A phase II trial of aclacinomycin-A in advanced squamous cell carcinoma of the head and neck

Sixteen patients with advanced squamous cell carcinoma of the head and neck were entered into a phase II trial of Aclacinomycin-A (ACM), 100 mg/M 2 administered by brief infusion every three weeks. All patients had received prior radiation therapy and prior non-anthracycline containing chemotherapy. No clinically significant disease regression was observed in fourteen patients having adequate trials. The major toxicity was myelosuppression; leukopenia occurred in 93% of patients. Gastro-intestinal toxicity was mild and included two patients with transient liver function test abnormalities. No antitumor activity was observed in this patient population which was heavily pre-treated and had a median Karnofsky performance status of only 60%. The results of other phase II trials of ACM-A have been similarly disappointing suggesting that it is not a clinically useful agent in the treatment of solid tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45289/1/10637_2004_Article_BF00170763.pd

Bisantrene (NSC 337766) (CL 216,942) in advanced breast cancer

Bisantrene (NSC 337766) is an anthracenedicarboxaldehyde hydrazone demonstrating a wide spectrum of activity in animal tumor model systems with no evidence of cardiotoxicity or alopecia, in contrast to doxorubicin. Thirty-three women with advanced adenocarcinoma of the breast were treated with 260 mg/m 2 IV every 3 weeks. All patients had received at least one prior combination chemotherapy regimen for metastatic disease and 32/33 were refractory to doxorubicin. Of 28 patients evaluable for response one had a partial response lasting 10 weeks and three patients had stable disease for 22, 22, and 9 weeks. The most significant toxicities were nonhematologic: nausea and vomiting (41%), phlebitic reactions (38%), hypotension, one fatal anaphylactic reaction, and the development of a 7th cranial nerve palsy during drug infusion. Hematologic toxicity, leukopenia, was dose-limiting but manageable without associated infections or bleeding. These results indicate that bisantrene in this dose and schedule is not a useful drug in heavily pretreated breast cancer patients. The incidence and severity of phlebitic reactions limited venous access and adversely affected patient compliance. Preliminary results of other phase II breast cancer trials indicate a similar spectrum of toxicity but suggest more significant antitumor activity even in patients previously treated with doxorubicin. Trials conducted in patients with minimal prior treatment and with bisantrene administered via central line appear warranted for definitive assessment of the activity of this agent in breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46914/1/280_2004_Article_BF00269035.pd

Phase II Trial of Docetaxel Chemotherapy in Patients with Incurable Adenocarcinoma of the Esophagus

Background : Chemotherapy remains theprimary mode of treatment for metastaticcarcinoma of the esophagus. The efficacyof various chemotherapeutic regimens hasbeen studied predominantly in patients withsquamous cell carcinoma of the esophagus. In light of the increasing incidence ofadenocarcinoma of the esophagus, studiesevaluating newer chemotherapy agents, suchas docetaxel, in this patient populationare necessary. The objective of this trialwas to determine the complete and partialresponse rate of docetaxel in patients withincurable adenocarcinoma of theesophagus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45210/1/10637_2004_Article_390685.pd

Phase II trial of N-methylformamide in advanced head and neck cancer

Eighteen patients with advanced epidermoid carcinoma of the head and neck were entered into a phase II trial of N-Methylformamide (NMF), 800 mg/M 2 IV daily for 5 days every 4 weeks. Seventeen patients had received prior radiation therapy and 11 were previously treated with chemotherapy. No complete or partial responses were observed. The major toxicity was gastrointestinal. Fifty percent of patients experienced nausea and vomiting or reversible hepatotoxicity with greater than a 3-fold elevation of liver enzymes. Mild reversible myelosuppression occurred in 2 patients. NMF in this dose and schedule was not a useful agent to treat recurrent epidermoid carcinoma of the head and neck.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45297/1/10637_2004_Article_BF00203547.pd

High-dose cisplatin in advanced head and neck cancer

In 22 patients with advanced squamous cell carcinoma of the head and neck we evaluated the efficacy and toxicity of 200 mg/m 2 cisplatin administered in 3% NaCl with vigorous hydration. Six patients had previously untreated stage IV disease and 16 patients had recurrent disease, including eight with prior chemotherapy including low-dose cisplatin and carboplatin. Cisplatin was administered as a brief infusion, either 40 mg/m 2 /day × 5 or 50mg/m 2 /day × 4, every 28 days. Objective responses were observed in 16 of 22 (73%) patients, including 5 of 6 (83%) previously untreated patients and 11 of 16 (69%) patients with recurrent disease. This included two comoplete responses, one confirmed pathologically. Fifty-seven courses of drug were administered and toxicity was monitored with serial creatinine clearance determinations, audiograms, and sensorimotor exams. Neuropathy and ototoxicity were dose-limiting and led to the stopping of treatment in 12 of the 16 responders after one to four courses (median three courses). Only two responding patients continued treatment until disease progression occurred at 3 and 4 months after achieving maximum response. Acute, transient nephrotoxicity occurred in four patients; two were retreated. Moderate myelosuppression occurred in all patients but was not treatment-limiting. For most patients the maximally tolerated number of courses was three. The median survival time was 33.5 weeks for recurrent disease patients, 108 weeks for newly diagnosed patients. This regimen is not recommended for the palliation of recurrent disease. However, the very high response rate suggests that high-dose cisplatin may have a useful role in induction or adjuvant chemotherapy regimens.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46916/1/280_2004_Article_BF00254569.pd

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial

Background: Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. Methods: This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confi rmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratifi ed by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fl uorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defi ned retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identifi cation of patients and treatment. This trial is registered with ClinicalTrials. gov, number NCT00460265. Findings: Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11.1 months (95% CI 9.8-12.2) in the panitumumab group and 9.0 months (8.1-11.2) in the control group (hazard ratio [HR] 0.873, 95% CI 0.729-1.046; p = 0.1403). Median progression-free survival was 5.8 months (95% CI 5.6-6.6) in the panitumumab group and 4.6 months (4.1-5.4) in the control group (HR 0.780, 95% CI 0.659-0.922; p = 0.0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11.7 months [95% CI 9.7-13.7] vs 8.6 months [6.9-11.1]; HR 0.73 [95% CI 0.58-0.93]; p = 0.0115), but this difference was not shown for p16-positive patients (11.0 months [7.3-12.9] vs 12.6 months [7.7-17.4]; 1.00 [0.62-1.61]; p = 0.998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0.70 [95% CI 0.47-1.04]). Interpretation: Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings

A systematic review and recommendations on the use of plasma EBV DNA for nasopharyngeal carcinoma

Introduction: Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Southeast Asia, particularly Southern China. The classical non-keratinising cell type is almost unanimously associated with latent Epstein-Barr virus (EBV) infection. Circulating plasma EBV DNA can be a useful biomarker in various clinical aspects, but comprehensive recommendations and international guidelines are still lacking. We conducted a systematic review of all original articles on the clinical application of plasma EBV DNA for NPC; we further evaluated its strengths and limitations for consideration as standard recommendations. Methods: The search terms 'nasopharyngeal OR nasopharynx', and 'plasma EBV DNA OR cell-free EBV OR cfEBV' were used to identify full-length articles published up to December 2020 in the English literature. Three authors independently reviewed the article titles, removed duplicates and reviewed the remaining articles for eligibility. Results: A total of 81 articles met the eligibility criteria. Based on the levels of evidence and grades of recommendation assessed, it is worth considering the inclusion of plasma EBV DNA in screening, pre-treatment work-up for enhancing prognostication and tailoring of treatment strategy, monitoring during radical treatment, post-treatment surveillance for early detection of relapse, and monitoring during salvage treatment for recurrent or metastatic NPC. One major limitation is the methodology of measurement requiring harmonisation for consistent comparability. Conclusions: The current comprehensive review supports the inclusion of plasma EBV DNA in international guidelines in the clinical aspects listed, but methodological issues must be resolved before global application. 2021 Elsevier Ltd. All rights reserved

Carboplatin (CBDCA), iproplatin (CHIP), and high dose cisplatin in hypertonic saline evaluated for tubular nephrotoxicity

We compared the acute tubular nephrotoxicity of three platinum compounds in children and adults with solid tumors by monitoring the urinary excretion of alanine aminopeptidase, N -acetyl-β-D-glucosaminidase, and total protein. Cisplatin (100 mg/m 2 ) was administered with mannitol, or at a twofold larger total dosage (50 mg/m 2 per day for 4 days) in a 3% saline infusion. Carboplatin (300 mg/m 2 ) was administered in combination with 5-fluorouracil, and iproplatin was administered in dosages ranging from 216 to 388 mg/m 2 . Enzymuria and proteinuria induced by cisplatin at a total dosage of 200 mg/m 2 on a divided schedule did not significantly differ from that observed for the single 100 mg/m 2 dose. Enzymuria and proteinuria induced by carboplatin and iproplatin were significantly less than that for cisplatin; however, one patient developed chronic tubular damage after three courses of carboplatin, and the acute tubular toxicity of iproplatin in one of 15 patients was exceptional. Our findings support the value of administering cisplatin in hypertonic saline on a divided schedule as a strategy to reduce acute tubular damage. Although carboplatin and iproplatin are less nephrotoxic than cisplatin, occasionally patients experience subclinical acute or chronic tubular damage that may lead to overt nephrotoxicity with continued therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46915/1/280_2004_Article_BF00296257.pd

Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

PURPOSE: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P \u3c .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN

Novel Immunotherapeutic Approaches to Treating HPV-Related Head and Neck Cancer

Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer