.014). The higher the fraction of SRC, the lower was the probability of pathCR (p = 0.03). G3 and SRC led to a shorter overall survival (OS) (p = 0.046 and p = 0.038, respectively). yp stage independently prognosticated OS and recurrence-free survival (p < 0.001). Conclusion: Our novel findings suggest that LGACs with SRC are relatively chemoradiation resistant compared to LGACs without SRC. A higher fraction of SRC is associated with higher resistance. Upon validation/biomarker(s) evaluation, reporting of the fraction of SRC may be warranted.