Does chemoselection open the door for immunotherapy?
Authors: M.T. Jacobs, A.L. Ruiz, E.E. Cohen
Journal: Annals of Oncology (2017)

The TISOC-1 trial addresses the important question of utilizing chemoselection with response to induction chemotherapy to stratify patients into early or late surgical resection of tumors [1.Inhestern J. Schmalenberg H. Dietz A. et al.A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5- fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1).Ann Oncol. 2017; 28: 1917-1922Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. This study raises several interesting ideas on how to tackle the challenges of treating cancer patients in an age where we are seeing an evolution of treatments available ranging from traditional chemoradiation to immunotherapy and targeted small-molecule inhibitors. Using a chemoselection approach, we have the potential to create tailored treatments for patients avoiding unnecessary toxicities. Several important questions emerge from the TISCO-1 trial, including (i) can induction chemotherapy be used to optimize current treatment options? (ii) in patients who respond to induction therapy can organ preserving surgery, avoiding radical neck dissections, be employed? and (iii) do induction chemotherapy nonresponders benefit from immunotherapy? Although there are currently many existing therapies in head and neck squamous cell carcinoma (HNSCC), significant delays still exist between drug development and clinical application. In recent years, enthusiasm for the use of docetaxel, cisplatin, and 5-fluorouracil (TPF) induction therapy has dampened because of minimal benefit in overall survival (OS), associated toxicities, and decreased ability to deliver subsequent cisplatin-based concomitant radiotherapy. However there may be a place for induction chemotherapy with TPF in patients with bulky tumor burden and unfavorable prognostic factors including T4, N2c-3 disease, extracapsular extension, lymphovascular or perineural invasion [2.Cohen E.E.W. et al.Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer.J Clin Oncol. 2014; 32: 2735-2743Crossref PubMed Scopus (381) Google Scholar]. In the TISCO-1 trial, the tri-modal therapy had a manageable toxicity profile, which opens the door to potential combinations and therapy sequences. Improvements in our understanding and treatment of HNSCC have led to increased OS. However, these improvements can also mean that an increased number of younger cancer patients are living with significant morbidity and decreased quality of life (QOL) due to the treatments they receive. One might ask whether patients with resectable disease should receive neoadjuvant therapy with induction chemotherapy before surgical resection to achieve organ preservation. The idea of chemoselection as a strategy for organ preservation is not a new one. Several studies in the past have looked at larynx preservation using a neoadjuvant approach based on response to induction chemotherapy but few studies have looked at the use of neoadjuvant treatment to avoid radical neck dissection for organ preservation. Studies such as the Landmark Veterans Administration Larynx Trial (LVAT), European Organization for Research and Treatment of Cancer and Radiation therapy Oncology Group 91-11 trial looked at the use of induction chemotherapy with or without postoperative radiation for larynx preservation. LVAT compared upfront surgery followed by postoperative radiation with induction chemotherapy using cisplatin and 5-fluoroucil (5-FU) followed by definitive intent radiation for patients who responded to induction chemotherapy or salvage laryngectomy for patients who did not respond to induction chemotherapy. Laryngeal sparing was achieved in approximately 66% of patients without compromising survival [3.Group* The Department of Veterans Affairs Laryngeal Cancer Study Group, T.D.o.V.A.L.C.S Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer.N Engl J Med. 1991; 324: 1685-1690Crossref PubMed Scopus (2282) Google Scholar]. The RTOG 91-11 trial randomized patients with advanced larynx cancer to induction cisplatin/5-FU followed by radiation, concurrent chemo radiotherapy or radiation alone. Long-term outcome demonstrated improved rates of laryngeal preservation with concurrent chemotherapy (82%) versus induction (68%) or radiation alone (64%). Primary composite end point of laryngectomy-free survival showed no significant difference between induction and concurrent arms (29% versus 24%; P > 0.73) with a hazard ratio of 1.05 [95% confidence interval (CI), 0.83–1.34; P = 0.68). The study also showed an unexplained trend toward a higher 10-year death rate with concurrent chemotherapy (72% versus 61%; P = 0.08) [4.Weber R.S. et al.Outcome of salvage total laryngectomy following organ preservation therapy: the Radiation Therapy Oncology Group trial 91-11.Arch Otolaryngol Head Neck Surg. 2003; 129: 44Crossref PubMed Scopus (407) Google Scholar, 5.Forastiere A.A. et al.Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer.J Clin Oncol. 2013; 31: 845-852Crossref PubMed Scopus (826) Google Scholar]. These studies offer strong support for the use of induction chemotherapy for laryngeal preservation in HNSCC as illustrated by similar survival rates seen in patients who received laryngeal sparing treatment as opposed to those who did not. Although the use of induction chemotherapy for laryngeal preservation has been addressed, a field which remains unexplored in HNSCC is the use of neoadjuvant therapy to avoid radical neck dissection in patients with stage III–IV resectable disease. A retrospective case series of patients who underwent surgical salvage with simultaneous radical neck dissection reported that the risk of occult nodal metastases is low [6.Temam S. et al.Treatment of the N0 neck during salvage surgery after radiotherapy of head and neck squamous cell carcinoma.Head Neck. 2005; 27: 653-658Crossref PubMed Scopus (47) Google Scholar]. As radical neck dissections can cause significant morbidity and decreased QOL, perhaps in the future with advances in immunotherapy and radiation, trials can be designed which address the question of determining if neoadjuvant chemoselection can identify patients who may be able to avoid neck dissection altogether. Common first-line therapies for recurrent or metastatic HNSCC such as the EXTREME regimen which consists of cisplatin, 5-FU and cetuximab, or taxane, platinum, and 5-FU-based regimens have demonstrated an OS of 10.1 months and response rates from 15% to 61% [7.Vermorken J.B. et al.Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.N Engl J Med. 2007; 357: 1695-1704Crossref PubMed Scopus (1346) Google Scholar, 8.Posner M.R. et al.Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.N Engl J Med. 2007; 357: 1705-1715Crossref PubMed Scopus (1348) Google Scholar, 9.Lefebvre J.L. et al.Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study.JCO. 2013; 31: 853-859Crossref PubMed Scopus (313) Google Scholar, 10.Blanchard P. et al.Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site.Radiother Oncol. 2011; 100: 33-40Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar, 11.Pignon J.P. et al.Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer.Lancet. 2000; 355: 949-955Abstract Full Text Full Text PDF PubMed Scopus (2226) Google Scholar]. Although first-line treatments for HNSCC are promising, patients who experience progression on these regimens or develop platinum resistance often have a significantly lower response rate to second-line therapies such as methotrexate, cetuximab, and taxanes. Response rate to these agents can range from 3% to 21% compared with programed death one and programmed death ligand one (PD-1/PD-L1) inhibitors, which showed a 15%–20% response rate with an arguably better side-effect profile compared with the EXTREME regimen or cetuximab [9.Lefebvre J.L. et al.Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study.JCO. 2013; 31: 853-859Crossref PubMed Scopus (313) Google Scholar, 10.Blanchard P. et al.Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site.Radiother Oncol. 2011; 100: 33-40Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar, 12.Chow L.Q. et al.Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort.J Clin Oncol. 2016; : 3839-3845Google Scholar, 13.Vermorken J.B. et al.Platinum-based chemotherapy plus cetuximab in head and neck cancer.N Engl J Med. 2008; 359: 1116-1127Crossref PubMed Scopus (2539) Google Scholar, 14.Vermorken J.B. et al.Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy.JCO. 2007; 25: 2171-2177Crossref PubMed Scopus (800) Google Scholar, 15.Machiels J.P. et al.Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.Lancet Oncol. 2015; 16: 583-594Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar]. Immunotherapy offers several advantages over traditional second-line agents. In the Keynote-012 trial, the biggest advantage seems to be in that 20%–30% of patients who received a PD-1 inhibitor for HNSCC develop long-term survival benefit, seen by the plateau in the Kaplan–Meyer curve. This subset of patients with long-term PFS seems to be higher than that observed with other traditional chemotherapies [16.Seiwert TY et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 17(7): 956–965.Google Scholar]. The Keynote-012 expansion cohort looked at patients with recurrent or metastatic (R/M) HNSCC treated with pembrolizumab and found an overall response rate of 18% (95% CI, 12%–26%) and 6-month PFS and OS rates of 23% and 59%, respectively [12.Chow L.Q. et al.Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort.J Clin Oncol. 2016; : 3839-3845Google Scholar]. Recently, the checkmate-141 phase III trial assessed the efficacy of nivolumab versus physician’s choice (cetuximab, methotrexate, or docetaxel) in platinum refractory disease. The trial was terminated early after an independent monitoring panel determined the primary end point of improvement in OS was met, with the nivolumab group having an OS of 7.5 months (95% CI, 5.5–9.1) versus 5.1 months (95% CI, 4.0–6.0) in the group that received standard therapy [17.Ferris R.L. et al.Nivolumab for recurrent squamous-cell carcinoma of the head and neck.N Engl J Med. 2016; 375: 1856-1867Crossref PubMed Scopus (2895) Google Scholar]. Trials such as the phase III Keynote-40 trial (NCT02252042) are currently underway to evaluate pembrolizumab compared with standard chemotherapy or cetuximab in the second-line setting. PD-1/PD-L1 blockade is currently being tested as a first-line agent for R/M disease and R/M platinum refractory disease. These trials will help explore if nonresponders to chemoradiation should go directly to immunotherapy as the treatment of choice. Moreover, if complete response (CR) is seen when immunotherapies are used as second-line agents in R/M disease and these responses appear to be durable, then it is possible that a meaningful CR rate will be seen in locally advanced-HNSCC. Given this, one could hypothesize that adding or substituting immunotherapy for neoadjuvant chemotherapy may be able to select patients to completely avoid surgery or radiation. As our understanding of immunology and molecular profiling advance, coupled with improved surgical and radiation techniques, the treatment of HNSCC is moving toward a more tailored personalized approach. In the future, we may be able to utilize immunotherapy to avoid surgery or radiation altogether. Immunotherapy alone may offer a cure for a subset of patients with HNSCC. Chemoselection may be another tool to add to our treatment armamentarium to identify patients early in their treatment process who are responders or nonresponders to first-line therapies, to quickly stratify them into high-risk and low-risk groups and get them the treatment that is most suitable to optimize cure rates and achieve organ preservation in HNSCC. None declared.